Samarium diiodide-induced asymmetric synthesis of optically pure unsymmetrical vicinal diamines by reductive cross-coupling of nitrones with N-tert-butanesulfinyl imines

Article abstract of DOI:10.1021/ol048444d

(Chemical Equation Presented) An efficient method for the preparation of optically pure unsymmetrical vicinal diamines by the SmI₂-induced reductive cross-coupling of nitrones with chiral N-tert-butanesulfinyl imines was developed. This is the

Full text of DOI:10.1021/ol048444d

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3953-3956
Samarium Diiodide-Induced Asymmetric
Synthesis of Optically Pure
Unsymmetrical Vicinal Diamines by
Reductive Cross-Coupling of Nitrones
with N-tert-Butanesulfinyl Imines
Yu-Wu Zhong, Ming-Hua Xu,* and Guo-Qiang Lin
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
xumh@mail.sioc.ac.cn
Received August 6, 2004
ABSTRACT
An efficient method for the preparation of optically pure unsymmetrical vicinal diamines by the SmI2-induced reductive cross-coupling of
nitrones with chiral N-tert-butanesulfinyl imines was developed. This is the first successful example of the highly diastereoselective and
enantioselective cross-coupling between two different imine species. It provides a straightforward access to enantiopure unsymmetrical vicinal
diamines that are widely applicable in asymmetric synthesis.
Optically pure vicinal diamines have played significant roles
in organic chemistry due to their broad utility, serving both
as useful units for many biologically active compounds and
as important chiral ligands or chiral auxiliaries for asym-
metric synthesis.1 In the past several years, although much
attention has been paid to the development of methods for
their preparation, the highly efficient asymmetric synthesis
of enantiopure vicinal diamines remains a challenging topic.
Among the approaches developed such as resolution,2 asym-
metric diamination,3 aza-Henry reaction,4 nucleophilic ad-
dition to imine derivatives,5 and alkylation of glycine amide
derivatives,6 those that involve stereoselective C-C bond
formation in a single transformation are of particular interest.
The simplest and most direct method for the preparation
of vicinal diamines is the reductive coupling between two
imine species. Generally, it is applied to the synthesis of
symmetrical 1,2-diamines via homocoupling.7,8 Efficient
cross-coupling of two different imines is apparently rather
difficult, mainly due to the competition of the homocoupling
(4) For a recent highlight article, see: Westermann, B. Angew. Chem.,
Int. Ed. 2003, 42, 151 and references therein.
(5) (a) Reetz, M. T.; Jaeger, R.; Drewlies, R.; Hu¨bel, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 103. (b) Alexakis, A.; Tomassini, A.; Chouillet,
C.; Roland, S.; Mangeney, P.; Bernardinelli, G. Angew. Chem., Int. Ed.
2000, 39, 4093. (c) Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002,
124, 6538. (d) Viso, A.; Pradilla, R. F. de la; Garc´ıa, A.; Guerrero-Strachan,
C.; Alonso, M.; Tortosa, M.; Flores, A.; Mart´ınez-Ripoll, M.; Fonseca, I.;
Andre´, I.; Rodr´ıguez, A. Chem.sEur. J. 2003, 9, 2867.
(6) Ooi, T.; Sakai, D.; Takeuchi, M.; Tayama, E.; Maruoka, K. Angew.
Chem., Int. Ed. 2003, 42, 5868.
(1) For a review on the chemistry of vicinal diamines, see: Lucet, D.;
Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(2) Selected examples: (a) Jacobsen, E. N.; Gao, Y.; Hong, Y.-P., Nie,
X.; Zepp, C. M. J. Org. Chem. 1994, 59, 1939. (b) Corey, E. J.; Lee,
D.-H.; Sarshar, S. Tetrahedron: Asymmetry 1995, 6, 3.
(3) (a) Mun˜iz, K.; Nieger, M.; Mansikkama¨ki, H. Angew. Chem., Int.
Ed. 2003, 42, 5958. (b) Mun˜iz, K.; Iaseto, A.; Nieger, M. Chem.sEur. J.
2003, 9, 5581.
(7) For selected homocoupling examples: (a) Kim, M.; Knettle, B. W.;
Dahle´n, A.; Hilmersson, G.; Flowers, R. A. Tetrahedron 2003, 59, 10397.
(b) Annunziata, R.; Benaglia, M.; Caporale, M.; Raimondi, L. Tetrahe-
dron: Asymmetry 2002, 13, 2727. (c) Selvakumar, K.; Harrod, J. F. Angew.
Chem., Int. Ed. 2001, 40, 2129. (d) Okaniwa, M.; Yanada, R.; Ibuka, T.
Tetrahedron Lett. 2000, 41, 1047. (e) Tanigushi, N.; Uemura, M. Synlett
1997, 51.
10.1021/ol048444d CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

