First asymmetric SmI2-induced cross-coupling of Cr(CO) 3 aromatic nitrone complexes with carbonyl compounds

Article abstract of DOI:10.1039/b405406g

The SmI₂-induced cross-coupling of Cr(CO)₃-complexed nitrones with carbonyl compounds is described. This highly chemo- and diastereoselective reaction affords enantiopure β-amino alcohol complexes in excellent yields.

Full text of DOI:10.1039/b405406g

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First asymmetric SmI2-induced cross-coupling of Cr(CO)3 aromatic
nitrone complexes with carbonyl compounds
Murielle Chavarot,a Michae¨l Rivard,a Franc¸oise Rose-Munch,*a Eric Rosea and Sandrine Pyb
a Laboratoire de Chimie Organique, UMR 7611, Universite´ P. et M. Curie, Tour 44 1er e´tage, BP181, 4
Place Jussieu, F-75252 Paris CEDEX 05, France. E-mail: rosemun@ccr.jussieu.fr
b LEDSS, UMR 5616, Universite´ J. Fourier, BP53, F-38041 Grenoble CEDEX 9, France
Received (in Cambridge, UK) 14th April 2004, Accepted 24th June 2004
First published as an Advance Article on the web 7th September 2004
The SmI2-induced cross-coupling of Cr(CO)3-complexed
Table 1 Cross-coupling of nitrones with carbonyl compounds
nitrones with carbonyl compounds is described. This highly
chemo- and diastereoselective reaction affords enantiopure
b-amino alcohol complexes in excellent yields.
b-Amino alcohols are an important class of ligands for asymmetric
synthesis.1 Their synthesis usually relies on transformations of
the chiral pool, thus limiting diversity in their design. Their
N-hydroxylamino derivatives have been far less studied, presum-
ably because of the lack of methods for their direct synthesis.
Therefore, new methods for the asymmetric synthesis of a
wide range of compounds in these two classes are highly desirable.
Recently, one of us reported a reductive cross-coupling of
nitrones with carbonyl compounds, yielding the corresponding
racemic b-N-hydroxylamino or b-amino alcohols with high
efficiency.2
In this communication, we wish to describe the first asymmetric
version of the SmI2-induced coupling of nitrones with carbonyl
compounds, based on chiral induction using planar chiral
(g6-arene) chromium tricarbonyl complexes.3 Such complexes
have emerged as valuable and versatile auxiliaries for several
reasons: i) the preparation of enantiopure planar chiral complexes
is well described, either by resolution of racemic mixtures,4 by
diastereoselective complexation4,5 or by asymmetric synthesis;6 ii)
they proved to be efficient building blocks for organic synthesis as
they induce high diastereoselectivities in a large variety of
reactions;7 iii) decomplexation of the arene ring is easily performed
at the end of the synthesis.
Although the chiral information could be introduced, in
principle, either on the carbonyl or on the nitrone partner,
organometallic nitrones were chosen as chiral substrates.8
Compared to the tricarbonylchromium complexed aldehydes or
imines, very few planar-chiral nitrones have been described to date.
To the best of our knowledge, most of these examples are limited to
N-methyl-derivatives, that were used either in 1,3-dipolar cycload-
dition reactions,9 or for the NMR determination of the
enantiomeric purity of their aldehyde precursors.10 Various
N-benzyl-nitrones 2 were prepared (Scheme 1) by condensation of
N-benzylhydroxylamine with the corresponding racemic tricarbo-
nylchromium benzaldehyde derivatives 1.11 When the achiral
organometallic nitrone 2a was reacted with acetone and SmI2,{ the
desired b-hydroxylamino alcohol 3a was obtained in 65% yield
(entry 1, Table 1) and no significant amount of any organometallic
by-product was isolated.
Entry Nitrone
R
R1
R2
Product Yield (%)a d.r.b
1
2
3
4
5
6
2a
2b
2c
2b
2b
2b
H
Me
Me Me 3a
Me Me 3b
65
95
93
88
96
83e
—
w 95 : 5
w 95 : 5
w 95 : 5
w 95 : 5c
w 95 : 5d
OMe Me Me 3c
Me
Me
Me
–(CH2)5– 3d
tBu
Et
H
H
3e
3f
a After purification. b At C7, determined by 1H NMR analysis of the
crude mixtures. c Diastereoisomeric ratio at C8 w 95 : 5. d Diaster-
eoisomeric ratio at C8 ~ 70 : 30. e Crude yield.
acetone{ (entries 2 and 3), giving the pure b-N-hydroxylamino
alcohols 3b and 3c in yields ¢ 90%. The coupling reaction is fast,
highly chemoselective, and completely diastereoselective, within the
1
limits of H NMR analysis of crude materials. Using cyclohex-
anone instead of acetone as the coupling partner (entry 4) did not
modify reactivity or selectivity. The reaction of nitrone 2b with
aldehydes was also highly chemoselective and led to the
corresponding b-N-hydroxylamino alcohols 3e and 3f in excellent
yields (entries 5 and 6). Remote diastereoselectivity at the carbon
C8 bearing the alcohol functionality seems to be dependent on the
size of the R2 group: while a single diastereomer was isolated from
the coupling of 2b with pivalaldehyde, a 70 : 30 diastereomeric
mixture was obtained from propionaldehyde.
