Room-temperature highly diastereoselective Zn-mediated allylation of chiral N-tert-butanesulfinyl imines: Remarkable reaction condition controlled stereoselectivity reversal

Article abstract of DOI:10.1021/ol062216x

(Chemical Equation Presented) An efficient method for the highly diastereoselective synthesis of chiral homoallylic amines by Zn-mediated allylation of chiral N-tert-butanesulfinyl imines at room temperature was developed. By simply tuning the reaction co

Full text of DOI:10.1021/ol062216x

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4979-4982
Room-Temperature Highly
Diastereoselective Zn-Mediated
Allylation of Chiral N-tert-Butanesulfinyl
Imines: Remarkable Reaction Condition
Controlled Stereoselectivity Reversal
Xing-Wen Sun,† Ming-Hua Xu,*,†,‡ and Guo-Qiang Lin*,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
xumh@mail.sioc.ac.cn; lingq@mail.sioc.ac.cn
Received September 7, 2006
ABSTRACT
An efficient method for the highly diastereoselective synthesis of chiral homoallylic amines by Zn-mediated allylation of chiral N-tert-butanesulfinyl
imines at room temperature was developed. By simply tuning the reaction conditions, the method allows the achievement of a highly remarkable
opposite stereocontrol, affording the desired stereochemical outcome in good yield and with excellent diastereoselectivity (up to 98% dr).
With N-sulfinyl ketimines, the corresponding quaternary carbon-containing chiral homoallylic amines could also be produced.
The asymmetric addition of allylic nucleophiles to the
carbonyl imino derivatives has been established as a powerful
method for the synthesis of chiral homoallylic amines1 which
are important precursors to numerous organic compounds.
Among the strategies developed, diastereoselective allyl
addition to chiral auxiliary derived imines has received major
attention.1b,2 With appropriate chiral auxiliaries, the reaction
can be carried out stereoselectively and provides enantiopure
amines effectively. Examples involving chiral R-amino acid
derivatives,2a-d sulfinyl imines,2e-g and hydrazones2h-j have
shown some success. In many cases, however, the diastereo-
selectivity and the efficiency of these reactions are not
predictable, and vary upon the change of the reaction
substrates as well as the allylic nucleophiles. With the same
auxiliary, the dramatic reversal of the stereoselectivity has
been observed, but often gave low diastereoselectivity.3 The
exploration of new approaches for readily preparing both of
the enantiomers of homoallylic amines using one chiral
auxiliary has been a subject of interest. Herein, we4 report
an efficient and practical synthesis of each of chiral homo-
allylic amines based on Zn-mediated allylation to chiral (R)-
N-tert-butanesulfinyl imines. By simply varying the reaction
(2) For examples, see: (a) Basile, T.; Bocoum, A.; Savoia, D.; Umani-
Ronchi, A. J. Org. Chem. 1994, 59, 7766. (b) Ken Lee, C.-L.; Ling, H. Y.;
Loh, T.-P. J. Org. Chem. 2004, 69, 7787. (c) van der Sluis, M.; Dalmolen,
J.; de Lange, B.; Kaptein, B.; Kellogg, R. M.; Broxterman, Q. B. Org. Lett.
2001, 3, 3943. (d) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y.
Tetrahedron Lett. 1997, 38, 865. (e) Hua, D. H.; Miao, S. W.; Chen, J. S.;
Iguchi, S. J. Org. Chem. 1991, 56, 4. (f) Cogan, D. A.; Liu, G.-C.; Ellman,
J. Tetrahedron 1999, 55, 8883. (g) Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2004, 15, 3823. (h) Enders, D.; Chelain, E.; Raabe, G. Bull.
Soc. Chim. Fr. 1997, 134, 299. (i) Friestad, G. K.; Ding, H. Angew. Chem.,
Int. Ed. 2001, 40, 4491. (j) Cook, G. R.; Maity, B. C.; Kargbo, R. Org.
Lett. 2004, 6, 1741. (k) Yanada, R.; Negoro, N.; Okaniwa, M.; Ibuka, T.
Tetrahedron 1999, 55, 13947. (l) Hunt, J. C. A.; Lloyd, C.; Moody, C. J.;
Slawin, A. M. Z.; Takle, A. K. J. Chem. Soc., Perkin Trans. 1 1999, 3443.
(m) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune,
Y. J. Org. Chem. 2005, 70, 3464.
† Shanghai Institute of Organic Chemistry.
‡ Shanghai Institute of Materia Medica.
(1) For reviews: (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(b) Ding, H.; Friestad, G. K. Synthesis 2005, 2815.
10.1021/ol062216x CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/22/2006