of each imine substrate. To the best of our knowledge, only
one example of direct intermolecular cross-coupling of two
different imine species to give racemic 1,2-diamines was
reported;9 a new strategy is still in high demand. Recently,
Uemura10 and Py11 showed their success in the reductive
cross-coupling of carbonyl compounds with imine derivatives
mediated by SmI2.12,13 Given our interest in SmI2-mediated
asymmetric reactions,14 we decided to explore the possibility
of the SmI2-induced reductive cross-coupling between two
different imine species. Herein, we report our preliminary
results for the asymmetric synthesis of unsymmetrical chiral
vicinal diamines by SmI2-induced reductive cross-coupling
of nitrones with N-tert-butanesulfinyl imines.
alcohol, the reaction proceeded as we expected, and the 1,2-
diamine derivative 3 resulting from this reductive cross-
coupling was isolated as a single diastereomer17 in an
acceptable yield of 54% (Table 1, entry 1). The stereochem-
istry of the two newly formed carbon centers of diamine 3
was determined to be (R,R)- by X-ray crystallography (Figure
1).18 In our attempt to optimize the reaction conditions, we
It has been reported that nitrones (iminium ion equivalents)
could be added to the carbonyl compounds11 or the R,â-
unsaturated esters15 in the presence of SmI2. The mechanism
may involve an R-aza-nucleophilic species from SmI2 to the
nitrone group. As we know, Ellman’s N-tert-butanesulfinyl
imines16 have shown versatile application in the asymmetric
synthesis of amines. However, they have never been em-
ployed in the SmI2-mediated reactions. To check the potential
of the cross-coupling between these two species, we began
our investigation by examining the reaction of nitrone
compound 1 with (R)-N-tert-butanesulfinyl imine 2 (see
scheme in Table 1).
Table 1. Initial Examination of the Cross-Coupling Reaction
Conditions
Figure 1. X-ray crystal structure of the cross-coupling product 3
found that the yield of product 3 could be increased to 63%
when more SmI2 (3 equiv) was used (entry 2). A further
improvement of the yield (∼ 75%) was achieved by
employing a slight excess of either substrate (entries 3 and
4). The effect of tert-butyl alcohol in the reaction was
examined, and a relatively lower yield (46%) was obtained
in its absence (entry 5).
Encouraged by these results, the cross-coupling of various
nitrones with N-tert-butanesulfinyl imines using the reaction
conditions of entry 4 in Table 1 was then studied. The
experimental results are summarized in Table 2. In entries
1-6, a range of nitrones with diverse steric and electronic
properties were tested to react with sulfinyl aldimine 2. It
was found that the coupling yield and diastereoselectivity
were largely influenced by steric hindrance.19 A less hindered
entrya
1 (mmol)
2 (mmol)
SmI2 (mmol)
yield (%)b
1
2
3
4
0.5
0.5
0.5
0.7
0.5
0.5
0.5
0.6
0.5
0.6
1.0
1.5
1.5
1.5
1.5
54
63
76
75
46
5c
a All reactions were reacted for 3-4 h. b Isolated yield of the single
diastereomer. c Reaction was conducted in the absence of t-BuOH.
To our delight, when a solution of nitrone 1 and N-tert-
butanesulfinyl imine 2 in THF at -78 °C was treated with
2 equiv of SmI2 in the presence of 2 equiv of tert-butyl
(13) For recent reviews on SmI2 in organic synthesis, see: (a) Molander,
G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (b) Molander, G. A.; Harris,
C. R. Tetrahedron 1998, 54, 3321. (c) Krief, A.; Laval, A. M. Chem. ReV.
1999, 99, 9, 745. (d) Kagan, H. B. Tetrahedron 2003, 59, 10351.
(14) (a) Xu, M.-H.; Wang, W.; Lin, G.-Q. Org. Lett. 2000, 2, 2229. (b)
Wang, W.; Xu, M.-H.; Lei, X.-S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773. (c)
Xu, M.-H.; Wang, W.; Xia, L.-J.; Lin, G.-Q. J. Org. Chem. 2001, 66, 3953.
(d) Wang, W.; Zhong, Y.-W.; Lin, G.-Q. Tetrahedron Lett. 2003, 44, 4613.
(15) (a) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem., Int.
Ed. 2003, 42, 2265. (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229.
(16) (a) Ellman, J. A.; Evans, J. W. J. Org. Chem. 2003, 68, 9948. (b)
Ellman, J. A.; wens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(17) No other stereoisomer was observed according to 1H NMR analysis
of the crude material.
(8) For intramolecular coupling: (a) Taniguchi, N.; Hata, T.; Uemura,
M. Angew. Chem., Int. Ed. 1999, 38, 1232. (b) Kise, N.; Oike, H.; Okazaki,
E.; Yoshimoto, M.; Shono, T. J. Org. Chem. 1995, 60, 3980. (c) Pansare,
S. V.; Malusare, M. G. Tetrahedron Lett. 1996, 37, 2859.
(9) Shimizu, M.; Suzuki, I.; Makino, H. Synlett 2003, 1635.
(10) (a) Tanaka, Y.; Taniguchi, N.; Uemura, M. Org. Lett. 2002, 4, 835.
(b) Taniguchi, N.; Uemura, M. J. Am. Chem. Soc. 2000, 122, 8301.
(11) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int. Ed. 2002, 41,
1772.
(12) Related reductive cross-coupling of imines with aldehydes has been
carried out using samarium diiodide in the presence of NiI2, see: Machrouhi,
F.; Namy, J.-L. Tetrahedron Lett. 1999, 40, 1315.
(18) For X-ray structure-related data, see Supporting Information.
3954
Org. Lett., Vol. 6, No. 22, 2004

