Table 1 1,2-Addition of trialkyl aluminium reagents to N-diphenylphosphinoylketimines
Entry
Reagent
R1
R2
Metal organyl
T/uC
Time/h
Yield (%)
1a
1b
1c
2
3a
3b
4a
4b
5
6
7
8
9
8
8
8
4
8
8
8
11
6
7
8
9
10
5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-O2NC6H4
2-MeOC6H4
Furyl
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
C6H5
4-MeOC6H4
C6H5
3 equiv. AlEt3
4 equiv. AlEt3
5 equiv. AlEt3
3 equiv. AlEt3
4 equiv. AlEt3
4 equiv. AlEt3
4 equiv. ZnEt2
4 equiv. ZnEt2
4 equiv. AlEt3
4 equiv. AlEt3
4 equiv. AlMe3
6 equiv. AlMe3
4 equiv. AlMe3
4 equiv. AlEt3
4 equiv. AlEt3
25
25
25
25
0
0.5
0.5
0.5
20
1
74
88
98
99
65
7
—
—
—
99
92
63
84
87
62
225
0
1
a
b
16
16
72
16
24
20
20
16
20
225
25
25
25
25
25
25
25
10
11
a
10
b
Addition of 0.1 equiv. (Rp,S)-paracyclophane-ligand in n-hexane, Addition of 1.0 equiv. N,N-dimethylethanolamine in toluene.
compound 8 (Table 1, entries 1a–c). We found that at least 3 to
4 equiv. of the aluminium reagent are needed to obtain yields up to
88%. However to obtain a quantitative yield within short reaction
times, 5 equiv. of the corresponding aluminium organyl are
required. Lowering the nucleophile loading to 3 equiv. required
prolonged reaction times (20 h) to achieve full conversion with
quantitative yield (Table 1, entry 2).
In our ongoing studies we are exploring this reaction to be
carried out in an asymmetric fashion to achieve enantiomerically
pure products.
This work has been supported by the BMBF (WING program)
and the Landesgraduiertenfo¨rderung (fellowship to R. R.).
Notes and references
Since the temperature is an important factor for the selectivity of
a chemical process we investigated the temperature limit for this
model reaction (Table 1, entries 3a and 3b).
{ General procedure for the addition of trialkylaluminium reagents to
N-diphenylphosphinoylketimines: Under a dry argon atmosphere, the
corresponding imine (0.5 mmol) was dissolved in 1.0 mL of dry toluene and
stirred for 0.5 h at room temperature to give a homogeneous solution. Then
AlEt3 or AlMe3 (4.00 mmol), used as a 1 M solution in toluene or
n-hexane, was added under argon and stirred for the indicated time. After
all of the starting material was consumed, the mixture was quenched by
addition of methanol and saturated solution of K/Na-tartrate. The aqueous
layer was extracted with ethyl acetate (3 6 5 mL), dried over MgSO4 and
filtered. The filtrate was concentrated under reduced pressure. The products
were obtained in high purity without further purification.
When the reaction was performed at 225 uC or below (see
ESI{) the starting material was recovered in almost (near to)
quantitative yield. The choice of solvents also has to be considered,
since there is no reaction taking place in coordinating solvents e.g.
Et2O or THF at temperatures around 0 uC or slightly below.
Additionally the considered imines are unreactive towards zinc
organyls as we tried to convert them with diethylzinc and different
N,O-additives (Table 1, entries 4a and 4b).
1 W.-H. Lin, H.-Z. Fu, J. Li, G. Cheng and R. A. Barnes, J. Chin. Pharm.
Sci., 2003, 12, 117.
2 I. Kitagawa, N. Yoshioka, C. Kamba, M. Yoshikawa and
Y. Hamamoto, Chem. Pharm. Bull., 1987, 35, 928.
3 G. X. Ayala and R. Tapia, Eur. J. Neurosci., 2005, 22,
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4 S. Bra¨se, T. Baumann, S. Dahmen and H. Vogt, Chem. Commun., 2007,
1881.
5 (a) D. Enders and U. Reinhold, Tetrahedron: Asymmetry, 1997, 8, 1895;
(b) R. Bloch, Chem. Rev., 1998, 98, 1407; (c) S. Kobayashi and
H. Ishitani, Chem. Rev., 1999, 99, 1069.
6 (a) P. I. Dosa and G. C. Fu, J. Am. Chem. Soc., 1998, 120, 445; (b)
C. Garcia, L. K. LaRochelle and P. J. Walsh, J. Am. Chem. Soc., 2002,
124, 10970.
7 (a) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M. Kanai and
M. Shibasaki, J. Am. Chem. Soc., 2006, 128, 7687; (b) Y. Suto, M. Kanai
and M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 500.
8 F. A. Cotton and G. Wilkinson, Advanced Inorganic Chemistry, Wiley,
New York, 4th edn, 1980, p. 342.
The scope of the optimized reaction is shown in Table 1,
entries 5–11. The 1,2-addition to electron-rich ketimines such as 6
(entry 5), the furyl-derivative 7 (entry 6) as well as 5 (entry 10)
proceed in good to excellent yields up to 99%, although longer
reaction times are necessary (16–20 h). The 1,2-addition to the
electron-poor ketimines 8, 9 and 10 (Table 1, entries 7–9) initiated
by trimethylaluminium proceed in up to 92% yield. Due to the
poor reactivity of trimethylaluminium the reaction needs to be run
24 h for completion.
It is worth mentioning that all products yielded by 1,2-addition
are of high purity without further purifications as flash-
chromatography or recrystallization. We explored this favourable
circumstance by a modified quenching procedure by saturated
K/Na-tartrate solution.
In summary we explored the first 1,2-addition of trialkylalumi-
nium organyls to N-diphenylphosphinoylketimines to obtain
a-trisubstituted amines in high yields up to 99%.
9 J. J. Eisch, in Comprehensive Organometallic Chemistry: Vol. 1, ed.
G. Wilkinson, F. G. A. Stone and E. N. Abel, Pergamon Press, Oxford
UK, 1982, ch. 6, and references therein.
106 | Chem. Commun., 2008, 105–107
This journal is ß The Royal Society of Chemistry 2008