Mechanistic investigations of the phosphine-mediated nitrone deoxygenation reaction and its application in cyclic imine synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.09.175

Carbohydrate-derived cyclic nitrones were deoxygenated to form the corresponding imines using tributylphosphine. Experimental and theoretical investigations by the way of MP2 calculations suggest a revision of the mechanism initially proposed by Kurtzweil

Full text of DOI:10.1016/j.tetlet.2009.09.175

Tetrahedron Letters 50 (2009) 7038–7042
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Tetrahedron Letters
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Mechanistic investigations of the phosphine-mediated nitrone
deoxygenation reaction and its application in cyclic imine synthesis
a,
b,
*
Pascale Cividino a, Marie-Louise Dheu-Andries a, Jun Ou b, Anne Milet a, , Sandrine Py , Patrick H. Toy
*
*
a Département de Chimie Moléculaire, UMR-5250, ICMG FR-2607, CNRS-Université Joseph Fourier, BP 53, 38041 Grenoble Cedex 09, France
b Department of Chemistry, The University of Hong Kong, Pokfulan Road, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbohydrate-derived cyclic nitrones were deoxygenated to form the corresponding imines using tribu-
tylphosphine. Experimental and theoretical investigations by the way of MP2 calculations suggest a revi-
sion of the mechanism initially proposed by Kurtzweil and Beak for the triarylphosphine-mediated
deoxygenation of nitrones.
Received 26 August 2009
Revised 25 September 2009
Accepted 29 September 2009
Available online 2 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitrone deoxygenation
Imines
Phosphines
MP2 calculations
Iminosugars
Polyhydroxylated nitrones have been recently prepared from
the corresponding O-acetal- and O-benzyl-protected precursors,
by means of a BCl3-promoted dealkylation reaction.1 While the
biological activities of such nitrones have not been reported, the
related polyhydroxylated endocyclic imines (i.e., polyhydroxylated
pyrrolines) have been previously described to be potent glycosi-
dase inhibitors.2,3 For example, nectrisine (FR-900483), a natural
product isolated from the fungus nectria lucida, is a selective inhib-
investigate the nitrone deoxygenation reaction promoted by triva-
lent phosphorus reagents, such as phosphites9 and phosphines.10,11
In our initial attempts, the treatment of nitrone 17a,12 with trim-
ethylphosphite in the presence of triethylamine9 or with triphenyl
phosphine in refluxing THF or toluene10 did not allow for the iso-
lation of imine 213 in useful yields (Scheme 1).
itor of
a
-glucosidases (IC50 4.8 Â 10À8 M, yeast
a-glucosidase) and
O
a potent immunomodulator.4 The biological activities of such com-
pounds and their potential applications as antiviral therapeutics
have motivated numerous synthetic efforts directed toward
accessing libraries of pyrrolines.5 Thus, as part of our ongoing re-
search regarding the synthesis of novel iminosugars using carbo-
hydrate-derived nitrones6 as intermediates,7 we became
interested in the transformation of functionalized endocyclic nitro-
nes into the corresponding imines (Fig. 1).
N
R
N
N
R
HO
?
OH
HO
HO
nectrisine
OH
HO
OH
(II)
(I)
R = H, CH2OH, CH(OH)CH2OH
Figure 1. Synthesis of endocyclic imines from nitrones.
Although several methods have been reported for the conver-
sion of nitrones to imines,8 only few of them afford high yields of
product. With our ultimate plan being to prepare highly water-sol-
uble polyhydroxylated imines II (Fig. 1), methods that did not
necessitate aqueous work-up were preferred. We thus decided to
O
N
N
BnO
BnO
R3P
solvent
BnO
OBn
BnO
OBn
2
1
* Corresponding authors. Tel.: +33 0 476 51 48 04; fax: +33 0 476 51 49 27 (A.M.);
tel.: +33 0 476 51 48 03; fax: +33 0 476 63 59 83 (S.P.); tel.: +852 2859 2167; fax:
+852 2857 1586 (P.H.T.).
