A new pseudo C2-symmetric tertiary diamine for the enantioselective addition of MeLi to aromatic imines

Article abstract of DOI:10.1016/j.tetasy.2006.03.026

A new tertiary pseudo C₂-symmetric 1,2-diamine derived from (1S,2S)-(+)-pseudoephedrine was synthesized and tested in the enantioselective addition of MeLi to aromatic imines. A comparative study with the analogous C₂-symmetric ligan

Full text of DOI:10.1016/j.tetasy.2006.03.026

Tetrahedron: Asymmetry 17 (2006) 1045–1047
A new pseudo C -symmetric tertiary diamine for the
2
enantioselective addition of MeLi to aromatic imines
S e´ gol e` ne Gille, Noemi Cabello, Jean-Claude Kizirian and Alexandre Alexakis*
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
Received 20 March 2006; accepted 23 March 2006
Available online 6 May 2006
Abstract—A new tertiary pseudo C
enantioselective addition of MeLi to aromatic imines. A comparative study with the analogous C
2
-symmetric 1,2-diamine derived from (1S,2S)-(+)-pseudoephedrine was synthesized and tested in the
-symmetric ligand successfully used
2
previously in the same reaction showed comparable selectivity and better reactivity for this novel diamine.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
backbone to a nitrogen atom, thus allowing space discrimi-
nation in a cyclic chelated intermediate (Scheme 1).
1
A large number of the ‘privileged ligands’ used in asym-
metric synthesis possess C -symmetry. The reason for
2
choosing a C -symmetric ligand is to reduce the number
2. Results and discussion
2
of possible diastereoisomeric metal complexes, as well
as the number of transition states. This consequence of
This concept was validated during a study of the asymmet-
C -symmetry can have a beneficial effect on stereocontrol,
2
ric addition of MeLi to N-p-methoxyphenyl imines pro-
because the competing less selective pathways can be
eliminated.
moted by C -symmetric tertiary diamines 1 based on the
2
cyclohexane core. Whereas product 4a was obtained in
0
0
only 20% ee with N,N,N ,N -tetramethylated diamine 1a,
68% ee was achieved with diamine 1b bearing two bulky
In our previous papers, we described conceptually new C2-
2
symmetric tertiary diamines in which nitrogen atoms could
phenethyl substituents on nitrogen (Scheme 2).
2
become stereogenic in the reactive species. Upon complex-
ation with a metal, it was expected that the diamine would
adopt its most favored conformation in which the bulky
O
O
substituent CH R’ would be in a trans relationship with
MeLi (3 equiv.)
2
1
a or 1b (0.2 equiv.)
the R group of the chiral backbone. In this context, we
could talk about chirality transfer from a chiral carbon
N
N
H
toluene, -78 ºC, 15 h
3a
Ph
N
(R)-4a
2
0% ee with 1a
8% ee with 1b
R'
N
6
R
R
R
R
N
N
1
R M
N
N
+
N
N
N
N
Ph
M
M
1
1
R
R
R
R
1a
1b
R'
favored
disfavored
Scheme 2.
Scheme 1.
Chirality transfer means that substitution on the nitrogen
may govern the stereochemical pathway to a much greater
extent than the chiral carbon backbone. It is reasonable to
believe that the cyclohexane core could be changed to
*
Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32 15;
e-mail: alexandre.alexakis@chiorg.unige.ch
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.026

1046
S. Gille et al. / Tetrahedron: Asymmetry 17 (2006) 1045–1047
another chiral carbon backbone without significant loss
of selectivity. This prompted us to design a new pseudo
C -symmetric diamine 2b based on the pseudoephedrine
2
were applied for purposes of comparison with diamine 1b
(Table 1). It should be noted that substoichiometric
amounts (20 mol %) of 2b were used.
core. In previous work dealing with the addition of phenyl-
lithium to the same kind of imines, it had been shown that
O
O
pseudo C -symmetric ligand 2a derived from (1S,2S)-(+)-
2
MeLi (3 equiv.)
