Asymmetric synthesis of N-diphenylphosphinoylamines by solvent-free enantioselective addition of dialkylzincs to N-diphenylphosphinoylimines

Article abstract of DOI:10.1039/b106775n

Solvent-free enantioselective addition of dialkylzincs to N-diphenylphosphinoylimines in the presence of chiral 2- morpholino-1-phenylpropan-1-ol affords N-diphenylphosphinoylamines with up to 97% ee. The reaction in the solvent-free system is faster than

Full text of DOI:10.1039/b106775n

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Asymmetric synthesis of N-diphenylphosphinoylamines by
solvent-free enantioselective addition of dialkylzincs to
N-diphenylphosphinoylimines
1
Itaru Sato, Ryo Kodaka and Kenso Soai*
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo,
Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.
E-mail: ksoai@ch.kagu.sut.ac.jp; Fax: ϩ81-3-3235-2214
Received (in Cambridge, UK) 26th July 2001, Accepted 4th October 2001
First published as an Advance Article on the web 15th October 2001
Solvent-free enantioselective addition of dialkylzincs to
N-diphenylphosphinoylimines in the presence of chiral 2-
morpholino-1-phenylpropan-1-ol affords N-diphenylphos-
phinoylamines with up to 97% ee. The reaction in the
solvent-free system is faster than in organic solvents.
2,9a N-diphenylphosphinoylimines 1a–e react with neat dialkyl-
zincs without any solvent (Scheme 1).
Enantioselective addition of diethylzinc (Et2Zn) to N-
diphenylphosphinoylimine 1a was examined (Table 1). In the
presence of (1R,2S)-2, neat Et2Zn was added to imine 1a at
0 ЊC to give (R)-N-diphenylphosphinoylamine 3a with 88% ee
in an isolated yield of 75% (entry 1). The reaction was homo-
geneous and was complete within 2 h. Compared to the enantio-
selective addition of Et2Zn to imine 1a using 2 in toluene (0 ЊC,
22 h),9a the reaction without solvent is much faster. Presumably,
the high concentration of Et2Zn due to the absence of solvent
is responsible for the acceleration of the reaction rate. Co-
ordination between Et2Zn, zinc alkoxide of 2, and imine is
considered to be enhanced because of the absence of the solv-
ation. Even at lower temperatures (Ϫ10 ЊC and Ϫ20 ЊC), the
reaction gave (R)-3a with 84 and 80% ee in 75 and 71% yields,
respectively (entries 3 and 4).
The development of solvent-free organic synthesis is of current
interest.1,2 Although solvent-free synthesis is reported, for
example, in polymerization,3 radical addition4 and ionic reac-
tions,5 the number of solvent-free enantioselective syntheses
has been very few.6,7 In many enantioselective syntheses, the
solvents are of paramount importance to achieve high enantio-
selectivity. Solvents are considered to play a crucial role in the
enantioselection by coordinating, more or less, to the chiral
reaction intermediates. Indeed, the enantioselectivity of a chiral
ligand or chiral catalyst often differs significantly with the
change of the structure of the solvent.8
Enantioselective alkylation of imines is one of the chal-
lenges in asymmetric synthesis. We previously reported the
enantioselective alkylation of N-diphenylphosphinoylimines
with diethylzinc in toluene in the presence of chiral β-amino
alcohols.9,10 Subsequent removal of the diphenylphosphinoyl
group by acid hydrolysis11 affords enantiomerically enriched
secondary amines. Compared to the enantioselective addition
of dialkylzincs to aldehydes,12 less attention has been paid
to the enantioselective addition of organometallic reagents to
imines.13
Enantioselective synthesis of various N-diphenylphosphino-
ylamines 3 is summarized in Table 2. By using the chiral ligand
(1R,2S)- and (1S,2R)-2, amines (R)-3a and (S)-3a with high
ee were synthesized, respectively (entries 1 and 2). Enantio-
selective addition of Et2Zn to 1b in the presence of (1R,2S)-2
afforded (R)-3b with 93% ee in a yield of 82% (entry 3). It
is noteworthy that the reaction of ferrocenylimine 1c in the
presence of (1R,2S)-2 proceeded in a highly enantioselective
manner to give 3c with as high as 97% ee (entry 5). This ee was
much higher compared with the reaction of ferrocenylimine 1c
in toluene (0 ЊC, 119 h, 90% ee).9b Alkylation of imines 1d and
1e also gave amines 3d and 3e with high (91 and 80%) ee’s,
respectively (entries 6 and 7). Next, enantioselective addition of
We wish to report here a solvent-free enantioselective
addition of dialkylzincs to N-diphenylphosphinoylimines. In
the presence of (1R,2S)-2-morpholino-1-phenylpropan-1-ol
Scheme 1
2912
J. Chem. Soc., Perkin Trans. 1, 2001, 2912–2914
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106775n