Scheme 1. Deoxygenation of endocyclic nitrone
1 to imine 2. Reagents and
E-mail addresses: anne.milet@ujf-grenoble.fr (A. Milet), sandrine.py@ujf-grenoble.
fr (S. Py), phtoy@hku.hk (P.H. Toy).
conditions: (i) (MeO)3P/Et3N (9:1), 50 °C, 1.5 h, 35%; (ii) Ph3P (20 equiv), THF or
toluene, reflux, 23 h, 17–35%; (iii) Bu3P (2 equiv), THF, 65 °C, 48 h, 69%.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.175

P. Cividino et al. / Tetrahedron Letters 50 (2009) 7038–7042
7039
Table 1
Deoxygenation of endocyclic nitronesa
Entry
Substrate
Product
Conv.b (%)
Yieldc (%)
O
N
N
BnO
BnO
BnO
BnO
BnO
1
>95
69
BnO
BnO
BnO
OBn
OBn
OBn
OBn
BnO
BnO
BnO
OBn
OBn
OBn
2
1
O
N
N
BnO
BnO
BnO
2
3
4
5
>95
>95
>95
60
60
4
3
O
N
N
50
6
5
O
N
N
53
BnO
BnO
OBn
8
7
O
N
N
n.d.d
10
9
a
b
c
Reagents and conditions: Bu3P (2 equiv) in THF at 65 °C for 48 h.
Conversion based on 1H NMR analysis of the reaction mixture determined by integration of the nitrone and imine vinyl protons.
Isolated yield.
Not determined due to product instability.
d
However, when triphenylphosphine was replaced by tributyl-
phosphine, the desired imine 2 could be isolated in 69% yield, after
48 h at 65 °C (Table 1, entry 1).
The applicability of this method to a selection of endocyclic nit-
rones was evaluated next. Thus, nitrones 3,14 5,7c 7,15 and 916 were
treated with tributylphosphine under the same reaction conditions
to afford imines 4,17 6, 8, and 10, respectively, in moderate to good
yields (Table 1, entries 2–5).18
PPh2
Ph Ph
P
path A
O
O
O
N
PMe3
O
N
N
N
t-Bu
t-Bu
path A
PMe3
11
12
O
PPh2
9
path B
16
path B
N
Ph
Ph
Ph
P
Ph
O
t-Bu
P
15
O
N
O
PMe3
N
Me3PO
N
N
t-Bu
t-Bu
13
14
10
17
Scheme 2. Beak’s proposed mechanisms for the transfer of oxygen from a nitrone
group to phosphorous(III).
Scheme 3. Mechanistic models used for MP2 calculations.

7040
P. Cividino et al. / Tetrahedron Letters 50 (2009) 7038–7042
improvement, as substantial decomposition occurred when the
temperature was raised above 70 °C.
In these reactions, we were surprised by the enhanced reactiv-
ity of tributylphosphine, which is more nucleophilic than trim-
ethylphosphite and triphenylphosphine (according to Swain-Scott
nucleophilicity parameters: nMeI = 1.3, 5.2, and 8.7, respectively,
for Ph3P, (MeO)3P, and Bu3P).19 This prompted us to re-examine
the mechanism of phosphine-mediated nitrone deoxygenation
that was previously proposed by Kurtzweil and Beak.20 The same
group had previously studied the intramolecular oxygen transfer
from the nitrogen of a hydroxylamine to the phosphorus of a tria-
rylphosphine and suggested a nucleophilic addition of oxygen to
the phosphorus atom rather than a substitution at the oxygen.21
In their analysis, the endocyclic restriction test22 was used to
investigate the mechanism of intramolecular oxygen transfer
(Scheme 2).
2.05
84º
1.81
1.44
1.45
1.86
68º
97º
91º
1.84
1.45
1.52
1.56
ONCP = 39º
1.58
17
Figure 2. Intermediate 17, distances in Å.