1
b or 2b (0.2 equiv.)
pseudoephedrine gave the same results as C -symmetric
2
Ar
N
Ar
N
H
6
a derived from (1S,2S)-diphenyldiaminoethane (Scheme
toluene, -78 ºC, 15 h
3
3). This represents an interesting feature given that pseudo-
3
a-f
4a-f
ephedrine derivatives could be easily prepared as described
below. As an analogue of diamine 1b bearing the same sub-
stituents on nitrogen atoms, it was expected that 2b would
afford the same level of enantioselectivity in the addition of
MeLi to N-p-methoxyphenyl imines.
a, Ar = C H
6
5
3 6 4
d, Ar = p-CF -C H
b, Ar = p-Me-C6H4
c, Ar = p-Cl-C6H4
e, Ar = 2-naphthyl
f, Ar = piperonyl
Ph
N
Ph
N
O
O
Ph
PhLi (2 equiv.)
N
Ph
N
6
a or 2a (0.2 equiv.)
Ph
Ph
N
N
H
toluene, -78 ºC, 2 h
1b
2b
S
S
3g
(R)-7g
Scheme 5.
5
9% ee with 6a
1% ee with 2a
Ph
Ph
N
N
N
N
6
Ph
Table 1. Enantioselective addition of MeLi to imines 3a–f promoted by
diamines 1b or 2b
a
b,c
6
a
2a
Entry
Product
Diamine
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
1b
2b
100 (98)
85 (78)
50
63 (52)
66 (57)
71 (61)
55 (35)
100 (80)
50 (42)
17
68 (R)
60 (S)
74 (R)
69 (S)
68 (R)
58 (S)
58 (R)
58 (S)
68 (R)
55 (S)
48 (R)
30 (S)
Scheme 3.
Diamine 2b was synthesized in two steps starting from
1S,2S)-(+)-pseudoephedrine following literature proce-
(
4
dures (Scheme 4). At first, N-alkylation was carried out
using anhydrous sodium carbonate and phenethyl bromide
in refluxing DMF, affording amino alcohol 5 in 64% yield.
Subsequent mesylation followed by ring-opening of the
aziridinium ion with commercially available N-methyl
5
d
9
d
1
1
0
1
6
e
100 (88)
100 (91)
e
phenethylamine cleanly afforded diamine 2b with an over-
all retention of configuration in 98% yield. Compound
12
4f
7
a
b
c
1
Determined by H NMR spectroscopy of the crude. Yields in parenthesis
refer to yields after column chromatography.
Determined by SFC Columns Chiracel OD-H for 4a and 4f, Chiralpak
AS-H for 4b, 4c, and 4e, Chiralpak AD for 4d.
The absolute configuration of 4a was determined on the basis of previous
work. For other products, the configurations were assigned by consid-
eration of the stereochemical pathway and of the systematic inversion of
configuration occurring using 1b or 2b.
1
2
b displays, in the H NMR spectrum, a vicinal coupling
constant of 10.1 Hz for the benzylic proton, which is char-
acteristic of the pseudoephedrine relative stereochemistry.
Ph
H
N
N
Ph(CH2)2Br
d
e
Reaction carried out for 35 h at ꢀ78 °C.
Ph
OH
Na2CO3, DMF, Ph
reflux, 24 h
OH
Reaction carried out for 15 h at ꢀ30 °C.
5
6
4%
Initially, in almost all cases, better conversions were
obtained with diamine 2b. In particular, imine 3d was
totally converted to product 4d using ligand 2b, whereas
only half conversion was reached using 1b (entry 8 vs 7).
However, for imines 3a and 3e bearing a non-substituted
aromatic part, diamine 2b was found to be less reactive
than 1b (entries 2 vs 1 and 10 vs 9). Systematic inversion
of configuration was obtained for all products, as expected
with the inversion of configuration at the chiral backbone
of the diamine. In terms of selectivity, ee’s induced by dia-
mine 2b, ranging from 30% to 69%, were comparable,
although slightly lower, to those induced by diamine 1b,
ranging from 48% to 74%. This could be due to a less effi-
cient chirality transfer in 2b than in 1b. These two diamines
Ph
Ph
1
. Et3N, MsCl, Et2O,
°C, 30 min
N
0
2
. Et3N, CH3NH(CH2)2Ph, Ph
rt, 16 h
N
2
b
9
8%
Scheme 4.
