V. Rai, I. N. N. Namboothiri / Tetrahedron: Asymmetry 19 (2008) 2335–2338
2337
ated within 2 h in high yields in most cases via LDA-mediated addi-
tion of phosphite 1 to nitroalkene 2. Low yields of racemic products
were obtained only in the case of nitrostyrene 2c (entry 3), 4-nitro-
nitrostyrene 2e (entry 5), and 2-furyl nitroethylene 2f (Table 2,
entry 6).
ably due to the formation of lithiated species comprising both tri-
valent and pentavalent tautomers in equilibrium.
3. Conclusions
In the enantioselective reactions, the addition of phosphite 1a
to nitrostyrenes possessing electron-donating groups on the aro-
matic ring 2a and 2b provided the Michael adducts 3a and 3b
respectively, in good yield and selectivity (Table 2, entries 1 and
2). While parent nitrostyrene 2c provided product 3c in moderate
yield (48%) and selectivity (75% ee, Table 2, entry 3), nitrostyrenes
with both weakly and strongly deactivating groups, 2d and 2e,
respectively, provided adducts 3d and 3e in moderate to good
yields and excellent selectivities (>99% ee, entries 4 and 5). The
addition of diethyl phosphite 1a to heteroaromatic nitroalkene 2f
(Table 2, entry 6) and the similar addition of dimethyl phosphite
1b to selected nitroalkenes 2a, 2c, and 2d, although proceeding
in low yields (10–24%), provided the desired products 3g–i in
excellent enantioselectivities (>99%, entries 7–9). Finally, these
optimized conditions were found not suitable for the addition of
diphenyl phosphite 1c to nitroalkenes 2 (Table 2, entry 10).
A mechanistic rationale provided in Scheme 2 suggests that the
lithium naphthoxide moiety, that is, the Brønsted base part of (S)-
ALB L5, could activate dialkyl phosphite 1 to give complex I. Fur-
ther co-ordination of the Lewis acidic Al center with the oxygen
atoms of the nitro group in 2 would furnish complex II. Such dou-
ble co-ordination of the catalyst L5 with both the reactants, nitro-
alkene 2 and dialkyl phosphite 1, orientates the latter in a manner
that leads to a face selective reaction in a chiral environment (see
Scheme 2).
In conclusion, the stereoselective conjugate addition of dialkyl
phosphites to nitroalkenes has been successfully carried out for
the first time. Compound (S)-ALB was found to catalyze the reac-
tion to provide the adducts in moderate to good yields and good
to excellent enantioselectivities. The transformation of the enan-
tiopure b-nitrophosphonates to b-aminophosphonic acids and the
biological evaluation of the latter are currently being investigated
in our laboratory.
Acknowledgments
The authors thank DST, India for financial assistance and SAIF,
IIT Bombay for selected NMR data and Mr Narasimhan Ayyagari
for additional experimental support. V.R. thanks CSIR, India for a
research fellowship.
References
1. For our recent reports on the asymmetric synthesis of c-nitrophosphonates via
Michael addition of phosphonates to nitroalkenes in the presence of Li-
cinchonine complex: (a) Rai, V.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2007, 18, 2719; (b) Rai, V.; Namboothiri, I. N. N. Tetrahedron:
Asymmetry 2008, 19, 767.
2. For a review: Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev. 2005, 105,
899 and the references cited therein.
3. For reviews: (a) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org.
Chem. 2006, 29; (b) Mikołajczyk, M. J. Organomet. Chem. 2005, 690, 2488.
4. For a review: Ma, J.-A. Chem. Soc. Rev. 2006, 35, 630.
5. Kolodiazhnyi, O. I.; Sheiko, S.; Grishkun, E. V. Heteroatom Chem. 2000, 11, 138.
6. (a) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000, 39, 4605; (b)
Enders, D.; Tedeschi, L.; Förster, D. Synthesis 2006, 1447.
7. Kjaersgaard, A.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 804.
8. (a) Cravotto, G.; Giovenzana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti, M.
Tetrahedron: Asymmetry 1998, 9, 745; (b) Thomas, A. A.; Sharpless, K. B. J. Org.
Chem. 1999, 64, 8379.
9. Qi, X.; Lee, S.-H.; Kwon, J. Y.; Kim, Y.; Kim, S.-J.; Lee, Y.-S.; Yoon, J. J. Org. Chem.
2003, 68, 9140.