The conclusion of their studies was that an addition–elimina-
tion pathway23 involving a valence expansion at phosphorus via
intermediate 12 was likely to occur (path A), rather than initial
addition of the phosphorus atom to the iminyl carbon9 (path B).
This hypothesis was proposed based on substituents effects, as
it was found that an electron-deficient phosphine was more reac-
tive for such oxygen transfer than an electron-rich one. Because
our experimental results contrast with those of Beak et al. we
decided to investigate the mechanism of these reactions using
MP2 calculations.24 The MP2 perturbation theory was used at the
In general, it was found that isolated yield of the imine was al-
ways lower than what was expected from the measurement of the
conversion of starting material into product by NMR analysis of
crude reaction mixtures. This may be linked to the intrinsic insta-
bility of the imine products. For example, imine 10 could not be
isolated in pure form (Table 1, entry 5). The role of the temperature
on the reaction rate was also evaluated; performing the reactions
at higher temperature in toluene, did not result in significant yield
25,26
**
second order in conjunction with the 6-311+G basis set
for
**
**
Figure 3. Reaction energy profile and optimized structures (activation energies in kcal molÀ1 at MP2/6-311+G //MP2/6-311+G level and distances in Å).

P. Cividino et al. / Tetrahedron Letters 50 (2009) 7038–7042
7041
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investigating the possible mechanisms of intermolecular oxygen
transfer from nitrones to phosphines. The reaction was modeled
using nitrone 9 and trimethylphosphine. The first mechanism
(Scheme 3, path A) corresponds to the mechanism proposed by
Beak; a nucleophilic attack from the oxygen of the nitrone toward
the phosphine to form intermediate 16.
On the other hand, the second mechanism (Scheme 3, path B)
involves the electrophilic character of the nitrone, and a nucleo-
philic attack by the phosphorus atom to the iminyl carbon, leading
to the cyclic intermediate 17, which may evolve toward 10.
Despite several attempts, we failed to characterize the interme-
diate 16 through geometry optimization, and the latter led either
to products or to intermediate 17, depending on the starting geom-
etry.27 On the contrary, we were able to optimize intermediate 17,
whose geometrical parameters are gathered in Figure 2.
The distance between the phosphorus and oxygen atoms in 17
suggests a strong interaction between them, and to gain insight
into the nature of this bond, an ELF analysis was performed.28 Even
if a 10% covalent contribution is present between these atoms, the
ELF analysis indicates a dominant electrostatic interaction. From an
energetic point of view, intermediate 17 is 12.8 kcal molÀ1 higher
in energy than the reactants. The transition state (TS) that connects
the reactants and the intermediate 17 has been characterized, and
the corresponding activation energy has been computed to be of
25.6 kcal molÀ1 (Fig. 3). The TS connecting intermediate 17 and
the products is also displayed in Figure 3. The structure is quite
unsymmetrical toward the dissociation of the N–O and C–P bond
lengths: The N–O bond length reached 2.61 Å whereas the C–P
bond length is still short, with a value of 1.86 Å. The P–O bond
length was determined to be 1.85 Å, compared with the 1.50 Å
and 2.05 Å P–O bond lengths in trimethylphosphine oxide (prod-
uct) and in 17 (intermediate), respectively. The activation energy
for the second step was estimated at 44.5 kcal molÀ1 in spite of a
rather exoenergetic process, since the energy difference between
the intermediate and the products is 71.9 kcal molÀ1. The magni-
tude of this energy barrier is compatible with the experimental re-
sults obtained for the deoxygenation of nitrones by
tributylphosphine, as heating to 65 °C is required. Nevertheless,
the whole process is strongly energetically favored due to an en-
ergy difference of 59.1 kcal molÀ1 between the reactants and the
products.