conditions, the method allows the achievement of a highly
remarkable opposite stereocontrol.
Our studies to develop the above proposed reactions were
initiated by using (R)-N-sulfinyl imine 1a as a substrate and
in situ generated allylzinc bromide as the allylation reagent
in THF. Unlike the allylindium addition2g that needs to be
carried out at 60 °C for completion (4 h), the reaction
proceeded very smoothly at room temperature to afford the
product 2a in 99% yield and 90:10 (1S:1R)7 dr in 30 min
(Table 1, entry 1). Not surprisingly, the observed stereocon-
Previously, the diastereoselective allylmagnesium2f and
allylindium2g addition to chiral N-tert-butanesulfinyl imines
have been reported by Ellman and Foubelo, respectively. In
their studies, a six-membered chair transition-state model was
proposed (Figure 1, TS-1), in which the allylmetal (M )
Table 1. Screening and Optimization of the Reaction
Conditionsa
Zn
time yieldc
drd
entry solventb (equiv)
additive
(h) (%) (1S:1R)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
DMF
DMF
DMSO
HMPA
HMPA
THF
1.5 none
0.5 99
90:10
99:1
Figure 1. Mechanistic proposals on stereocontrol.
1.5 In(OTf)3 (1.1 equiv) 12
2.0 In(OTf)3 (1.1 equiv) 10
3.0 In(OTf)3 (1.3 equiv) 10
2.0 TMEDA (2.0 equiv) 12
2.0 HMPA (2.0 equiv)
2.0 none
2.0 TMEDA (2.0 equiv) 12
2.0 none
2.0 none
2.0 H2O (10 µL)
2.0 H2O (10 µL)
73
93
97
99
99
99
98
98
99
97
81
98:2e
99:1e
81:19
53:47
38:62
16:84
32:68
26:74
1:99e
72:28
Mg, In) was coordinated to the sulfinyl oxygen. For example,
when (R)-N-tert-butanesulfinyl imine is employed, the si-
face addition will be favored, thus leading to the majority
of (S)-amine product. With this framework in mind, we
assumed that an acyclic transition state (TS-2) might be
engaged if a rather strong Lewis acid was presented in the
reaction system. As a result, the chelation of Lewis acid with
both nitrogen and sulfinyl oxygen of imine would direct allyl
attack selectively from the sterically unblocked si-face to
give (S)-amine. On the other hand, we can assume another
type of acyclic transition state model TS-3, in which the
allylmetal is coordinated to additional Lewis bases rather
than the sufinyl oxygen. As depicted, the uncoordinated
N-sulfinyl group adopts an approximate synperiplanar con-
figuration.5 The allyl addition to the less hindered re-face
of imine would be preferred, thereby facilitating (R)-amine
formation. Thus, with the unique nature of chiral N-tert-
butanesulfinyl imine, we rationalized that the opposite
stereocontrol of the allylation might be achieved using
coordination protocol.6
1
1
4
1
12
12
10
11
12
a Reaction was performed with 0.25 mmol of imine 1a in 5 mL of solvent
at rt. b Dry solvent. c Isolated yield. d Determined by 1H NMR of the crude
materials. e Enantiomeric ratio by HPLC, see ref 7.
trol is consistent with the cyclic chelation model TS-1.
Taking into account the proposed acyclic transition state