X-Ray analysis of crystals of the racemic b-N-hydroxylamino
alcohol 3c12 (Fig. 1) allowed the determination of its relative
configuration, and an (S) configuration was revealed for the newly
created stereogenic benzylic carbon, coupled with the (pS)
configuration of the chromium complex.13 The NMR spectrum
The ortho-substituted nitrones 2b and 2c were also reacted with
Fig. 1 X-Ray structure of b-N-hydroxylamino alcohol 3c.
Scheme 1
2 3 3 0
C h e m . C o m m u n . , 2 0 0 4 , 2 3 3 0 – 2 3 3 1
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Notes and references
{ Typical procedure for the reductive cross-coupling: A solution of nitrone
(0.5 mmol in 10 mL) and of the carbonyl compound (1 equiv.) in THF was
cooled to 278 uC. A solution of SmI2 (0.1 mol L21, 10 mL, 2 equiv.) in
THF was then added drop by drop. The mixture was stirred at 278 uC for
30 min before being quenched by addition of saturated solutions of
Na2S2O3 (10 mL) and NaHCO3 (10 mL). The yellow mixture was
extracted by AcOEt. The combined organic layers were washed with a
saturated aqueous NaCl solution and dried over MgSO4. After
concentration in vacuo, the crude mixture was purified either by washing
with cyclohexane (3b, 3c and 3e) or by chromatography on silica gel (3a, 3d
and 3f) to afford the pure b-N-hydroxylamino alcohols.
For the one-pot synthesis of b-amino alcohols, 6 equivalents of SmI2 were
used, and the reaction mixture was stirred for 30 min at 278 uC, then
15 hours at room temperature.
1 For recent reviews on the synthesis of b-amino alcohols, see:
(a) D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96,
835; (b) S. C. Bergmeier, Tetrahedron, 2000, 56, 2561. For the use of
b-amino alcohols in enantioselective additions of organozinc reagents to
carbonyl compounds see: ; (c) K. Soai and S. Niwa, Chem. Rev., 1992,
92, 833; (d) L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757.
2 G. Masson, S. Py and Y. Valle´e, Angew. Chem., Int. Ed., 2002, 41, 1772.
3 Selected references: (a) M. J. Morris, in Comprehensive Organometallic
Chemistry II; Ed. E. W. Abel, F. G. A. Stone and G. Wilkinson; Elsevier
Science Ltd; Oxford, 1995; Vol. 5, p. 471; (b) F. Rose-Munch and
E. Rose, Curr. Org. Chem., 1999, 3, 445; (c) A. R. Pape, K. P. Kaliappan
and E. P. Ku¨ndig, Chem. Rev., 2000, 100, 2917; (d) S. E. Gibson and
H. Ibrahim, Chem. Commun., 2002, 2465; (e) F. Rose-Munch and
E. Rose, Eur. J. Inorg. Chem., 2002, 6, 1269.
4 A. Alexakis, P. Mangeney, I. Marek, F. Rose-Munch, E. Rose and
A. Semra, J. Am. Chem. Soc., 1992, 114, 8288 and references therein.
5 J. Tweddell, D. A. Hoic and G. C. Fu, J. Org. Chem., 1997, 62, 8286.
6 Selected references: (a) A. Alexakis, T. Kanger, P. Mangeney, F. Rose-
Munch, A. Perrotey and E. Rose, Tetrahedron: Asymmetry, 1995, 6,
2135; (b) C. Bolm and K. Mun˜iz, Chem. Soc. Rev., 1999, 28, 51;
(c) S. E. Gibson and E. G. Reddington, Chem. Commun., 2000, 989;
(d) L. E. Overman, C. E. Owen and G. G. Zipp, Angew. Chem., Int. Ed.,
2002, 41, 3884.
Scheme 2 Reagents and conditions: a: 1 eq MeCOMe, 2eq SmI2, THF,
278 uC, 30 min. b: 1 eq MeCOMe, 6 eq SmI2, THF, 278 uC to RT, 15 h. c:
pyridine, reflux.
of these crystals corresponded to the spectrum of the most
abundant diastereoisomer.
The observed diastereoselectivity is in agreement with the
previously accepted transition state models for nucleophilic
additions to aldehydes and imines,7,14 as well as for [1,3]-dipolar
cycloadditions of nitrones,9 and originates in the following factors:
due to steric hindrance, the ortho-substituent governs the
conformation of the nitrone group, which adopts an anti
orientation, coplanar with the aromatic ring; additionally, as
the Cr(CO)3 moiety blocks one face of the arene, the carbonyl
partner preferentially approaches the substrate on the opposite
face.
