Chiral N-phosphonyl imine chemistry: new reagents and their applications for asymmetric reactions

Article abstract of DOI:10.1016/j.tetlet.2008.01.028

Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C₂-symmet

Full text of DOI:10.1016/j.tetlet.2008.01.028

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1573–1577
Chiral N-phosphonyl imine chemistry: new reagents and
their applications for asymmetric reactions
Adiseshu Kattuboina, Guigen Li *
Department of Chemistry and Biochemistry, Texas Tech University Lubbock, TX 79409-1061, USA
Received 7 November 2007; revised 4 January 2008; accepted 4 January 2008
Available online 11 January 2008
Abstract
Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl
imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C2-symmetric chiral
auxiliary tolerates oxidation, is not sensitive to racemization and can be recycled for large scale synthesis.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Phosphoramide; N-Phosphonyl imines; Aziridine; aza-Darzens reaction; aza-Henry reaction; C2-Symmetric diamine
The chiral imine chemistry has been one of the most
active topics in asymmetric synthesis because the drug
development and discovery heavily depend on the amine
functionality.1–3 In the past several decades, this field has
been represented by N-sulfinyl imine (or sulfinimine) chem-
istry, which was pioneered by Davis,1,4 Ellman,2,5 and sev-
eral others6,7 (Fig. 1, A and B). Very recently, it has been
addressed that asymmetric nucleophilic additions of organo-
metallic reagents to C@N bonds of chiral sulfinimines
represent ‘the most direct and reliable method for the
asymmetric construction of diverse amine derivatives
having a nitrogen attached to a stereogenic center’.1b In
our recent effort on the development of new chiral nitrogen
sources to render asymmetric aminohalogenation and
diamination reactions,8,9 we found that one of these nitro-
gen sources, the free NH2 group-attached phosphoramide
(Fig. 1, 1), can be readily converted into chiral N-phos-
phonyl imines (Fig. 1, C) to serve as electrophiles for asym-
metric nucleophilic additions by organometallic reagents.
Even though a great progress has been made on N-sulfi-
nyl imine chemistry, there still exist some limitations during
the use of N-sulfinyl imines for asymmetric synthesis. In
addition to the shortcomings described in the literature,2
the N-sulfinyl functionality is sensitive to oxidative
Me
Me
Me
Me
H
H
H
H
N
N
O
N
N
O
P
S
S
P
N
O
O
N
H2N
N
R
R
R
A
B
C
1
Fig. 1. Chiral N-sulfinyl and N-phosphonyl imines.
*
Corresponding author. Tel.: +1 806 742 3015; fax: +1 806 742 1289.
E-mail address: guigen.li@ttu.edu (G. Li).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.028

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A. Kattuboina, G. Li / Tetrahedron Letters 49 (2008) 1573–1577
conditions, which makes some further transformations
inconvenient. The deprotection of N-sulfinyl group is per-
formed by treating with Brønsted-Lowry acids, which
destroys the chiral functionality and makes the recovery
of chiral auxiliary impossible; or, possible racemization
can occur on sulfur center if other methods are used. In
addition, this functionality cannot well tolerate strong
Lewis acids (e.g., TiCl4Þ.10 Therefore, it is necessary to
develop new chiral imines to overcome shortcomings of
N-sulfinyl imines. In this Letter, we would like to report
our preliminary results on the design and the synthesis of
new chiral N-phosphonyl imines and the study of asym-
metric aza-Darzens reaction11,12 by using these new chiral
imines as represented by Scheme 1 and the results are
summarized in Tables 1 and 2. Also, the initial study on
asymmetric aza-Henry reaction13 by using chiral N-phos-
phonyl imines is disclosed.
We initially chose chiral hydrobenzoin and (1R,2R)-1,2-
diphenylethylenediamine for the design and the synthesis of
chiral phosphonyl imine derivatives, but the unwanted
opening of the five-membered ring and soluble problems
caused us to put off this project for a while until recently
when we came up with the idea of using (1R,2R)-diamino-
cyclohexane to replace (1R,2R)-1,2-diphenylethylenedi-
amine. When this modification was made, the resulting
new chiral N-phosphonyl imines can be dissolved in most
organic solvents even at low temperature; this led to the
present success.
