Asymmetric addition of diethylzinc to N-(diphenylphosphinoyl) imines

Article abstract of DOI:10.1016/S0040-4020(00)01142-X

The addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines is a convenient method for the preparation of optically enriched amines. Herein we present our most recent results on this reaction, including solvent effects on the enantioselectivity

Full text of DOI:10.1016/S0040-4020(00)01142-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1615±1618
Asymmetric addition of diethylzinc to
N-(diphenylphosphinoyl) imines
Pedro Pinho and Pher G. Anderssonp
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 531, S-751 21 Uppsala, Sweden
Received 25 September 2000; revised 13 November 2000; accepted 30 November 2000
AbstractÐThe addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines is a convenient method for the preparation of optically
enriched amines. Herein we present our most recent results on this reaction, including solvent effects on the enantioselectivity and the
extension of this method to a variety of N-(diphenylphosphinoyl) imines. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
for the evaluation of the addition reaction to phosphinoyl
imines 2b±k (Fig. 2).
Since its introduction as a method to generate chiral second-
ary alcohols, the addition of organozinc reagents to pro-
chiral aldehydes has seen a tremendous growth.1 However,
the corresponding addition to imines as a method for the
preparation of chiral amines is not so well documented in
the literature and only a limited number of publications have
been devoted to the subject.2 We have been, for some time,
interested in the titled reaction3a±c and have recently
reported on a very ef®cient chiral auxiliary (1a, Fig. 1) for
this transformation.3c
2. Results and discussion
The addition of diethylzinc to phosphinoyl imine 2a in the
presence of one equivalent of the auxiliary 1b in dry toluene
afforded the addition product in .70% isolated yield and
97% optical purity over the (S)-isomer.3d
Due to the low number of publications dedicated to this
transformation, solvent studies are rare and to our know-
ledge only one example can be found in the literature.5 It
was therefore considered appropriate to investigate the
possible solvent effect on the reaction. Imine 2a was chosen
as the model substrate and the solvent in¯uence on the
stoichiometric addition reaction was studied. As observed
from Table 1, solvents like THF, ether and dichloromethane
proved to be unsuitable and no products were detected.
Various aromatic solvents, however, proved to be adequate
for the reaction, giving a range of yields and enantiomeric
excesses of the product. At best, phosphinoyl amine 3a was
obtained with an optical purity of 98% when using chloro-
benzene as solvent.
The promising results obtained with the auxiliary 1a for
the addition of diethylzinc to N-(diphenylphosphinoyl)-
benzalimine (2a, Fig. 2) encouraged us to further investigate
the scope of the reaction. We now wish to present our most
recent progress in the extension of this methodology as a
tool to synthesize chiral building blocks from the easily
prepared starting materials.4 In a recent publication3d we
described the preparation of chiral auxiliary 1b, which
proved to be even more ef®cient than its analogue 1a in
the addition of the alkylzinc reagent to imine 2a (Fig. 2).
Auxiliary 1b was therefore prepared on a multigram scale
The addition of diethylzinc to phosphinoyl imines 2a±k was
thereafter performed in chlorobenzene and toluene.
Although the reaction of diethylzinc with the tBu substituted
phosphinoyl imine (2b) did not lead to any addition product,
all the aromatic substituted amines were obtained in good
yields and selectivities. An exception being made for phos-
phinoyl imine 2f which also failed to react. The results of
the addition reactions to the different imines displayed in
Fig. 2 are summarized in Table 2. At best, the addition
product was obtained in 91% yield and 98% ee (entry 5,
imine 2e).
Figure 1. Chiral auxiliaries for the addition of diethylzinc to phosphinoyl
imines.
Keywords: asymmetric additions; diethylzinc; amino alcohols; chiral
auxiliaries.
Corresponding author. E-mail: phera@kemi.uu.se
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01142-X

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P. Pinho, P. G. Andersson / Tetrahedron 57 (2001) 1615±1618
Figure 2. N-(diphenylphosphinoyl) imines.
Table 1. Results of the solvent study
Attention should be drawn to the products 3d and 3i which
represent the reason for the change in the reaction solvent.
The solvent effect was not very pronounced in the reaction
of imine 2a, but in the case of imines 2d and 2i the addition
products were obtained with slightly higher enantiomeric
excesses in chlorobenzene rather than toluene (entries 4
and 9, Table 2).