Interestingly, using an excess of SmI2, b-amino alcohols 4 could
be directly prepared with good overall yields (4a, 60%; 4b, 81%) in a
one-pot sequence,{ by reduction of the in situ generated
hydroxylamine. It is noteworthy that when the reaction was
performed in identical conditions with the corresponding N-benzyl-
imine complex, the expected b-amino alcohol was not isolated at all
but a 40 : 60 mixture of diamine (homocoupling) and benzylic
amine (two-electron-reduction of the imine) was obtained. This
observation is in good agreement with the studies realised by
Uemura et al.15
7 (a) A. Solladie´-Cavallo, in: Advances in Metal-Organic Chemistry, Vol. 1
(Ed.: L. S. Liebenskind), JAI Press, Greenwich, 1989, p. 99;
(b) S. G. Davies and T. D. McCarthy, in Comprehensive Organometallic
Chemistry II; Ed. E. W. Abel, F. G. A. Stone and G. Wilkinson; Elsevier
Science Ltd; Oxford, 1995; Vol. 12, p. 1039.
8 When the (g6-benzaldehyde)Cr(CO)3 complex was reacted with
N-benzylpropylidene imine N-oxide, the organometallic diol resulting
from homocoupling was isolated in 80% yield.
These promising results prompted us to use an enantiopure
nitrone as starting material. The enantiopure ortho-methyl
benzaldehyde complex was synthesized according to the procedure
developed a few years ago in our group.4 The corresponding
nitrone was prepared as before, by condensation with
N-benzylhydroxylamine, with no racemisation.10
9 (a) C. Baldoli, P. Del Buttero, E. Licandro, S. Maiorana and A. Papagni,
Tetrahedron:Asymmetry, 1995, 6, 1711; (b)C.Mukai,I.J.Kim,W.J.Cho,
M. Kido and M. Hanaoka, J. Chem. Soc., Perkin Trans. 1, 1993, 2495.
10 H. Ratni, J. J. Jodry, J. Lacour and E. P. Ku¨ndig, Organometallics, 2000,
19, 3997.
11 For the preparation of the g6-(o-substituted benzaldehyde)Cr(CO)3
complexes, see: (a) C. A. Merlic and J. C. Walsh, J. Org. Chem., 2001,
66, 2265; (b) A. Solladie´-Cavallo, G. Solladie´ and E. Tsamo, J. Org.
Chem., 1979, 44, 4189.
Nitrone (pR)-2b16,17 was first reacted with acetone and two
equivalents of SmI2{ (Scheme 2) to yield the enantiopure b-N-
hydroxylamino alcohol (pR,S)-3b17 in 95% yield. Decomplexation
of the chromium entity occurred quantitatively, giving access to
b-N-hydroxylamino alcohol (R)-5b.17 When six equivalents of
SmI2 were used in the reaction mixture, the corresponding
b-amino alcohol complex (pR,S)-4b17 was also isolated in excellent
yield.
In conclusion, the reductive cross-coupling of Cr(CO)3-
complexed nitrones with carbonyl compounds is very efficient. It
allows for the chemo- and enantioselective synthesis of b-N-
hydroxylamino or b-amino alcohols under mild conditions. The
use of planar chiral substrates induces excellent diastereoselec-
tivities in the C–C bond formation. We are currently extending the
scope of this synthetically useful reaction to various carbonyl
compounds.
12 Crystal data for 3c. C21H23CrNO6, M ~ 437.41; triclinic, a ~
˚
9.2513(18), b ~ 9.7274(12), c ~ 13.164(3) A, a ~ 110.720(13), b ~
3
˚
101.703(19), c ~ 100.932(11)u, U ~ 1039.9(4) A , T ~ 295 K, space
group P1, Z ~ 2, m(Mo-Ka) ~ 0.587 mm21, 13582 reflections measured,
¯
3934 unique (Rint ~ 0.11) which were used in all calculations. The final
wR(F2) was 0.0453 (all data). CCDC 233610. See http://www.rsc.org/
suppdata/cc/b4/b405406g/ for crystallographic data in .cif or other
electronic format.
13 For the nomenclature of planar chirality, see: K. Schlo¨gl, Top.
Stereochem., 1967, 1, 39.
14 S. Pache, P. Romanens and E. P. Ku¨ndig, Organometallics, 2003, 22, 377
and references therein.
15 N. Taniguchi and M. Uemura, Tetrahedron, 1998, 54, 12775.
16 Although nitrone 2b is isostructural with (pS)-2c, its stereochemical
assignment is (pR).
20
20
C. Duhayon (LCIMM, UMR 7071, Universite´ P. et M. Curie,
Paris) is acknowledged for performing the X-ray structure
analysis.
17 (pR)-2b: [a]D ~ 12109 (0.22; CHCl3). (pR,S)-3b: [a]D ~ 1150
~
(0.26; CHCl3). (pR,S)-4b: [a]D20 ~ 117 (0.24; CHCl3). (R)-5b: [a]D
257 (0.22; CHCl3).
20
C h e m . C o m m u n . , 2 0 0 4 , 2 3 3 0 – 2 3 3 1
2 3 3 1