9. Milliet, P.; Lusinchi, X. Tetrahedron 1979, 35, 43–49.
10. (a) Horner, L.; Hoffmann, H. Angew. Chem. 1956, 68, 473–485; (b) Agolini, F.;
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In conclusion, themechanismof theintermolecular tributylphos-
phine-promoted deoxygenation of nitrones has been investigated
and it appears that this process involves the formation of an azaox-
aphosphetane intermediate that results from nucleophilic addition
of phosphorus to the iminyl carbon of the nitrones. This observation
is divergent from the proposal by Kurtzweil and Beak, who found
that related intramolecular arylphosphine-mediated reactions pro-
ceed via attack of oxygen at phosphorous. Regardless of the detailed
mechanism of the reaction, it was synthetically useful for preparing
functionalized, carbohydrate-derived pyrrolines, which are poten-
tial precursors of glycosidase inhibitors.
11. Recently the groups of Merino and Goti have used a combination of 10% PPh3 in
trimethylphosphite and triethylamine to deoxygenate nitrone 1 to form the
corresponding imine 2 in 65% yield: Merino, P.; Delso, I.; Tejero, T.; Cardona, F.;
Marradi, M.; Faggi, E.; Parmeggiani, C.; Goti, A. Eur. J. Org. Chem. 2008, 2929–2947.
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2003, 44, 2315–2318; (b) Carmona, A. T.; Wightman, R. H.; Robina, I.; Vogel, P.
Helv. Chim. Acta 2003, 86, 3066–3073.
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42, 7949–7952; (b) Bonger, K. M.; Wennekes, T.; de Lavoir, S. V. P.; Esposito, D.;
van den Berg, R. J. B. H. N.; Litjens, R. E. J. N.; van der Marel, G. A.; Overkleeft, H.
S. QSAR Comb. Sci. 2006, 25, 491–503. See also Ref. 11.
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15. (a) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337–1342; (b) Tsou, E.-L.;
Yeh, Y.-T.; Liang, P.-H.; Cheng, W.-C. Tetrahedron 2009, 65, 93–100.
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Tetrahedron 1992, 48, 8677–8684.
17. (2R,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyrrole (4):
Acknowledgments
MS (ESI) m/z (%): 402 [M+H]+. IR:
m H
(cmÀ1) 3059, 3024, 2916, 2898, 2872, 1497. 1
NMR (300 MHz, CDCl3): d 3.77 (dd, 2H, J = 4.5, 1.5 Hz, 5CH2); 4.18 (dd, 1H, J = 6.5,
4.5 Hz, 3CH); 4.33–4.38 (m, 1H, 4CH); 4.50–4.68 (m, 7H, 2CH and BnCH2);
7.25–7.36 (m, 15H, ArCH); 7.67 (d, 1H, J = 2 Hz, 1CH). 13C NMR (75 MHz, CDCl3): d
67.9 (5CH2); 72.5 (BnCH2); 72.6 (4CH); 72.7 (BnCH2); 73.4 (BnCH2); 83.0 (3CH); 88.5
The authors are thankful to the Procore Transnational Exchange
Program France-Hong Kong (Ref. No. 14568RD), the Research
Grants Council of the Hong Kong S.A.R. (Project No. F-HK27/06T),
and the Agence Nationale pour la Recherche (Grant No. ANR-05-
JCJC-0130-01) for supporting this research, and the CECIC for pro-
viding computer facilities.
(2CH); 126.9–128.6
( ( ( (
ArCH); 137.6 ArCq); 137.9 ArCq); 138.4 ArCq); 167.1
(1CH).
18. Typical procedure for tributylphosphine-mediated nitrone deoxygenation: To a
stirred solution of nitrone (0.12 mmol) in THF (2 mL) under argon, 60
lL
tributylphosphine (0.24 mmol, 2 equiv) was added in one portion. The reaction
mixture was heated to 65 °C and stirred at this temperature for 24–72 h, after
which the solvent was evaporated under reduced pressure. The resulting crude
product was purified by chromatography on silica gel to afford the expected
imine.
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7042
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**
atom were also attempted at the B3LYP and BLYP levels using the 6-31+G
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basis set (for computational cost reasons). They were unsuccessful and led
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intermediate 12 (Scheme 2) was not successful, whereas intermediate 14 was
optimized.
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Silvi, B. Actual Chim. 2001, 3, 15–22.