Entry
Solvent
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
Toluene
Dichloromethane
Diethylether
Tetrahydrofuran
Benzene
Ethylbenzene
72
±
±
97
±
±
±
±
35
38
52
47
43
75
60
59
57
46
69
90
90
95
94
92
98
96
94
90
77
95
Tri¯uorotoluene
Anisole
Another point of interest was the possibility to make the
process catalytic. Unfortunately, a decrease in the amount
of the auxiliary 1b, rapidly decreased the optical purity of
the product. This decrease was not dramatic when going
from a full equivalent of 1b (75% yield, 97% ee) to half
the amount (68% yield, 92% ee), but when using only
25 mol% of the auxiliary the addition required a reaction
time of two days to afford the product in 62% yield and 80%
ee (Table 3). The addition of silylating agents has been
previously reported to increase the catalytic activity of the
amino alcohols allowing good results and shorter reaction
times when using sub-stoichiometric amounts of the chiral
auxiliary.6 This was, however, not the case for our system.
In the presence of TIPSCl a low enantiomeric excess of only
54% was obtained when using 25 mol% of 1b, even if the
reaction was completed in the usual 18 h. Finally, a full
equivalent of methanol or triethylamine were added to the
9
p-Methylanisole
Chlorobenzene
o-Dichlorobenzene
m-Dichlorobenzene
o-Chlorotoluene
m-Chlorotoluene
p-Chlorotoluene
10
11
12
13
14
15
a
Refers to the isolated yield after ¯ash chromatography.
Determined by HPLC analysis on a chiral column (ChiralCel OD-H).
b
Table 2. Results of the addition reactions to imines 2
Table 3. In¯uence of the amount of auxiliary and additives in the reaction
outcome
Entry
Imine
Yield (%)a
ee (%)b
Toluene
Chlorobenzene
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
75
±
72
70
91
±
97
±
91
77
98
±
98
±
89
87
98
±
Entry
Amount of 1b (equiv.)
Additive
Yield (%)a
ee (%)b
7
8
9
10
11
2g
2h
2i
2j
2k
67
65
70
70
65
95
96
85
90
90
95
92
97
96
94
1
2
3
4
5
6
1
±
±
±
75
68
62
40
50
50
97
92
80
54
90
93
0.5
0.25
0.25
1
TIPSCI
MeOH
Et3N
1
a
Refers to the isolated yield after ¯ash chromatography.
Determined by HPLC analysis on a chiral column (ChiralCel OD-H or
Chiralpak-AD) under the conditions described in Section 4.
b
a
Refers to the isolated yield after ¯ash chromatography.
Determined by HPLC analysis on a chiral column (ChiralCel OD-H).
b

P. Pinho, P. G. Andersson / Tetrahedron 57 (2001) 1615±1618
1617
reaction mixture in order to eventually break the product-
zinc-auxiliary chelate, but these additives proved to be
ineffective. A drop in both the yield and enantioselectivity
was observed even at stoichiometric levels of the auxiliary,
50% yield and 90% ee when methanol was used and 50%
yield and 93% ee in the case of triethylamine.
(31), 216 (100), 200 (20), 199 (57) and 152 (10). HRMS:
calcd for C25H20NOP 381.1282, found 381.1283.
4.2. General procedure for the addition reactions
A dry 25 mL round-bottom ¯ask was loaded with a
magnetic bar, chiral auxiliary 1b (100 mg, 0.34 mmol)
and N-(diphenylphosphinoyl) benzalimine 2a (104 mg,
0.34 mmol). The reaction vessel was thereafter evacuated,
placed under argon and dry chlorobenzene (3 mL) was
added via syringe. After stirring for 10 min the solution
was cooled to 08C and diethylzinc (1.1 M in toluene or
hexane, 0.95 mL, 1.04 mmol) was added dropwise. The
ice-bath was removed and the reaction allowed to stir over-
night at rt. The reaction mixture was then quenched by the
addition of saturated NH4Cl solution and extracted with
CH2Cl2. The combined extracts afforded a residue that
was puri®ed by ¯ash chromatography on silica gel using a
gradient of pentane/acetone.
3. Conclusions
The utility of the diethylzinc addition to phosphinoyl imines
as a method for the preparation of optically active amines
has been demonstrated. It has been shown that this metho-
dology is extendable to substrates other than N-(diphenyl-
phosphinoyl)benzalimine and that good enantioselectivities
can be obtained using 1b as a chiral auxiliary. Although the
addition reaction is still performed using a full equivalent of
the chiral auxiliary, it should be noted that approximately
90% of the auxiliary could be recovered during work-up and
re-used without any loss of optical purity of the product.