The C2-symmetry is the most common structural char-
acteristic in asymmetric chemistry, and it exists in common
chiral reagents.14,15 The present new chiral N-phosphonyl
imines containing this structural unit are certainly very
attractive to asymmetric field. Although the C2-symmetric
diaminocyclohexane-based phosphoramides have been
widely utilized as Lewis base ligands for asymmetric cata-
lysis,15 surprisingly, the free NH2 group-attached chiral
phosphoramides have not been introduced to asymmetric
synthesis yet. This situation is probably due to the fact that
the reactivity, selectivity, stability, and solubility of these
phosphoramides are unknown. Certainly, it has not been
known if the chiral phosphoramide-derived imines can
undergo the asymmetric aza-Darzens reaction or not.
Phosphoramide 1 was prepared starting from (1R,2R)-
1,2-diaminocyclohexane according to the procedure for
the synthesis of N-alkyl phosphoramides without the use
of chromatography.15 The synthesis of phosphoramide 1
has been carried out on a 40.0 g-scale to give consistent
chemical yields of >90%. This white solid product has been
stored at rt without inert gas protection for several months;
there was no sign of decomposition as revealed by TLC, 1H
H
H
H
H
N
N
O
OLi
THF, -78 °C, 6 h
N
N
O
+
Br
P
P
N
N
OCH3
CO2Me
Ph
Ph
99% de,74% yield
Scheme 1. Asymmetric aza-Darzens reaction using N-phosphonimine.
Table 1
Results of the synthesis of chiral N-phosphonyl imines
1 M TiCl4, DIPEA
CH2Cl2, 0 °C - rt, 48 h
H
H
H
H
N
N
N
O
N
R-CHO
+
P
P
N
O
H2N
R
1
2
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
Phenyl
2a
2b
2c
2d
2e
2f
65
66
65
68
64
74
69
66
67
63
4-MeO-phenyl
4-BnO-phenyl
4-Me-phenyl
2-Me-phenyl
4-F-phenyl
4-Cl-phenyl
2-Cl-phenyl
4-Br-phenyl
2-Thienyl
2g
2h
2i
10
a
2j
Isolated yields after flash column chromatography.

A. Kattuboina, G. Li / Tetrahedron Letters 49 (2008) 1573–1577
1575
Table 2
Results of asymmetric aza-Darzens reaction18
OLi
R
Aux
N
Bn
N
P
N
Bn
H
H
Br
O
OCH3
N
Aux
Aux =
R
THF, -78 °C, 6 h
O
OCH3
2a - 2j
3a - 3j
Entry
R
Product
dea (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Phenyl
3a
3b
3c
3d
3e
3f
>99
92
94
88
92
88
86
88
86
80
74c
81
72
78
76
64
66
59
68
82
4-MeO-phenyl
4-BnO-phenyl
4-Me-phenyl
2-Me-phenyl
4-F-phenyl
4-Cl-phenyl
2-Cl-phenyl
4-Br-phenyl
2-Thienyl
3g
3h
3i
10
a
3j
Determined by the crude 1H NMR or 31P NMR analysis.
Combined yields of the two diastereomers.
Isolated yield of a single diastereomer.
b
c
NMR, and 31P NMR analysis. The X-ray crystal structure
of this compound has been obtained and shown in Figure
2.16 In the crystalline state, the C2-symmetry can be clearly
identified and two benzyl groups are arranged asymmetri-
cally so as to participate in the asymmetric induction.
The synthesis of chiral N-phosphonyl imines was first
conducted by reacting chiral phosphoramide 1 with benzal-
dehyde in CH2Cl2 in the presence of milder Lewis acids
such as TiðOiPrÞ4 and TiðOEtÞ4, which follows the proce-
dure of N-sulfinimine synthesis.5 However, the reaction
did not give any product at rt and even under refluxing
condition. After the stronger Lewis acid, TiCl4, was
employed in the presence of N,N-diisopropyl ethylamine
(DIPEA), a low yield (35%) of product was obtained at
0 °C after 48 h. The yield was improved to 65% when the
temperature was raised to rt. Increased amounts of TiCl4
(1:1 mol ratio) were dissolved in dichloromethane. The
resulting mixture was cooled down to 0 °C under nitrogen
protection. N,N-diisopropylethylamine was added prior to
dropwise additions of TiCl4 solution in CH2Cl2 (1.0 M,
0.5 equiv). The reaction was stirred at 0 °C for 30 min
and then at rt for 48 h. The results for the synthesis of
ten chiral N-phosphonyl imines (2) were summarized in
Table 1.
