Origin of 1, 3-induction in the addition of alkyl lithium to imines bearing an N-stereogenic center

Article abstract of DOI:10.1039/b300478c

The origin of diastereoselectivity in the addition of alkyl lithium to chiral Schiff bases has been investigated experimentally and theoretically and the formation of the major diastereomer can be explained from the energy minimized structure of the Schiff base in which the phenyl group has been found to orient in such a manner that it posed lesser steric hindrance to the incoming nucleophile as compared to the alkyl group.

Full text of DOI:10.1039/b300478c

Origin of 1, 3-induction in the addition of alkyl lithium to imines bearing
an N-stereogenic center
Nancy,a Soma Ghosh,a Nishan Singh,a Gurmeet Kaur Nanda,a P. Venugopalan,a Prasad V. Bharatamb
and Sanjay Trehan*a
a Department of Chemistry, Panjab University, Chandigarh-160 014, India. E-mail: trehan_s@yahoo.com
b Department of Chemistry, Guru Nanak Dev University, Amritsar-143 005, India
Received (in Cambridge, UK) 14th January 2003, Accepted 11th April 2003
First published as an Advance Article on the web 16th May 2003
The origin of diastereoselectivity in the addition of alkyl
lithium to chiral Schiff bases has been investigated experi-
mentally and theoretically and the formation of the major
diastereomer can be explained from the energy minimized
structure of the Schiff base in which the phenyl group has
been found to orient in such a manner that it posed lesser
steric hindrance to the incoming nucleophile as compared to
the alkyl group
observed when the nucleophile used was n-Butyl lithium in
ether at 278 °C. The stereochemistry of the major isomer in
other cases was determined by comparison with the methyl
lithium addition product. Increase in the steric bulk of R should
further facilitate the reorganisation of Schiff base 5 into a
conformation similar to 3 to minimize increased 1,2 steric
interaction. This should result in decrease in diastereoselectivity
as the steric hindrance from the side of methyl increases when
it is replaced with ethyl or isopropyl. Thus, these results rule out
the possibility of conformation 3 leading to the major
diastereomer formation.
Construction of optically active amines by addition of organo-
metallic reagents to imines bearing a stereogenic centre on
nitrogen has been investigated in detail.1 The method simulta-
neously achieves formation of optically active amine and the
construction of carbon framework. Despite all the remarkable
achievements synthetically, very few efforts have been directed
towards understanding the origin of diastereoselectivity.1b
Yamamoto proposed an empirical model to explain the
observed diastereoselectivity in their allylation reaction.2 The
reaction was proposed to proceed via conformation 1 and the
product formation occurred via attack from the side of the
hydrogen. Recently, Savoia, based on the NOE studies on the
Schiff bases complexed with Lewis acids, proposed an alternate
model based on the assumption that the N-chiral centre with
conformation 2 undergoes reorientation to an alternate con-
formation 3 after complexation with alkyl lithium. The product
formation occurs by attack of nucleophile from the side of the
methyl group.3 Herein we propose a conceptually new model
based on experimental and theoretical results. Based on these
investigations we also report a chiral amine whose Schiff bases
result in high CNN p facial selectivity.
Table 1 Addition of alkyl lithium to various Schiff bases 5
Isolated
yield (%)
Entry
R
RALi
Diastereomeric Ratioa
1
2
3
4
5
6
Me
Et
MeLi
MeLi
MeLi
n-BuLi
n-BuLi
n-BuLi
70 : 30 (2.3 : 1)
86 : 14 (6.1 : 1)
92 : 08 (11.5: 1)
73 : 27 (2.7 : 1)
74 : 26 (2.8 : 1)
97 : 03 (32.3 : 1)
63
52
51
79
76
82
iPr
Me
Et
iPr
a Diastereomeric ratio was determined from 300MHz 1HNMR.
In order to understand the observed diastereoselectivity we
have carried out ab initio MO and DFT studies on the structure
of Schiff bases 8–10.5 The energies of various minima for 8–10
is compiled in Table 2. Theoretical structure of all the Schiff
bases showed syn arrangement (H–C–N–C–H) to be the most
stable as expected according to 1,3-allylic strain model.6 The
other conformations with phenyl and methyl syn were appre-
ciably higher in energy for 8 at all levels of calculation. In the
case of 9 the minima for phenyl syn and ethyl syn were not well
defined and they appeared as shoulders at 90° and 240°
respectively. In the case of 10 the minima with isopropyl syn
was also not seen and a shoulder appeared at 240° which is
To evaluate the proposed models racemic chiral amines with
R being methyl, ethyl, isopropyl and tert-butyl were prepared4
and were condensed with benzaldehyde to give corresponding
Schiff bases. The Schiff bases were treated with methyl lithium
at 0 °C in ether. The Schiff base having R as tert-butyl group did
not undergo any reaction and starting material was recovered.
The addition products in other cases were purified via flash
column chromatography. Due care was taken to avoid separa-
tion of the diastereomers. The relative stereochemistry of the
major diastereomer, in cases where R is either ethyl or
isopropyl, was determined by X-ray crystallographic analy-
sis.†
Table 2 Relative energies (in kcal mol21) of minima of 8–10
Schiff
base
Dihedral
Angle
HF/
3-21G
HF/
6-31+G*
MP2/
6-31+G*
B3LYP/
6-31+G*
8
8
8
9
9
0
120
240
0
0
0
0
0
2.47
3.72
0
3.59
5.94
0
2.95
7.03
6.70
2.55
3.98
0
3.49
5.96
0
2.96
5.92
6.52
1.57
3.83
0
2.84
5.20
0
2.56
5.44
6.07
1.89
3.33
0
2.74
4.94
0
2.42
4.69
5.42
90a
240a
0
9
10
10
10
10
90
150
240a
(1)
It is interesting to note that the diastereoselectivity increased
as the size of the alkyl group increased from methyl to ethyl to
isopropyl (Table 1, entries 1–3). A similar trend was also
a Appear as shoulder on the potential energy surface
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CHEM. COMMUN., 2003, 1420–1421
This journal is © The Royal Society of Chemistry 2003