Diamine 2b was then tested in the enantioselective addition
of MeLi to various N-p-methoxyphenyl imines (Scheme
). The same reaction conditions as previously reported
8
2
5

S. Gille et al. / Tetrahedron: Asymmetry 17 (2006) 1045–1047
1047
induced the best selectivity with imine 3b prepared from p-
tolualdehyde (entries 3 and 4). An interesting point is that
dried over MgSO
purified by distillation in a Kugelrohr apparatus (bp = 160 °C/
.3 mmHg) to give (1.69 g, 64%) as yellow oil;
aꢁ ¼ þ65:3 (c 1.02, CHCl ); H NMR (300 MHz, CDCl )
4
, and concentrated. The crude product was
0
½
5
a
4
2
a was obtained in 60% ee with 2b (Table 1, entry 2) and in
0% ee with 1a (Scheme 2), confirming that the substitution
2
D
5
1
3
3
d (ppm) 0.84 (d, J = 6.6 Hz, 3H), 2.44 (s, 3H), 2.65–3.00 (m,
H), 4.29 (d, J = 9.6 Hz, 1H), 4.89 (br s, 1H), 7.28–7.50
on the nitrogen may govern the stereochemical pathway to
a much greater extent than the chiral carbon backbone.
5
(
13
3
m, 10H); C NMR (75 MHz, CDCl ) d (ppm) 7.3, 34.7, 36.0,
5
5.1, 65.7, 74.6, 126.1, 127.2, 127.5, 128.0, 128.3, 128.5, 139.8,
1
41.9; IR (neat): 3028, 2967, 1495, 1453, 1132, 1044, 750,
ꢀ
1
3
. Conclusion
700 cm ; MS (EI), m/z (%): 268 (Mꢀ1), 178 (10), 163 (19),
1
62 (100), 148 (41), 106 (11), 105 (90), 91 (12), 84 (22), 77 (23),
+
In summary, novel chiral pseudo C -symmetric 1,2-di-
58 (16); HRMS (ESI) calcd for C18
found 270.1855.
H23NO [M+H] 270.1900,
2
amine 2b was easily synthesized in two steps starting from
commercially available (1S,2S)-(+)-pseudoephedrine. It
was tested as a ligand for the enantioselective addition of
MeLi to aromatic imines 3a–f. In comparison with the
analogous C -symmetric cyclohexane diamine based 1b,
lower enantioselectivities and generally better conversions
6
. (a) Dieter, R. K.; Deo, N.; Lagu, B.; Dieter, J. W. J. Org.
Chem. 1992, 57, 1663–1671; (b) O’Brien, P.; Towers, T. D.
J. Org. Chem. 2002, 67, 304–307.
. (1S,2S)-(+)-N,N -Dimethyl-N,N -diphenethyl-1-phenylprop-
ane-1,2-diamine 2b was prepared according to the procedure
described in Ref. 6b: MsCl (0.20 mL, 2.58 mmol) was added
dropwise to a stirred solution of amino alcohol 5 (584 mg,
0
0
7
2
of products 4a–f were obtained. This study shows the
potential of pseudo C -symmetric diamines based on the
2.17 mmol) and NEt3 (0.50 mL, 3.60 mmol) in dry Et O
2
2
pseudoephedrine core and describes a procedure that could
be applied to the preparation of various other diamines
possessing different substituents on nitrogen atoms.