The asymmetric aza-Darzens reaction was next studied
by using the above chiral N-phosphonyl imines as the elec-
trophiles. This reaction is among the most suitable model
reactions to examine chiral imine chemistry because it con-
sists of two steps in a one-pot operation; and the resulting
chiral aziridine-2-carboxylic esters are invaluable building
blocks for many biologically important compounds,1 such
as a- and b-amino acids, b-substituted a-amino acids,
b-hydroxy a-amino acids, a-amino aldehydes, and ketones.
Although chiral N-p-toluenesulfinyl imines have been pro-
ven to be suitable for aza-Darzens reaction,11a a successful
aza-Darzens example by the use of chiral tert-butanesul-
finyl imines has not been reported yet.11d,e The procedure
of this N-phosphonyl imines asymmetric reaction is similar
to that of N-p-toluenesulfinyl imine-based system in which
N-phosphonyl imines (2, 1.0 equiv) were added into pre-
formed lithium enolate of methyl 2-bromoacetate
(2.0 equiv) in THF solution and stirred at ꢀ78 °C for 6 h.
Modest to good chemical yields (59–82%) and good to
excellent diastereoselectivity (80–99% de) were obtained
(Table 2). As compared with the previous N-p-toluenesulfi-
nyl imine-based aziridination in which 2.5 h are needed, the
present process required a longer period of 6 h. This pro-
longed period indicates N,N-dibenzylphosphonyl imines 2
have lower electrophilicity than N-p-toluenesulfinyl imines.
Importantly, the electrophilicity of our new chiral N-phos-
phonyl imines can be controlled by introducing a variety of
˚
and adding 4 A molecular sieves did not show any benefi-
cial effect on this reaction. The optimized condition is
described below: Chiral phosphoramide 1 and aldehydes
Fig. 2. X-ray structure of chiral phosphoramide 1.

1576
A. Kattuboina, G. Li / Tetrahedron Letters 49 (2008) 1573–1577
electron-donating or electron-withdrawing groups onto
nitrogen to replace the benzyl group. This controlling strat-
egy cannot be realized in N-sulfinyl imine chemistry. In
addition, these new imines have been proven to be more
stable than N-sulfinyl imines.
six-membered transition state. The asymmetric arrange-
ment of the C2-symmetric benzyl groups on two nitrogens
is resulted from the X-ray structural analysis of chiral
phosphoramide 1 shown in Figure 1. As revealed in Figure
3, there are two smaller steric moieties, hydrogen and a
lone pair of electrons existing along the enolate attacking
pathway within a widely open space of N-phosphonimine
template. This asymmetric environment ensures the result-
ing S-chirality on the carbonyl addition center as well as
the chirality of the a-position of N-phosphonyl aziridine-
2-carboxylic esters.
Finally, the new chiral N-phosphonyl imines also
showed promising results for the aza-Henry reaction. The
chiral N-phosphonyl imine 2a reacted with the nitro-
methane-derived lithium anion to give b-nitro amine 4 in
72% yield and 92% de (Scheme 2).17 Our ongoing research
indicated that these results can be improved simply by
using different lithium bases.
In summary, the free NH2 group-attached chiral phos-
phoramide 1 and novel chiral N-phosphonyl imines 2 have
been designed and synthesized. The reactivity and stability
of these N-phosphonyl imines proved to be suitable for
asymmetric aza-Darzens reaction and asymmetric aza-
Henry reaction. New conditions for the synthesis of chiral
N-phosphonyl imines, the improvements on yields and dia-
stereoselectivity for these two asymmetric reactions and the
applications of chiral N-phosphonyl imines to a series of
other asymmetric C–C bond formations will be investi-
gated. The larger scale synthesis for recycling chiral auxil-
iary will also be studied in our laboratories. We believe
the chiral N-phosphonimine results described in this Letter
can open a new door for chiral imine chemistry, and will
attract a widespread attention among organic community.