model TS-2, we investigated the addition of Lewis acids.
Ideally, those Lewis acidic activities stronger than Zn(II) will
work. Under similar reaction conditions, various Lewis acids
were examined as additives. Among them, In(OTf)3 was
found to be the best, a significant improvement in diaste-
reoselectivity up to 99:1 could be obtained (entries 2-4).
Notably, the use of 2 equiv of Zn (entry 3) or more (entry
4) was found useful to provide a higher yield than 1.5 equiv
(entry 2).
Encouraged by the above success, we next attempted to
test the possibility of stereoselectivity reversal as hypoth-
esized in TS-3. Lewis base TMEDA was initially examined
as additive, despite a moderate diastereoselectivity (1S/1R
81:19), it shows the potential of opposite stereocontrol (entry
(3) For selected examples, see: (a) Yamamoto, Y.; Nishii, S.; Maruyama,
K.; Komatsu, T.; Itoh, W. J. Am. Chem. Soc. 1986, 108, 7778. (b) Ukaji,
Y.; Kume, K.; Watai, T.; Fujisawa, T. Chem. Lett. 1991, 173. (c) Basile,
T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59,
7766. (d) Alvaro, G.; Savoia, D. Tetrahedron: Asymmetry 1996, 7, 2083.
(e) Cainelli, G.; Giacomini, D.; Galletti, P.; Quintavalla, A. Eur. J. Org.
Chem. 2002, 3153. (f) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M.
D.; Diez, R.; Galvez, J. A. Eur. J. Org. Chem. 2002, 3763. (g) Alvaro, G.;
Savoia, D. Synlett 2002, 651.
(4) For our recent work involving chiral N-tert-butanesulfinyl imines,
see: (a) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 3953. (b)
Zhong, Y.-W.; Isumi, K.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2004, 6, 4747.
(c) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Isumi, K.; Xu, M.-H.; Lin, G.-
Q. J. Am. Chem. Soc. 2005, 127, 11956.
(5) For related crystal structures and theoretical calculations support,
see: (a) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J. Am.
Chem. Soc. 2001, 123, 1539. (b) Owens, T. D.; Souers, A. J.; Ellman, J. A.
J. Org. Chem. 2003, 68, 3. (c) Schenkel, L. B.; Ellman, J. A. Org. Lett.
2003, 5, 545. (d) Tietze, L. F.; Schuffenhauer, A. Eur. J. Org. Chem. 1998,
1629. (e) Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc.,
Perkin Trans. 2 2000, 43.
(6) Examples of stereoselectivity reversal using N-tert-butanesulfinyl
imines have been reported for organomagnesium or organolithium reagents
addition, Strecker reaction and very recently hydride reduction; see: (a)
Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303. (b) Lu,
B. Z.; Senanayake, C.; Li, N.; Han, Z.; Bakale, R. P.; Wald, S. A. Org.
Lett. 2005, 7, 2599. (c) Wang, H.; Zhao, X.; Li, Y.; Lu, L. Org. Lett. 2006,
8, 1379. (d) Colyer, J. T.; Andersen, N. G.; Tedrow, J. S.; Soukup, T. S.;
Faul, M. M. J. Org. Chem. 2006, 71, 6859.
(7) The configuration was assigned by comparison with literature data
for the free homoallylic amine; see the Supporting Information for details.
4980
Org. Lett., Vol. 8, No. 21, 2006