higher in energy by 5.42–6.70 kcal mol21 at different levels of
calculation. Two minima were seen with respect to phenyl syn
and they appeared at H–C–N–C–Ph dihedral angle of +30° and
230° at +2.42–2.95 kcal mol21 and 4.69–7.03 kcal mol21
higher in energy respectively than the H syn conformation. The
calculated rotational barriers for 8, 9 and 10 are 4.8, 7.5 and 8.8
kcal mol21 respectively. It is interesting to note that with an
increase in rotational barrier, diastereomeric excess of the
product increases.
Table 3 Addition of butyl lithium to various Schiff bases of 1-phenyl-
2-methylpropylamine
Diastereomeric
ratioa
Isolated
yield (%)
Entry
R
1
2
3
4
5
6
7
o-Me–Ph
p-Me–Ph
o-Cl–Ph
p-Cl–Ph
Naphthyl
Cyclohexyl
tert-Bu
93 : 7
92 : 8
98 : 2
93 : 7
98 : 2
97 : 3
99 : 1
81
83
83
72
74
70
71
The phenyl and alkyl in the global minima of Schiff bases
8–10 adopts a preferential conformation which is strikingly
similar to 1-methyl-1-phenylcyclohexane 11.7 In 11, phenyl in
axial position is preferred over the equatorial position as
compared to methyl because it can adapt a conformation to
minimize 1,3-diaxial interaction. The relationship between the
incoming nucleophile and phenyl or alkyl of the chiral centre in
the Schiff bases 8–10 is 1,3 that can have serious steric
implications.8 We propose that phenyl poses less steric
interaction to the incoming nucleophile in comparison to the
alkyl group and as a result the major product is formed by attack
from the side of the phenyl. If this is true then preference for
attack from the side of the phenyl should increase as the size of
alkyl group increases as observed. It is important to note that in
the minimized structure of 10, a methyl group of the isopropyl
moiety is positioned in such a way to increase 1,3-steric
interaction with the incoming nucleophile.
a Diastereomeric ratio was determined from 300 MHz 1H NMR.
In conclusion, we have proposed a new model to explain
diastereoselectivity observed in the alkyl lithium addition
reaction to Schiff bases bearing an N-stereogenic centre with no
additional heteroatom. During this investigation we have also
identified Schiff bases derived from 1-phenyl-2-methylpropyla-
mine show superior CNN p facial selectivity as compared to the
Schiff bases derived from the commonly used 1-phenethyla-
mine. Work is in progress in our laboratory to show the
superiority of 1-phenyl-2-methylpropylamine over 1-phenethy-
lamine in different systems.
S. T. thanks DST, New Delhi for financial support of this
project. S. G. and G. K. N. thank UGC and CSIR respectively
for senior research fellowships.
Notes and references
† In the case of 6 (R = Et) crystals for X-ray crystallography were obtained
from corresponding hydrochloride salt C17H22Cl1N1, M = 275.81, T =
293(2) K, Monoclinic, P21/n, a = 11.098(4), b = 8.006(2), c = 18.969(9)
To substantiate further that attack occurs from the side of the
phenyl group it was changed to ortho-toluyl keeping R as
isopropyl. The resulting product after methyl lithium addition
under identical conditions had lower diastereoselectivity (87 :
13, compare with table 1 entry 3) thus corroborating further that