Compounds 3a,3b,c,4h,6,8 3c,4h 3g,3b 3h3b,c,4h,9 and 3i9 were
obtained with the yields and enantioselectivities shown in
Table 1. Racemic samples for HPLC comparison were
prepared by addition of EtMgBr to imines 2 in THF/ether.
4. Experimental
For general experimental information see Ref. 7. Flash
chromatography was performed on silica gel (Matrex 60A,
37±70 mm). TLC's were performed on precoated plates,
silica gel 60 F254, purchased from Merck. HPLC analyses
were carried out using a chiral column (ChiralCelOD-H or
Chiralpak-AD), an UV detector and the appropriate mixture
of iPrOH and hexane (see below).
4.2.1. N-[1-(3-Pyridyl)propyl]-P,P-diphenylphosphinoyl-
amide (3d). This compound was obtained as a low melting
white solid in 70% yield and 87% ee; HPLC conditions:
Chiralpak AD, 10% iPrOH in hexane, 1.0 mL/min, retention
times 30.3 min (minor) and 47.6 min (major). Rf 0.10 (pen-
24
tane/acetone: 1/1); [a]D ˆ212.4 (c 5.5, CH2Cl2); IR (neat,
cm21) 3401, 1645, 1438, 1181 and 1124; 1H NMR
(400 MHz, CDCl3) d 0.79 (3H, t, Jˆ7.6 Hz), 1.89 (2H,
ddq, Jˆ13.0, 7.6, 5.6 Hz), 3.43 (1H, br s), 3.75 (1H, m),
7.51 (13H, m) and 8.41 (1H, m); 13C NMR (100 MHz,
CDCl3) d 10.5, 32.1 (d, JC±Pˆ4.5 Hz), 54.8, 128.2, 128.3,
128.5, 131.6, 131.8, 131.9, 132.0, 134.2 and 135.6; MS (EI)
m/z (rel. intensity) 337 (M1, 8%), 308 (16), 307 (55), 231
(11), 219 (31), 216 (16), 201 (100), 183 (10), 173 (11), 169
(14), 168 (17) and 107 (10). HRMS calcd for C20H21N20P
336.1391, found 336.1392.
Compounds 2a,4a±c,e 2b,4g 2c,4f 2e,4d,e 2f, 4c,g 2g, 4c±e 2h, 4c±e
2i4f,j and 2k4b,c,g were prepared following a literature
procedure.4e
4.1. General procedure
4.1.1. N-(3-Pyridylmethylidene)-P,P-diphenylphosphi-
namide (2d). This compound was prepared following a
literature procedure4i and was obtained in 65% yield as a
white solid. Mpˆ129±1308C; IR (neat, cm21) 3435, 1620,
4.2.2. N-[1-(4-Methoxyphenyl)propyl]-P,P-diphenylphos-
phinoylamide (3e). This compound was obtained as a
white solid in 91% yield and 98% ee; HPLC conditions:
1
1199, 1125 and 695; H NMR (400 MHz, CDCl3) d 7.46
(7H, m), 7.94 (4H, m), 8.32 (1H, ddd, Jˆ8.0, 6.0, 2.0 Hz),
8.78 (1H, dd, Jˆ4.4, 2.0 Hz), 9.15 (1H, d, Jˆ2.0 Hz) and
9.38 (1H, d, JH±Pˆ31.2 Hz); 13C NMR (100 MHz, CDCl3) d
123.8, 128.5, 128.6, 131.5, 131.6, 132.0, 136.2, 151.9, 153.9
and 171.3 (d, JC±Pˆ7.6 Hz); MS (EI) m/z (rel. intensity) 306
(M1, 100%), 201 (40), 182 (17) and 181 (52). HRMS: calcd
for C18H15N2OP 306.0922, found 306.0923.