5 vs 1). With HMPA, a diastereomeric ratio of 53:47 (1S/
1R) was observed (entry 6). When DMF, DMSO or HMPA
was directly used as solvent instead of THF, a clear reversal
of the diastereofacial selectivity was attained (entries 7, 9,
and 10). More excitingly, performing the reaction with
TMEDA in DMF resulted in a much better 2a (1R) selectivity
(1S/1R 16:84, entry 8). These results suggests that the zinc-
(II) ion is coordinated to the solvent molecules or TMEDA.
To further improve this opposite stereocontrol, the reaction
conditions were carefully screened. Eventually, we were very
pleased to find that the desired 2a (1R) product could be
isolated in 97% yield and with 98% de (1:99 dr) in HMPA
in the presence of proper amount of H2O8 (entry 11). The
critical role of H2O in the reaction system is not clear at this
time, it seems that H2O disrupts the chelation of Zn(II) with
sufinyl imine (entry 12).
proved to be excellent substrates in both systems, giving 90-
98% de in allylation. For aliphatic imines (entries 11-14),
the HMPA system gave even better diastereoselectivities.
Thus, with two different reaction systems, the opposite
stereocontrol could be easily achieved.
We also examined N-sulfinyl ketimines 3 as substrates to
produce the corresponding quaternary carbon-containing
chiral homoallylic amines. The asymmetric allylation of
ketoimines is a very challenging topic in organic synthesis,
to our knowledge, only a limited number of examples have
been reported to date.9 Ketimines are relatively less reactive
than aldimines, in our case, 3a did not even react with
allylzinc bromide in THF when no additive was used. To
our delight, using the conditions of entry 4 in Table 1 for
THF system, the reactions proceeded well to a series of
ketimine substrates and afforded the desired products in
moderate yields and excellent distereomeric ratios (Table 3).
With two optimized conditions established, we began to
evaluate the reaction scope. A wide variety of N-sulfinyl
aldimines (1) were investigated using the reaction conditions
of entry 3 and 11 in Table 1, respectively (Table 2).
Table 3. Diastereoselective Allylation to
(R)-N-tert-Butanesulfinyl Ketimines with THF Systema
Table 2. Diastereoselective Allylation to
(R)-N-tert-Butanesulfinyl Aldimines with Two Different
Reaction Systemsa
entry
3
R
4
yieldb (%)
drc
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
69
67
89
76
83
85
79
66
81
97:3
96:4
96:4
95:5
97:3
97:3
97:3
95:5
98:2
4-MeC6H4
4-CF3C6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
THF systemb
HMPA systemc
yieldd (%) dre
entry
1
R
yieldd (%)
dre
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a C6H5
93
98
98
93
95
91
91
95
98
81
98
99
93
96
92
83
98:2
98:2
98:2
97:3
96:4
95:5
97:3
98:2
98:2
95:5
86:14
97:3
88:12
94:6
90:10
91:9
97
97
96
99
88
81
73
89
99
86
97
94
92
94
93
87
1:99
1:99
3:97
2:98
3:97
2:98
2:98
3:97
2:98
3:97
4:96
3:97
5:95
2:98
4:96
6:94
3-MeC6H4
3-ClC6H4
1b 4-FC6H4
1c 4-ClC6H4
1d 4-BrC6H4
1e 4-MeC6H4
a Reactions were carried out with 0.25 mmol of imine 3, 0.75 mmol of
Zn/allyl bromide, and 0.325 mmol of In(OTf)3 in 5 mL of dry THF at rt.
b Isolated yield. c Determined by 1H NMR of the crude materials.
1f
4-MeOC6H4
1g 2-ClC6H4
1h 2-MeC6H4
1i
1j
1k cyclopropyl
1l cyclohexyl
1m ethyl
1n isopropyl
1o phenethyl
1p phenetheneyl
3-BrC6H4
â-naphthyl
In most cases, 90-96% de’s were observed. These results
are among the best in asymmetric allylation of aromatic
ketoimines. Presumably, the added Lewis acid In(OTf)3
increases the reactivity of ketimines. With the optimized
HMPA system, however, ketimines are not activated; thus,
the reactions did not take place.
In summary, we have developed a highly diastereoselective
Zn-mediated allylation of chiral N-tert-butanesulfinyl imines.
The method enables efficient and general synthesis of
enantiomerically enriched homoallylic amines including
quaternary ones at room temperature in high yields. By
simply tuning the reaction solvent and additive, a remarkable
reversal of diastereofacial selectivity can be achieved to
afford the desired stereochemical outcome. Further studies
a Reactions were carried out with 0.25 mmol of imine 1, 0.5 mmol of
Zn/allyl bromide, and additive in 5 mL of dry solvent at rt. b 0.275 mmol
of In(OTf)3 was used as additive. c 10 µL of H2O was used as additive.
d Isolated yield. e Determined by H NMR of the crude materials.
1
Gratifyingly, all the reactions went smoothly and afforded
the allylation products in good yields as well as high
diastereoselectivities. N-sulfinyl imines of aromatic aldehyde
(9) For recent advances on asymmetric allylation of ketimines, see: (a)
Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7687. (b) Berger, R.; Duff, K.; Leighton,
J. L. J. Am. Chem. Soc. 2004, 126, 5686. For examples of allylmagnesium
bromide addition to N-sulfinyl ketoimines, see ref 2e,f.
(8) The amount of H2O has a substantial influence on the reaction yield
and diastereoselectivity; see the Supporting Information for details. Also,
a similar water effect was found for additions to imines, see refs 2a and 6c.
Org. Lett., Vol. 8, No. 21, 2006
4981

are being conducted to better understand the mechanistic
details of the chelation control.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20402018, 203900506),
Shanghai Rising-Star Program (05QMX1467), and the
Chinese Academy of Sciences is gratefully acknowledged.
OL062216X
4982
Org. Lett., Vol. 8, No. 21, 2006