The diastereoselectivity was determined by the crude 1H
NMR or 31P NMR analysis of aziridine products. The
phosphorus decoupled 1H NMR analysis revealed that
the methyl aziridine-2-carboxylate products were con-
trolled in cis-geometry (J = 6.5 Hz for coupling of C-2
and C-3 protons). Interestingly, unlike the N-p-toluenesul-
finyl imine-based aziridination, there were no trans isomers
detected for all the cases we examined by the crude NMR
analysis.
The absolute structure was determined by converting an
aziridine product into an authentic sample, b-hydroxyl a-
amino acid methyl ester.11a The ring opening hydrolysis
was performed by treating N-phosphonyl aziridine-2-carb-
oxylic ester with trifluoroacetic acid in acetone and water at
rt. Two diastereoisomers were obtained in a ratio of 4:1.
Under this condition, the N-phosphonyl protection group
can be cleaved simultaneously, which enables the recovery
of diamine auxiliary.
Based on resulting chirality on the carbonyl addition, a
cyclic six-membered transition state is proposed as shown
in Figure 3. Attacking of E-configured lithium enolate of
methyl 2-bromoacetate onto N-phosphonimine should be
directed onto its Re-face. Very interestingly, unlike N-p-tol-
uenesulfinyl imine-based aza-Darzens reaction, the coordi-
nation of phosphonyl oxygen with lithium cation to form
an additional four-membered ring is inhibited during the
present reaction process. The bulky moiety of chiral auxil-
iary is pushed away by the sterically hindered side of the
Ph
Ph
OCH3
Li
N
H
N
H
Ph
P
O
H
N
Br
O
Enolate attacking
from Re face
N
Ph
P
O
N
H
H
N
Ph
H
Ph
Fig. 3. Proposed transition state model for aza-Darzens reaction.
H
H
H
H
CH3NO2,
1M LiHMDS/THF
N
N
O
N
N
O
P
P
THF, -78 °C, 6 h
(92% de, 72%)
N
HN
Ph
NO2
Ph
2a
4
Scheme 2. Asymmetric aza-Henry reaction using N-phosphonimine.

A. Kattuboina, G. Li / Tetrahedron Letters 49 (2008) 1573–1577
1577
11. (a) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy, G. V.; Zhang, Y.
J. Org. Chem. 1999, 64, 7559–7567; (b) Sweeney, J. B.; Cantrill, A. A.;
McLaren, A. B.; Thobhani, S. Tetrahedron 2006, 62, 3681–3693; (c)
Giubellina, N.; Mangelinckx, S.; Tornroos, K. W.; De Kimpe, N. J.
Org. Chem. 2006, 71, 5881–5887; (d) Wang, J.-Y.; Wang, D.-X.;
Zheng, Q.-Y.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72,
2040–2045; (e) Yang, X. F.; Mang, M. J.; Hou, X. L.; Dai, L. X. J.
Org. Chem. 2002, 67, 8097–8103; (f) Zheng, J. C.; Liao, W. W.; Sun,
X. X.; Tang, Y.; Dai, L. X.; Deng, J. G. Org. Lett. 2005, 7, 5789–
5792; (g) Ruano, J. L. G.; Fernandez, I.; Catalina, M. D. P.; Cruz, A.
A. Tetrahedron: Asymmetry 1996, 7, 3407–3414; (h) Morton, D.;
Pearson, D.; Field, R. A.; Stockman, R. A. Synlett 2003, 1985–
1988.
Acknowledgments
We gratefully acknowledge the Robert A. Welch foun-
dation (D-1361) for the generous support of this work.
We thank our co-workers, Dr. Yining Wang, Parminder
Kaur, Ai Teng, Aaron Olmos, and Thao Nguyen for their
helpful discussions and assistance, David W. Purkiss for his
assistance in NMR and Eileen Duesler (Univ. of New Mex-
ico) for X-ray analysis.
References and notes
12. (a) Alickmann, D.; Frohlich, R.; Wurthwein, E. U. Org. Lett. 2001, 3,
1527–1530; (b) McLaren, A. B.; Sweeney, J. B. Org. Lett. 1999, 1,
1339–1341; (c) Arroyo, Y.; Meana, A.; Rodriguez, J. F.; Santos, M.;
Sanz-Tejedor, M. A.; Ruano, J. L. G. Tetrahedron 2006, 62, 8525–
8532.