i
ChiralCel OD-H, 5% PrOH in hexane, 0.5 mL/min, reten-
tion times 36.3 min (minor) and 40.5 min (major). Rf 0.20
24
(pentane/acetone: 2/1), mpˆ112±1138C; [a]D ˆ229.3
(c 2.97, CH2Cl2); IR (neat, cm21) 3208, 1612, 1513 and
1180; 1H NMR (400 MHz, CDCl3) d 0.76 (3H, t,
Jˆ7.6 Hz), 1.90 (2H, ddq, Jˆ13.0, 7.6, 5.6 Hz), 3.16 (1H,
m), 3.79 (3H, s), 4.05 (1H, m), 6.81 (2H, m), 7.07 (2H, m),
7.41 (6H, m) and 7.81 (4H, m); 13C NMR (100 MHz,
CDCl3) d 10.6, 32.5 (d, JC±Pˆ3.8 Hz), 55.2, 56.6, 113.8,
127.6, 128.29, 128.33, 128.5, 131.75, 131.84 and 132.5;
MS (EI) m/z (rel. intensity) 365 (M1, 5%), 337 (21), 336
(96), 219 (14), 201 (61), 165 (13) and 164 (100). Anal.
Calcd for C22H24NO2P: C, 72.31; H, 6.62; N, 3.83. Found:
C, 72.11; H, 6.62; N, 3.86.
4.1.2. N-Biphenylmethylidene-P,P-diphenylphosphina-
mide (2j). This compound was prepared following a litera-
ture procedure4e and was obtained in 55% yield as a pale
yellow solid. Mpˆ121±1228C; IR (neat, cm21) 3234, 1602,
1
1185, 1125 and 695; H NMR (400 MHz, CDCl3) d 7.45
(9H, m), 7.63 (2H, app. d, Jˆ7.2 Hz), 7.72 (2H, app. d,
Jˆ8.0 Hz), 7.93 (4H, m), 8.08 (2H, app. d, Jˆ8.0 Hz) and
9.35 (1H, d, JH±Pˆ32.0 Hz); 13C NMR (100 MHz, CDCl3) d
127.2, 127.6, 128.3, 128.4, 128.5, 129.0, 130.7, 131.5,
131.6, 131.8, 139.8, 146.4 and 173.2 (d, JC±Pˆ7.6 Hz);
MS (EI) m/z (rel. intensity) 381 (M1, 3%), 218 (12), 217
4.2.3. N-(1-Biphenylpropyl)-P,P-diphenylphosphinoyl-
amide (3j). This compound was obtained as a white solid
in 70% yield and 97% ee; HPLC conditions: Chiralpak AD,

1618
P. Pinho, P. G. Andersson / Tetrahedron 57 (2001) 1615±1618
10% iPrOH in hexane, 1.0 mL/min, retention times 33.0 min
(major) and 37.1 min (minor). Rf 0.27 (pentane/acetone: 2/
2. For a review on catalytic enantioselective additions to imines,
see: (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
For a recent example, see: (b) Sato, I.; Kodaka, R.; Shibata, T.;
Hirokawa, Y.; Shirai, N.; Ohtake, K.; Soai, K. Tetrahedron:
Asymmetry 2000, 11, 2271.
24
1), mpˆ150±1518C; [a]D ˆ276.1 (c 4.61, CH2Cl2); IR
1
(neat, cm21) 3181, 1438 and 1187; H NMR (400 MHz,
CDCl3) d 0.83 (3H, t, Jˆ7.6 Hz), 1.95 (2H, ddq, Jˆ13.0,
7.6, 5.6 Hz), 3.27 (1H, m), 4.15 (1H, m), 7.41 (15H, m) and
7.83 (4H, m); 13C NMR (100 MHz, CDCl3) d 10.6, 32.4 (d,
JC±Pˆ3.8 Hz), 56.8, 127.0, 127.1, 127.2, 128.2, 128.3,
128.4, 128.5, 128.7, 131.8, 131.9, 132.5 and 132.6; MS
(EI) m/z (rel. intensity) 412 (M1, 4%), 383 (15), 382 (60),
219 (23), 211 (21), 210 (100), 202 (12) and 201 (68). Anal.
Calcd for C27H26NOP: C, 78.81; H, 6.37; N, 3.40. Found: C,
78.63; H, 6.50; N, 3.47.
3. (a) Andersson, P. G.; Guijarro, D.; Tanner, D. Synlett 1996, 727.
(b) Andersson, P. G.; Guijarro, D.; Tanner, D. J. Org. Chem.
1997, 62, 7364. (c) Guijarro, D.; Pinho, P.; Andersson, P. G.
J. Org. Chem. 1998, 63, 2530. (d) Brandt, P.; Hedberg, C.;
Lawonn, K.; Pinho, P.; Andersson, P. G. Chem. Eur. J. 1999,
5, 1692.