for the cross-coupling reactions (entries 12-14). Notably,
these obtained cross-coupling products that bear hydroxy-
lamino and sulfinylamino functions may be useful ligands
in asymmetric synthesis.
Table 2. SmI2-Induced Reductive Cross-Coupling of Nitrones
with N-tert-Butanesulfinyl Imines
Conversion of the cross-coupling product to the corre-
sponding free diamine could be easily accomplished in a
three-step reaction sequence. For example, as shown in
Scheme 1, deoxygenation of the hydroxylamino function of
Scheme 1
the coupling product 3 by Zn/Cu(OAc)2,21 followed by the
removal of the sulfinyl and benzyl group, afforded the
optically pure (R,R)-3-methyl-1-phenyl-butane-1,2-diamine
(4) in 87% overall yield.22
A plausible reaction mechanism for the observed stereo-
selective cross-coupling process is presented in Scheme 2.
1
a Isolated yield. b According to H NMR of the crude materials.
Scheme 2. Proposed Reaction Mechanism
nitrone (R1 ) n-hexyl) gave the best yield of 85% (entry 3).
However, when the R1 substituent became bulky, the yield
of the coupling product decreased, and in the case of entry
6 (R1 ) tert-butyl), only 22% of the product was produced.
In most cases, excellent diastereoselectivities were achieved,
and extremely high diastereoselectivities were observed when
isopropyl-, cyclohexyl-, and tert-butyl-substituted nitrones
were employed (entries 1, 2, and 6). Surprisingly, no reaction
occurred if both substrates were aromatic (R1 ) R2 ) Ph)
or aliphatic (R1 ) R2 ) iPr), probably due to the electronic
effect. We also investigated the reactions of nitrone 1 with
a variety of aromatic N-tert-butanesulfinyl imines containing
electron-donating or electron-withdrawing substituents at the
para position, and the cross-coupling products could be
formed in reasonable yields (entries 7-11). Reactions with
imines having electron-withdrawing substituents were much
faster (entries 9 and 10). For the diamines obtained in entries
9-11, it is noteworthy that the para-halogen or acetoxyl
substituent on the benzene ring would largely facilitate their
subsequent synthetic applications. For example, in entry 11,
the readily available phenol group would be a very useful
functionality to attach the chiral 1,2-diamine moiety onto
solid support materials.20 Different substituted long-chain
aliphatic nitrones were also found to be effective substrates
Upon treatment with SmI2, the nitrone 5 is first reduced to
generate probably an R-aza-nucleophilic anion (6) by two-
electron reduction, which then adds intermolecularly to the
CdN bond of the N-tert-butanesulfinyl imine. Two inde-
pendent experimental studies seem to be able to support this
hypothesis.23 First, mainly the reduced product of nitrone 1
(21) Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.; Trombini, C. Liebigs
Ann. Chem. 1992, 1289.
(22) Chiral HPLC showed 99.6% ee of its diacetate derivative. For
comparison, (S,S)-4 was also prepared by the reaction of nitrone 1 with
(S)-N-tert-butanesulfinyl imine 2; see Supporting Information for details.
(23) Other experimental results that may be supportive are as follows:
When nitrone 5 (R1 ) Ph) was treated with SmI2, the corresponding
homocoupling product was obtained in 75% yield, indicating a radical
mechanism and the formation of the nitrone radical. However, nitrone 5
(R1 ) Ph) did not react with N-tert-butanesulfinyl imine 2 in the presence
of SmI2 under similar conditions. Thus, this suggests that a radical-based
addition of the nitrone radical to the imine followed by further reduction
of the nitrogen-based radical may not be preferred.
(19) In most cases in Table 2, the yields of most of the cross-coupling
reactions are modest mainly due to the remaining starting material N-tert-
butanesulfinyl imines.
(20) For a recent example: Itsuno, S.; Tsuji, A.; Takahashi, M.
Tetrahedron Lett. 2003, 44, 3825.
Org. Lett., Vol. 6, No. 22, 2004
3955