10. Mandal, T.; Samanta, S.; Zhao, C. G. Org. Lett. 2007, 9, 943.
11. (a) Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Wang, W. Adv.
Synth. Catal. 2007, 349, 1052; (b) Terada, M.; Ikehara, T.; Ube, H. J. Am. Chem.
Soc. 2007, 129, 14112.
12. For instance, the pKa values in DMSO calculated for dimethyl phosphite is 18.4
whereas for diphenyl phosphite it is 9.0, see: Li, J.-N.; Liu, L.; Fu, Y.; Guo, Q.-X.
Tetrahedron 2006, 62, 4453.
13. (a) Mastrykukova, T. A.; Aladzheva, I. M.; Lemont’eva, I. V.; Petrovski, P. V.;
Fedin, E. I.; Kabachnik, M. I. Pure Appl. Chem. 1980, 52, 945; (b) Kosolapoff, G.
M.; Maier, L. Organic Phosphorus Compounds; John Wiley and Sons: New York,
1973; vol. 5.
O
P
OR
OR
O
O
Li
O
O
Ar
Al
O
*
*
*
O
Ar
NO2
O
P
N
OR
+
NO2
O
3
2
OR
Ar
II
O
O
Al
*
*
OH
OH
O
Li
L4
*
O
P
OR
I
BINOL
OR
LiAlH4
O
O
O
O
Li
O
P
14. For reports on the utilization of phosphonate tautomer T2 by using chiral Lewis
acids in the hydrophosphonylation of aldehydes, aldimines, and cyclic imines,
see: (a) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993,
4, 1779; (b) Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 1978; (c)
Groger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.; Shibasaki, M. Tetrahedron
Lett. 1996, 37, 9291.
Al
*
RO
RO
*
H
1
L5
15. Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int.
Ed. 1996, 35, 104.
Scheme 2. Proposed mechanism.
16. For reviews: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36,
1237; (b) Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49, 511.
17. General procedure for the (S)-ALB-catalyzed conjugate addition of dialkyl
phosphites to nitroalkenes: To a solution of lithium aluminium hydride (6 mg,
0.15 mmol) in THF (0.5 ml) was added dropwise a solution of (S)-BINOL L4
(86 mg, 0.3 mmol) in THF (1.0 ml) at 0 °C. After stirring at 0 °C for 1 h, the
reaction mixture was concentrated in vacuo to afford a colorless powder of (S)-
ALB L5 (90 mg, 0.15 mmol). Next, under a nitrogen atmosphere, toluene (2 ml)
was added followed by dialkyl phosphite (1 mmol). After stirring the reaction
mixture for 15 min, nitroalkene 2 (1.2 mmol) in toluene (1 ml) was added to
the reaction mixture, which was further stirred for 2 d. The reaction mixture
was quenched with 1 M HCl solution (2 ml), further saturated with NaCl, and
extracted with ethyl acetate (3 Â 10 ml). The combined organic layers were
washed with brine (5 ml), dried (anhyd Na2SO4), and concentrated in vacuo.
The residue was purified by silica gel column chromatography (ethyl acetate/
pet ether, 0–80%, gradient elution). The solid compounds were further purified
by recrystallization (CH2Cl2/pet ether ꢀ10:1). Representative experimental
Our preliminary DFT calculations to determine the relative sta-
bilities of tautomers T1 and T2 of diethyl phosphite confirmed that
T1 was more stable by ꢀ6 kcal molÀ1 than T2. Further, 31P NMR
investigations show that the T1–T2 equilibrium is different in the
presence of LDA and (S)-ALB L5. For instance, addition of ALB to
diethyl phosphite (d 6.65, dq, J = 696.1, 9.2 Hz) has not changed
the 31P NMR pattern of diethyl phosphite (d 6.85, dq, J = 696.1,
9.2 Hz) to any significant extent suggesting the overwhelming pre-
dominance of the ‘resting’ pentavalent species T1 in the equilib-
rium mixture. This is also reflected in the rate of ALB-catalyzed
reactions (see Table 2). On the other hand, the addition of LDA
leads to disappearance of this peak and appearance of two new
broad peaks (d 38.5 and 143.4) in a 35:65 ratio, which is presum-