4. For the preparation of N-(diphenylphosphinoyl) imines, see:
(a) Krzyzanowska, B.; Stec, W. J. Synthesis 1978, 521.
(b) Boyd, D. R.; Jennings, W. B.; McGuckin, R. M.;
Rutherford, M.; Saket, B. M. J. Chem. Soc., Chem. Commun.
1985, 582. (c) Boyd, D. R.; Malone, J. F.; McGuckin, M. R.;
Jennings, W. B.; Rutherford, M.; Saket, B. M. J. Chem. Soc.,
Perkin Trans. 2 1988, 1145. (d) Jennings, W. B.; Lovely, C. J.
Tetrahedron Lett. 1988, 29, 3725. (e) Jennings, W. B.; Lovely,
C. J. Tetrahedron 1991, 47, 5561. (f) Soai, K.; Hatanaka, T.;
Miyazawa, T. J. Chem. Soc., Chem. Commun. 1992, 1097.
(g) Cantrill, A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M. I.;
Raphy, J.; Sweeney, J. B. Chem. Commun. 1996, 2631.
(h) Suzuki, T.; Shibata, T.; Soai, K. J. Chem. Soc., Perkin
Trans. 1 1997, 2757. (i) Hayase, T.; Osanai, S.; Shibata, T.;
Soai, K. Heterocycles 1998, 48, 139. (j) Hou, X. L.; Yang,
X. F.; Dai, L. X.; Chen, X. F. Chem. Commun. 1998, 747.
5. For an example of a solvent study, see: Soai, K.; Suzuki, T.;
Shono, T. J. Chem. Soc., Chem. Commun. 1994, 317.
4.1.6. N-[1-(4-Bromophenyl)propyl]-P,P-diphenylphos-
phinoylamide (3k). This compound was obtained as a
white solid in 65% yield and 94% ee; HPLC conditions:
i
ChiralCel OD-H, 5% PrOH in hexane, 0.5 mL/min, reten-
tion times 27.8 min (minor) and 32.7 min (major). Rf 0.21
24
(pentane/acetone: 2/1), mpˆ131±1328C; [a]D ˆ245.8 (c
1
4.03, CH2Cl2); IR (neat, cm21) 3153, 1438 and 1186; H
NMR (400 MHz, CDCl3) d 0.79 (3H, t, Jˆ7.6 Hz), 1.85
(2H, ddq, Jˆ13.0, 7.6, 5.6 Hz), 3.24 (1H, m), 4.06 (1H,
m), 7.02 (2H, app. d, Jˆ8.4 Hz), 7.39 (8H, m) and 7.79
(4H, m); 13C NMR (100 MHz, CDCl3) d 10.5, 32.3 (d, JC±P
ˆ3.8 Hz), 56.5, 128.2, 128.3, 128.4, 131.5, 131.7, 131.8,
132.4 and 132.5; MS (EI) m/z (rel. intensity) 416 and 414
(M1, 2%), 386 (13), 385 (60), 384 (14), 323 (60), 219 (51),
214 (23), 212 (23), 202 (14), 201 (100). Anal. Calcd for
C21H21BrNOP: C, 60.88; H, 5.11; N, 3.38. Found: C,
61.02; H, 5.18; N, 3.47.
Á
6. Jimeno, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.;
Riera, A. Tetrahedron Lett. 1999, 40, 777.
7. Bertilsson, S. K.; Tedenborg, L.; Alonso, D. A.; Andersson,
P. G. Organometallics 1999, 18, 1281.
Acknowledgements
8. (a) Hutchins, R. O.; Abdel-Magid, A.; Stercho, Y. P.;
Wambsgans, A. J. Org. Chem. 1987, 52, 702. (b) Weber, B.;
Seebach, D. Tetrahedron 1994, 50, 6117. (c) Ramon, D. J.; Yus,
M. Tetrahedron: Asymmetry 1997, 8, 2479.
We thank the Swedish Natural Research Council (NFR),
The Swedish Foundation for Strategic Research (SSF) and
The Swedish Research Council for Engineering Sciences
(TFR) for generous ®nancial support.
9. Suzuki, T.; Hirokawa, Y.; Ohtake, K.; Shibata, T.; Soai, K.
Tetrahedron: Asymmetry 1997, 8, 4033.
References
1. For a review, see: (a) Noyori, R.; Kitamura, M. Angew. Chem.
Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.; Niwa, S. Chem. Rev.
1992, 92, 833.