Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Article abstract of DOI:10.1016/j.tetlet.2008.04.038

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereose

Full text of DOI:10.1016/j.tetlet.2008.04.038

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3722–3724
Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions
of allylmagnesium bromides
Adiseshu Kattuboina, Parminder Kaur, Thao Nguyen, Guigen Li *
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
Received 9 March 2008; revised 5 April 2008; accepted 7 April 2008
Available online 10 April 2008
Abstract
Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl
imines. The C2-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities
were obtained for eight examples.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chiral N-phosphonyl imines; Homoallylic amines; Grignard reagents; Allylmagnesium bromide; 1,2-Addition
Homoallylic amines are key building blocks for the syn-
thesis of complex natural products and biologically active
compounds.1 Asymmetric 1,2-addition of allylic nucleo-
philes to chiral imines is one of the most commonly used
strategies for generating these compounds in optically pure
forms. Several chiral imines derived from amino acid deriv-
atives, chiral N-sulfinyl imines and hydrazones have been
used for this purpose.2–4 Among these known cases, the
chiral N-sulfinyl imines are particularly effective5,6 in
directing allylic nucleophilic attack onto imine carbon to
afford N-sulfinyl homoallylic amines with excellent diaste-
reoselectivities and very good yields. Very recently, Lin
and co-workers have reported an interesting methodology
to synthesize N-sulfinyl homoallylic amines by using chiral
N-tert-butanesulfinyl imines.7 They found that the asym-
metric induction can be reversed by simply changing the
reaction conditions.
reaction (Scheme 1).8,9 Very good results were obtained
in terms of both yields and diastereoselectivities.
In continuation of our efforts on using chiral N-phos-
phonyl imines in various nucleophilic addition reactions,
we sought to explore the reaction of Grignard reagents
with these chiral N-phosphonyl imines. Herein, we report
our preliminary results of the reaction of allylmagnesium
bromides with chiral N-phosphonyl imines derived from
different aromatic aldehydes.
Initially, the reaction of chiral N-phosphonyl imine hav-
ing N-benzyl groups in the auxiliary (1) with allylmagne-
sium bromide was examined (Scheme 2).
Even though the reaction provided quantitative yield of
product, the diastereoselectivity was only moderate (dr
70:30). In order to investigate the effect of non-coordinat-
ing solvents for the reaction shown in Scheme 2, methylene
chloride and toluene were used. However, in contrast to N-
sulfinyl imines where significant improvements in diastereo-
selectivities were observed,4b the use of both methylene
chloride and toluene as reaction media resulted in
decreased diastereoselectivities (methylene chloride: dr
60:40; toluene: dr 65:35).10 The use of diethyl ether as a sol-
vent did not improve the diastereoselectivity either.
At this point, attempts were made to optimize the chiral
N-phosphonyl auxiliary by changing different alkyl
groups (R1, Table 1) on C2-symmetric nitrogens of chiral
Recently, in our labs we have synthesized some new chi-
ral N-phosphonyl imines and successfully proven that the
C2-symmetric chiral N-phosphonyl group could efficiently
control the diastereoselectivity of nucleophilic addition
reactions such as aza-Darzens reaction and aza-Henry
*
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.2008.04.038