(12 mL) at 0 °C under Ar. After 30 min, NEt (0.60 mL,
3
4.30 mmol) was added and the mixture allowed to warm to
room temperature. Then, commercially available N-methyl-
phenethylamine (5.0 g, 37.0 mmol) was added and the mixture
stirred vigorously overnight at room temperature. The layers
were separated and the aqueous one extracted with Et O. The
2
Acknowledgement
combined organic layers were washed with aqueous 5%
3 2 4
NaHCO , water, dried over Na SO , and concentrated. The
crude product was purified in a Kugelrohr apparatus by
The authors wish to thank PPG-SIPSY for financial
support.
distillation of N-methylphenethylamine in excess to afford 2b
2
D
5
(
836 mg, 99%) as a yellow oil; ½aꢁ ¼ þ19:1 (c 1.25, CHCl
3
);
1
3
H NMR (400 MHz, CDCl ) d (ppm) 0.63 (d, J = 6.6 Hz, 3H),
2
.11 (s, 3H), 2.27 (s, 3H), 2.40–2.85 (m, 8H), 3.08–3.25 (m,
References
1H), 3.38 (d, J = 10.1 Hz, 1H), 6.80–6.98 (m, 2H), 7.00–7.25
1
3
(
3
m, 13H); C NMR (125 MHz, CDCl ) d (ppm) 11.1, 29.7,
1
2
. Yoon, P. Y.; Jacobsen, E. N. Science 2003, 299, 1691–1693.
. (a) Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron Lett.
34.6, 36.3, 37.4, 56.3, 56.5, 57.3, 70.9, 125.8, 127.8, 128.2,
128.3, 128.8, 129.2, 141.0; IR (neat): 3026, 2931, 1495, 1453,
ꢀ1
2
003, 44, 8893–8895; (b) Kizirian, J.-C.; Cabello, N.; Pinchard,
1124, 1031, 748, 699 cm ; MS (EI), m/z (%): 388 (M+2, 8),
L.; Caille, J.-C.; Alexakis, A. Tetrahedron 2005, 61, 8939–8946.
. (a) Cabello, N.; Kizirian, J.-C.; Alexakis, A. Tetrahedron Lett.
252 (10), 224 (67), 162 (100), 146 (12), 134 (15), 118 (16), 105
3
(85), 91 (59), 77 (23); HRMS calcd for C27
found 386.2722.
H N 386.5723,
34 2
2
004, 45, 4639–4642; (b) Cabello, N.; Kizirian, J.-C.; Gille, S.;
Alexakis, A.; Bernardinelli, G.; Pinchard, L.; Caille, J.-C. Eur.
J. Org. Chem. 2005, 4835–4842.
8. Enantioselective addition of MeLi to aromatic imines 3a–f.
Typical procedure. MeLi (low halide, 0.90 mL as a 1.6 M
4
5
. Mealy, M. J.; Bailey, W. F.; Bech, S. M.; Luderer, M. R. WO
Patent 082565, 2004.
. (1S,2S)-(+)-2-(Methyl(phenethyl)amino)-1-phenylpropan-1-ol
solution in Et
2
O) was added at ꢀ78 °C to a stirred solution of
imine (0.48 mmol) and diamine (0.096 mmol) in dry toluene
(8 mL). The mixture was stirred at ꢀ78 °C for 15 h unless
otherwise indicated in Table 1. It was then quenched at low
temperature with MeOH and then at room temperature with
water. The organic layer was separated and the aqueous one
5
was prepared according to the procedure described in
Ref. 4: A suspension of (1S,2S)-(+)-pseudoephedrine (1.62 g,
.80 mmol), anhydrous Na CO (2.07 g, 19.5 mmol), and
9
2
3
phenethyl bromide (1.66 mL, 12.2 mmol) in DMF (33 mL)
was heated at reflux for 24 h. After cooling to room temper-
ature, the mixture was filtered, and the filtrate partitioned
was extracted with Et
2
O. The combined organic extracts were
1
dried over Na SO and concentrated. H NMR spectrum of
2
4
this crude was analyzed to determine the conversion of the
reaction. Finally, purification by silica gel column chromato-
graphy gave pure amines 4a–f already fully characterized in
Ref. 2b.
between Et
aqueous one extracted thoroughly with Et
organic layers were washed twice with water, once with brine,
2
O and water. The layers were separated and the
2
O. The combined