by SmI2 was formed in the absence of N-tert-butanesulfinyl
imine 2. Second, no reaction occurred when only N-tert-
butanesulfinyl imine 2 was treated with SmI2. The tert-
butanesulfinyl group serves as a nice chiral directing group
in the reaction. Due to its steric bulkiness, the nitrone anion
approaches preferably from the Si-face of the CdN bond
(see 7), and formation of transition state 8 could be explained
by chelation control and steric repulsion between R1 and R2.
Therefore, the addition reaction takes place with very high
stereospecificity. Optically pure unsymmetrical vicinal di-
amine 9 is then afforded after protonation by tert-butyl
alcohol.
species. It provides straightforward access to enantiopure
vicinal diamines that are widely useful in asymmetric
synthesis. Further efforts are being directed toward exploring
the applicability of those cross-coupling products and their
corresponding diamines, both as chiral ligands in asymmetric
catalysis and as precursors in natural products synthesis.
Acknowledgment. Financial support from the National
Natural Science Foundation of China, the Major State Basic
Research Development Program (G2000077506), and the
Shanghai Municipal Committee of Science and Technology
is acknowledged.
In conclusion, we have developed an efficient method for
the preparation of optically pure unsymmetrical vicinal
diamines by the SmI2-induced reductive cross-coupling of
nitrones with chiral N-tert-butanesulfinyl imines. This is the
first successful example of highly diastereoselective and
enantioselective cross-coupling between two different imine
Supporting Information Available: Experimental pro-
cedure and characterization data, including X-ray crystal-
lographic data of 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL048444D
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Org. Lett., Vol. 6, No. 22, 2004