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Table 1 Solvent-free enantioselective addition of diethylzinc to N-diphenylphosphinoylimine 1a in the presence of (1R,2S)-2
(R)-N-Diphenylphosphinoylamine
3ab
Entrya
2 (mol equiv.)
T /ЊC
t/h
Yield (%)
Ee (%)
1
2
3
4
(1R,2S)-2 (1.0)
(1R,2S)-2 (0.5)
(1R,2S)-2 (1.0)
(1R,2S)-2 (1.0)
0
0
Ϫ10
Ϫ20
2
24
4
75
42
75
71
88
75
84
80
6
a Reactions were carried out on a 0.5 mmol scale using 6–8 mol equivalents of neat Et2Zn. b The ee was determined by HPLC analysis using a chiral
stationary phase (Chiralcel OD). For the absolute configuration, see ref. 9a.
Table 2 Solvent-free enantioselective synthesis of various N-diphenylphosphinoylamines
N-Diphenylphosphinoylamine
3b
Entrya
N-Diphenylphosphinoylimine 1
Chiral ligand
R2 Zn
Yield (%)
Ee (%) (config.)
2
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1d
1e
1a
(1R,2S)-2
(1S,2R)-2
(1R,2S)-2
(1S,2R)-2
(1R,2S)-2
(1R,2S)-2
(1R,2S)-2
(1R,2S)-2
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
i-Pr2Zn
3a 75
3a 76
3b 82
3b 82
3c 58
3d 88
3e 84
4a 89
88 (R)
84 (S)
93 (R)
89 (S)
97 (R)
91 (R)
80 (R)
84 (R)c
a Reactions were carried out in 0.5 mmol scale at 0 ЊC using 1.0 mol equivalent of (1R,2S)-2 and 6–8 mol equivalent of R2 Zn. b Ee’s were determined
2
by HPLC analyses using chiral stationary phases (Chiralcel OD for 3a,b,d,e and Chiralpak AS for 3c). Absolute configurations of 3b–e are
tentatively assigned based on the analogy with (R)-3a. c The ee was determined by HPLC analysis using a chiral stationary phase (Chiralcel OD). The
configuration of 4a is tentatively assigned by analogy with (R)-3a.
3 (a) J. Hornke, R. Lipphardt and R. Meldt, in Produktionsintegrierter
Umweltschutz in der chemischen Industrie, ed. J. Wiesner, Decheme,
Frankfurt/Main, 1990, pp. 17–18; (b) K. Komiya, S. Fukuoka,
M. Aminaka, K. Hasegawa, H. Hachiya, H. Okamoto, T. Watanabe,
H. Yoneda, J. Fukawa and T. Dozono, in Green Chemistry, Design-
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Williamson, American Chemical Society, Washington D.C., 1996,
pp. 20–32.
neat diisopropylzinc was examined. In the presence of (1R,2S)-
2, addition of diisopropylzinc to N-diphenylphosphinoylimine
1a gave the corresponding amine 4a with 84% ee in a yield of
89% (entry 8).
A typical experimental procedure is as follows (Table 2, entry
5): to an ice-cooled 2-necked flask containing N-diphenyl-
phosphinoylimine 1c (0.21 g, 0.5 mmol) and (1R,2S)-2-
morpholino-1-phenylpropan-1-ol 2 (0.11 g, 0.5 mmol), neat
Et2Zn (0.49 g, 4 mmol) was transferred through a cannula
under an argon atmosphere. After the mixture was stirred
at 0 ЊC for 2 h, the completion of the reaction was confirmed
by TLC analysis. After additional stirring for 2.5 h, excess
Et2Zn was removed under reduced pressure and saturated aq.
ammonium chloride was added to the residue. The mixture was
extracted with dichloromethane and the combined organic
layer was dried over anhydrous sodium sulfate. Concentration
of the organic layer and purification of the residue on silica
gel TLC gave (R)-3c (0.13 g, 58%). The ee was determined
to be 97% by HPLC analysis using a chiral stationary phase
(Chiralpak AS).
4 (a) J. O. Metzger and R. Mahler, Angew. Chem., Int. Ed. Engl., 1995,
34, 902; (b) J. O. Metzger, R. Mahler and A. Schmidt, Liebigs Ann.,
1996, 693.
5 G. Bram and G. Decodts, Synthesis, 1985, 543.
6 (a) L. E. Martinez, J. L. Leighton, D. H. Carsten and E. N.
Jacobsen, J. Am. Chem. Soc., 1995, 117, 5897; (b) D. Rajagopal, K.
Rajagopalan and S. Swaminathan, Tetrahedron: Asymmetry, 1996,
7, 2189.
7 I. Sato, T. Saito and K. Soai, Chem. Commun., 2000, 2471.
8 For example, enantioselective addition of butyllithium to benz-
aldehyde using a chiral ligand in a mixed solvent of dimethyl ether
and dimethoxymethane affords 1-phenylpentanol with much higher
ee than the reaction in hexane. T. Mukaiyama, K. Soai, T. Sato,
H. Shimizu and K. Suzuki, J. Am. Chem. Soc., 1979, 101, 1455.
9 (a) K. Soai, T. Hatanaka and T. Miyazawa, J. Chem. Soc., Chem.
Commun., 1992, 1097; (b) T. Hayase, Y. Inoue, T. Shibata and
K. Soai, Tetrahedron: Asymmetry, 1996, 7, 2509; (c) T. Suzuki,
N. Narisada, T. Shibata and K. Soai, Tetrahedron: Asymmetry, 1996,
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As described, enantioselective addition of dialkylzincs to
N-diphenylphosphinoylimine under solvent-free conditions
proceeds more rapidly than the reaction in toluene and the
corresponding amines with high ee’s are obtained.14
10 For related reactions: (a) P. G. Andersson, D. Guijarro and D.
Tanner, J. Org. Chem., 1997, 62, 7364; (b) C. Jimeno, K. S. Reddy,
L. Solà, A. Moyano, M. A. Pericàs and A. Riera, Org. Lett., 2000,
2, 3157.
11 T. W. Green and P. G. M. Wutz, in Protective Groups in Organic
Synthesis third edition, Wiley, New York, 1999, p. 598.
Acknowledgements
This work was supported by a Grant-in Aid for Scientific
Research from the Ministry of Education, Science, Sports and
Culture.
12 Reviews: (a) K. Soai and S. Niwa, Chem. Rev., 1992, 92, 833;
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14 Solvent-free asymmetric addition of Et2Zn to imine 1a using
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