A. Kattuboina et al. / Tetrahedron Letters 49 (2008) 3722–3724
3723
OLi
Bn
Ar
Br
Aux
H
H
(2.0 equiv)
N
N
O
OCH3
C, 6 h
N Aux
Aux =
P
Ar
THF, -78
°
N
O
Bn
OCH3
up to > 99% de
up to 82% yield
Aux
Aux
N
CH3NO2 (4.0 equiv.),
HN
H
H
1M LiHMDS/THF (2.0 equiv.)
NO2
N
O
R'
R'
Aux =
P
THF, -10 °C, 8 h
N
up to 92:8 dr
up to 98% yield
Scheme 1. Asymmetric aza-Darzens and aza-Henry reactions using chiral N-phosphonyl imines.
H
R
H
H
N
R
H
N
O
N
O
N
R
R
P
P
THF
-78 °C, 3 h
Quant.
HN
N
MgBr
+
R = Bn, dr 70:30
R = iPr, dr 95:5
Scheme 2. Reaction of allylmagnesium bromide with chiral N-phosphonyl imine 1.
N-phosphonyl group. Results of these optimization studies
are summarized in Table 1.
of chiral N-phosphonyl group of the auxiliary, dramatic
improvement in diastereoselectivity was observed; and the
product was obtained in near quantitative yield. The
improved diastereoselectivity with iso-propyl groups in
the auxiliary could be attributed to increased steric bulki-
ness at C2-symmetric nitrogens of the chiral auxiliary. This
result was in complementary to what we observed in the
case of aza-Henry reaction using chiral N-phosphonyl
imines.9
Encouraged by this result, different chiral N-phosphonyl
imines derived from various aldehydes were synthesized9
and subjected to reaction with allylmagnesium bromide.
The results are presented in Table 2. As can be seen from
Table 2, nearly quantitative yields of N-phosphonyl homo-
allylic amines were obtained in all the cases that were stud-
ied.11 The diastereoselectivities, in general, were good.
Slightly decreased diastereoselectivities were observed in
the cases when ortho-substituents (entries 4and 5) and elec-
tron-withdrawing substituents were present on the aro-
matic rings (entries 6 and 7). Chiral N-phosphonyl imine
derived from heteroaromatic aldehyde (thiophene-2-car-
boxaldehyde) also worked well for this reaction (entry 8).
The absolute stereochemistry of the products was assigned
by converting product 3b into a known compound and by
comparing their optical rotation values.12,2a
The presence of N-benzyl group (entry 1) in the auxiliary
provided only moderate diastereoselectivity of 70:30. When
iso-butyl group were utilized (entry 2) to replace benzyl
group, dramatic decrease in diastereomeric ratio was
observed. No significant improvement in stereoselectivity
was obtained even when the bulkier neo-pentyl groups
(entry 3) was used for this purpose. Pleasantly, when iso-
propyl groups were attached onto C2-symmetric nitrogens
Table 1
The results of optimization of chiral N-phosphonyl auxiliary
H
H
R1
H
R1
H
R1
N
N
N
N
N
O
R1
P
P
O
THF
HN
MgBr
-78 °C
+
Entry
R1
Time (h)
% Yielda,b
drc
1
2
3
4
a
–CH2Ph
3
3
6
6
Quant.
Quant.
84d
70:30
55:45
65:35
95:5
–CH2–CH(CH3)2
–CH2–C(CH3)3
–CH(CH3)2
Quant.
In summary, several chiral N-phosphonyl imines were
synthesized and utilized for nuclephilic addition reactions
with allylmagnesium bromide. The C2-symmetric chiral
phosphonyl auxiliary was optimized for this reaction.
Excellent yields and good diastereoselectivities were
Isolated yield after standard aqueous work-up.
Combined yields of both diastereomers.
Determined by 1H NMR and 31P NMR analysis of crude reaction
b
c
products.
d
Yield after trituration with ether.