the attack of nucleophile occurs from the side of the phenyl
group. If conformation 1 proposed by Yamamoto2 represents
the true conformation leading to the desired product, then there
should not be any change in the diastereoselectivity when
phenyl is changed to ortho-toluyl. In any case the conformation
1 does not correspond to an energy minimum (not even a local
minimum) on the potential energy surface of 1.
Å, b = 101.97(3)°, V = 1648.8(11) Å3, Z = 4, m(MoKa) = 0.220mm21
,
2373 reflections measured, 2251 unique (Rint = 0.0402), 1510 observed [I
> 2 s (I)], R = 0.0629, wR = 0.1598 and R = 0.0961, wR = 0.1845 for
i
observed and all data respectively. In the case of 6 (R = Pr) crystals for X-
ray analysis were prepared from its salt with p-nitrobenzoic acid.
¯
C25H28N2O4, M = 420.49, T = 293(2) K, Triclinic, P1, a = 8.631(1), b =
12.435(2), c = 12.704(2) Å, a = 117.72(1), b = 101.03(1), g = 96.19(1)°,
V = 1153.9(3) Å3, Z = 2, m(MoKa) = 0.082 mm21, 3692 reflections
measured, 3418 unique (Rint = 0.0167), 2730 observed [I > 2s(I)], R =
0.0428, wR = 0.1127 and R = 0.0560, wR = 0.1230 for observed and all
data respectively.CCDC 201482
& 201483. See http://www.rsc.org/
suppdata/cc/b3/b300478c/ for crystallographic data in .cif or other elec-
tronic format.
1 (a) R. Bloch, Chem. Rev., 1998, 98, 1407; (b) G. Alvaro and D. Savoia,
Synlett., 2002, 651.
2 Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu and W. Ito, J. Am.
Chem. Soc., 1986, 108, 7778.
(2)
3 G. Alvaro, D. Savoia and M. R. Valentinetti, Tetrahedron, 1996, 52,
12571.
4 D. J. Hart, K. Kanai, D. G. Thomas and T. K. Yang, J. Org. Chem.,
1983, 48, 289.
5 Gaussian 98W package was used. Gaussian Inc., Pittsburgh USACom-
plete optimisations have been performed on 8–10 at HF/3-21G and
single point energies calculated at HF/6-31+G*, MP2/6-31+G*,
B3LYP/6-31+G* levels.
6 (a) R. W. Hoffmann, Chem. Rev., 1989, 89, 1841; (b) M. J. Lucero and
K. N. Houk, J. Am. Chem. Soc., 1997, 119, 826.
7 (a) E. L. Eliel and M. Manoharan, J. Org. Chem., 1981, 46, 1959; (b) K.
B. Wiberg, H. Castejon, W. F. Bailey and J. Ochterski, J. Org. Chem.,
2000, 65, 1181.
Since Schiff base derived from 1-phenyl-2-methylpropyla-
mine gave product in high diastereoselectivity, it was evaluated
further from the synthetic point of view. The amine was
resolved by converting into ( )-camphorsulfonic acid salt.
D
Optically pure amine was obtained after three crystallizations
from water and basification of the recrystallized salt. Amine
was obtained in 94–96% optical purity.9 The configuration of
the chiral centre was determined by comparison with the
reported optical rotaion.10 The optically pure 1-phenyl-2-me-
thylpropylamine was condensed with various aldehydes and the
resulting Schiff bases were treated with n-butyl lithium in ether
at 278 °C. The results are compiled in Table 3. The products
were obtained in consistently high diastereoselectivity and good
yield.
8 R. W. Hoffmann, Angew. Chem., Int. Ed., 2000, 39, 2054.
9 J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973, 95, 512.
10 M. Pallavicini, E. Valoti, L. Villa and O. Piccolo, Tetrahedron
Asymmetry, 1997, 8, 1069.
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