13. (a) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153; (b)
Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 6366–6370; (c) Storer, R. I.; Carrera, D. D.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86; (d)
Knudsen, K. R.; Risgaad, T.; Nishiwaki, N.; Gothelf, K. V.;
Jorgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843–5844.
14. (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J.
Am. Chem. Soc. 1991, 113, 7063–7064; (b) Jacobsen, E. N. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH, 1993; Chapter
4.1; pp 159–202.
15. (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2581–2627; (b) Denmark, S. E. Nature 2006, 443, 40–41 and
references cited therein.
16. CCDC 647795 contains the supplementary crystallographic data for
this Letter. The data can be obtained free of charge from the
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
1. (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. Rev. 1998, 27, 13–
18; and references cited therein; (b) Davis, F. A. J. Org. Chem. 2006,
71, 8993–9003.
2. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984–995; (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39–46; and
references cited therein.
3. (a) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905;
(b) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z. H.; Han, Z. X.;
Gallou, I. Aldrich Chim. Acta 2005, 38, 93–104.
4. Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398–8407.
5. (a) Cogan, D. A.; Liu, G. C.; Kim, K. J.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011–8019; (b) Weix, D. J.; Shi, Y. L.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092–1093.
6. (a) Kong, J.-R.; Cho, C.-W.; Krische, M. J. J. Am. Chem. Soc. 2005,
127, 11269–11270; (b) Han, X.; Krishnamurthy, D.; Grover, P.; Fang,
Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880–7881; (c)
Sun, X. W.; Xu, M. H.; Lin, G. Q. Org. Lett. 2006, 8, 4979–4982; (d)
Zhao, C. H.; Liu, L.; Wang, D.; Chen, Y. J. Eur. J. Org. Chem. 2006,
2977–2986; (e) Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org.
Chem. 1991, 56, 4–6.
7. (a) Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.; Faul,
M. M. J. Org. Chem. 2006, 71, 6859–6862; (b) Denolf, B.; Leemans,
E.; De Kimpe, N. J. Org. Chem. 2007, 72, 3211–3217; (c) Denolf, B.;
Mangelinckx, S.; Tornroos, K. W.; De Kimpe, N. Org. Lett. 2007, 9,
187–190; (d) Denolf, B.; Mangelinckx, S.; Tornroos, K. W.; De
Kimpe, N. Org. Lett. 2006, 8, 3129–3132.
8. (a) Li, G.; Wei, H.-X.; Kim, S. H.; Carducci, M. D. Angew. Chem.,
Int. Ed. 2001, 40, 4277–4280; (b) Pei, W.; Wei, H.-X.; Chen, D.;
Headley, A. D.; Li, G. J. Org. Chem. 2003, 68, 8404–8408.
9. (a) Li, Q.; Shi, M.; Timmons, C.; Li, G. Org. Lett. 2006, 8, 625–628;
(b) Xu, X.; Kotti, S. R. S. S.; Liu, J.; Cannon, J. F.; Headley, A. D.;
Li, G. Org. Lett. 2004, 6, 4881–4884.
10. (a) Li, G.; Wei, H.-X.; Whittlesey, B.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061–1064; (b) Wei, H.-X.; Hook, J. D.; Fitzgerald, K. A.;
Li, G. Tetrahedron: Asymmetry 1999, 10, 661–665.
17. The asymmetric induction is assumed to be the same as that of aza-
Darzens reaction. For 1H NMR spectrum for this product, see
supporting materials.
18. Typical procedure for the aza-Darzens reaction: Into an oven dried and
N2 flushed vial were loaded with methyl 2-bromoacetate (0.8 mmol)
and THF (4.0 mL). Reaction was cooled to ꢀ78 °C and lithium
bis(trimethylsilylamide) (1 M solution in THF, 0.8 mmol) was added
slowly. After the resulting mixture was stirred for 30 min at ꢀ78 °C, a
precooled solution of N-phosphonyl imine (2, 0.4 mmol) was added
dropwise via a cannula at the same temperature. Stirring was
continued at ꢀ78 °C for 6 h and then quenched with water
(1.0 mL). The crude product was obtained after standard work-up
and purified via flash column chromatography (hexane/EtOAc = 7:3)
to give the product as an oil.