3724
A. Kattuboina et al. / Tetrahedron Letters 49 (2008) 3722–3724
Table 2
Reaction of allylmagnesium bromide with chiral N-phosphonyl imines 2a–h
H
H
Aux
Aux
THF
N
N
O
HN
N
Aux =
P
MgBr
+
-78 °C, 6 h
Ar
Ar
½aꢂ2D5; CHCl3
d
Entry
Ar
Product
% Yielda,b
drc
1
2
3
4
5
6
7
8
a
Phenyl
3a
3b
3c
3d
3e
3f
Quant.
Quant.
Quant.
96
Quant.
Quant.
Quant.
Quant.
95:5
100:0
95:5
86:14
90:10
85:15
81:19
95:5
ꢀ18.7 (c 1.03)
ꢀ6.9 (c 0.64)
ꢀ9.4 (c 0.34)
ꢀ28.8 (c 0.84)
ꢀ18.0 (c 3.15)
ꢀ26.5 (c 1.45)
ꢀ20.3 (c 1.32)
ꢀ21.3 (c 0.86)
4-MeO–phenyl
4-Me–phenyl
2-MeO–phenyl
2-Me–phenyl
4-F–phenyl
4-Cl–phenyl
2-Thienyl
3g
3h
Isolated yield after standard aqueous work-up.
Combined yields of both diastereomers.
Determined by 1H NMR and 31P NMR analysis of crude reaction products.
Concentration in g/100 mL.
b
c
d
Jiang, Y.-Z.; Mi, A.-Q.; Jong, T.-T. J. Org. Chem. 1994, 59, 914; (c)
Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J. Tetrahedron:
Asymmetry 1995, 6, 349; (d) Cogan, D. A.; Liu, G.-C.; Ellman, J.
Tetrahedron 1999, 55, 8883; (e) Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2004, 15, 3823.
obtained in all the examples examined. Studies are in pro-
gress in our laboratory to extend this methodology to other
non-stabilized and more basic Grignard reagents such as
methyl- and ethylmagnesium bromides. Furthermore, the
work is also being pursued to use other organometallics
such as organoindium, organozinc, and organolithium
compounds as nucleophiles and the results would be
reported in the due course.
4. (a) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40,
4491; (b) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6,
1741.
5. (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. Rev. 1998, 27, 13–
18; (b) Davis, F. A. J. Org. Chem. 2006, 71, 8993–9003.
6. (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.
7. Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
8. Kattuboina, A.; Li, G. Tetrahedron Lett. 2008, 49, 1573–1577.
9. Kattuboina, A.; Kaur, P.; Ai, T.; Li, G. Chem. Biol. Drug Des. 2008,
216–223.
10. Reaction was stirred for 9 h with toluene as a solvent.
11. Typical procedure for the reaction of allylmagnesium bromide with
chiral N-phosphonyl imines is as follows. Into an oven dried 25 mL
round-bottomed flask flushed with N2 was taken a solution of chiral
N-phosphonyl imine (0.5 mmol) in 10.0 mL of dry THF. The flask
was cooled to ꢀ78 °C, and 1.0 mmol of allylmagnesium bromide
(1.0 mL, 1.0 M solution in THF) was added drop wise. After stirring
for 6 h at this temperature the reaction was quenched with 1.0 mL of
saturated NH4Cl and brought to room temperature. 5.0 mL of water
was then added to the reaction and extracted with 2 ꢁ 20 mL of
ethylacetate. The combined organic layers were washed with water
(1 ꢁ 10 mL) and dried over anhydrous Na2SO4. Sodium sulfate was
filtered off, and the solvent was evaporated to obtain crude product as
a pale yellow solid. This was washed with minimum amount of
hexanes to get pure product as a white solid.
Acknowledgments
Financial support by Robert A. Welch Foundation
(D-1361) and Howard Hughes Medical Institute (Under-
graduate Science Education Program) is gratefully
acknowledged. We want to thank Dr. Jianlin Han and
Teng Ai for helpful discussions and David W. Purkiss for
assistance in NMR.
References and notes
1. (a) Ochoa-Puentes, C.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39,
595; (b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815.
2. (a) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.;
Ohfune, Y. J. Org. Chem. 2005, 70, 3464; (b) Basile, T.; Bocoum, A.;
Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59, 7766; (c) Ken
Lee, C.-L.; Ling, H. Y.; Loh, T.-P. J. Org. Chem. 2004, 69, 7787.
3. (a) Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem.
1991, 56, 4; (b) Yang, T.-K.; Chen, R.-Y.; Lee, D.-S.; Peng, W.-S.;
12.
Aux
HN
Boc
NH2
. HCl
HN
HCl / i-PrOH
Boc2O
H3CO
rt, 12 h
H3CO
Et3N, CH2Cl2
H3CO
5
3b
4
25
α
[ ]D
+ 82.4 (CHCl3, c 0.85)
24
Lit.2a
+ 76.0 (CHCl3, c 1.00)
er 93:7
α
[ ]D