Enantioselective 1,3-dipolar cycloaddition of nitrones to methacrolein catalyzed by (η5-C5Me5)M{(R)-Prophos} containing complexes (M = Rh, Ir; (R)-Prophos = 1,2-bis(diphenylphosphino) propane): On the origin of the enantio

Article abstract of DOI:10.1021/ja0539443

The rhodium and iridium Lewis-acid cations [(η⁵-C ₅Me₅)M{(R)-Prophos}(H₂O)]²⁺ ((R)-Prophos = 1,2-bis(diphenylphosphino)propane) efficiently catalyze the enantioselective 1,3-dipolar cycloaddition of n

Full text of DOI:10.1021/ja0539443

Published on Web 08/31/2005
Enantioselective 1,3-Dipolar Cycloaddition of Nitrones to
Methacrolein Catalyzed by (η5-C5Me5)M{(R)-Prophos}
Containing Complexes (M ) Rh, Ir; (R)-Prophos )
1,2-bis(Diphenylphosphino)propane): On the Origin of the
Enantioselectivity
Daniel Carmona,*,† M. Pilar Lamata,† Fernando Viguri,† Ricardo Rodr´ıguez,†
Luis A. Oro,† Fernando J. Lahoz,† Ana I. Balana,† Toma´s Tejero,‡ and
Pedro Merino‡
Contribution from the Departamento de Qu´ımica Inorga´nica and Departamento de Qu´ımica
Orga´nica, Instituto UniVersitario de Cata´lisis Homoge´nea, Instituto de Ciencia de Materiales de
Arago´n, UniVersidad de Zaragoza-Consejo Superior de InVestigaciones Cient´ıficas,
50009 Zaragoza, Spain
Received June 15, 2005; E-mail: dcarmona@unizar.es
Abstract: The rhodium and iridium Lewis-acid cations [(η5-C5Me5)M{(R)-Prophos}(H2O)]2+ ((R)-Prophos
) 1,2-bis(diphenylphosphino)propane) efficiently catalyze the enantioselective 1,3-dipolar cycloaddition of
nitrones to methacrolein. Reactions occur with perfect endo selectivity and with enantiomeric excesses up
to 96%. Intermediates [(η5-C5Me5)M{(R)-Prophos}(methacrolein)](SbF6)2 (M ) Rh (3), Ir (4)) have been
spectroscopically and crystallographically characterized. The nitrone complexes [(η5-C5Me5)M{(R)-Prophos}-
(nitrone)](SbF6)2 (M ) Rh, nitrone ) 1-pyrrolidine N-oxide (5), 2,3,4,5,-tetrahydropyridine N-oxide (6), 3,4-
dihydroisoquinoline N-oxide (7); M ) Ir, nitrone ) 1-pyrrolidine N-oxide (8)) have been isolated and
characterized including the X-ray crystal structure of compounds 6 and 8. The equilibrium between
methacrolein and nitrone complexes is also studied. [Ir]-adduct complexes are detected by 31P NMR
spectroscopy. A catalytic cycle involving [M]-methacrolein, [M]-nitrone, as well as [M]-adduct species is
proposed, the first complex being the true catalyst. The absolute configuration of the adduct 4-methyl-2-
N,3-diphenyl-isoxazolidine-4-carbaldehyde (9) was determined through its (S)-(-)-R-methylbenzylamine
derivative diastereomer. Structural parameters strongly suggest that the disposition of the methacrolein in
3 and 4 is fixed by CH/π attractive interactions between the pro-S phenyl ring of the Ph2PCH(CH3) moiety
of the (R)-Prophos ligand and the CHO aldehyde proton. Proton NMR data indicate that this conformation
is maintained in solution. From the structural data and the results of catalysis the origin of the
enantioselectivity is discussed.
Scheme 1. 1,3-DCR between Nitrones and Alkenes
Introduction
Asymmetric catalysis is an efficient method for synthesizing
optically active organic compounds and the use of chiral metal
complexes as homogeneous molecular catalysts is one of the
most powerful strategies. Usually, coordination of the organic
substrates to the metal facilitates the reaction, renders it catalytic
and may allow for an efficient control of the selectivity.1 Among
the wide variety of metal-catalyzed asymmetric transformations,
cycloadditions are atom-economic processes that permit the
creation of adjacent chiral centers in a concerted fashion.2 In
particular, the enantioselective 1,3-dipolar cycloaddition reaction
(DCR) of an alkene with a nitrone leads to the construction of
up to three contiguous asymmetric carbon centers. The resulting
five-membered isoxazolidine derivatives (Scheme 1) may be
converted into amino alcohols, precursors to biologically
important amino acids, alkaloids, or â-lactams.3 However,
despite its tremendous synthetic potential, the use of metal
catalysts remains almost unexplored, in sharp contrast, for
example, to the broad application of chiral metal complexes as
catalysts in the related asymmetric Diels-Alder cycloadditions.4
† Departamento de Qu´ımica Inorga´nica.
‡ Departamento de Qu´ımica Orga´nica.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Vol I-III, Suppl. 1 and
2, Springer: New York, 2004. (b) Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: Weinheim, Germany, 2000. (c) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; John Wiley and Sons: New York, 1994.
(2) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen,
K. A., Eds.; Wiley-VCH: Weinheim, 2002.
(3) (a) Synthetic applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley
and Sons: Hoboken, New Jersey, 2003. (b) Frederickson, M. Tetrahedron
1997, 53, 403-425.
9
13386
J. AM. CHEM. SOC. 2005, 127, 13386-13398
10.1021/ja0539443 CCC: $30.25 © 2005 American Chemical Society

On the Origin of the Enantioselectivity
A R T I C L E S
Chart 2. Ligands for DCR of Nitrones with R,â-Unsaturated
Chart 1. 3-Alkenoyl-oxazolidinones
Aldehydes
Two types of activation can be envisaged for this reaction.
An electron-deficient alkene may be activated through coordina-
tion to the metal catalyst, in this way, the interaction between
the alkene LUMO and the HOMO of the nitrone is favored. In
this case, it is said that the process proceeds with normal
electron-demand (NED). Alternatively, the nitrone may be
activated by coordination to the catalytic complex. Now,
interaction is favored between the HOMO of an electron-rich
alkene and the LUMO of the nitrone and it is said that the
process occurs with inverse electron-demand (IED).5
Usually, coordination of a nitrone to the Lewis acid is more
feasible than coordination of a carbonyl compound. For this
reason, alkenes that enable a bidentate coordination to the Lewis
acid, such as 3-alkenoyl-oxazolidinones (Chart 1), have been
frequently employed as model system to study the metal-
catalyzed NED 1,3-dipolar cycloaddition of nitrones.6 In
contrast, examples of one point binding catalysts for the
activation of electron deficient monofunctionalized alkenes are
scarce.7-9 Only very recently has it been possible to find a few
examples in the literature, the first being Kundig’s group, which,
in 2002, published the use of Binop-F iron and ruthenium
complexes for the enantioselective DCR of nitrones with R,â-
unsaturated aldehydes;7 Yamada et al. published their work
about â-ketoiminato cationic cobalt(III) complexes applied to
the same type of reactions.8 Two years later, Kanemasa and
co-workers reported on the use of chiral DBFOX/Ph complexes
of nickel(II), magnesium(II), or zinc(II) in the DCR of nitrones
with R-alkyl- and R-arylacroleins9 (Chart 2). Moreover, current
understanding of the metallic species involved in catalysis is
very limited. Ku¨ndig crystallographically characterized the
methacrolein- ruthenium complex10 [(η5-C5H5)Ru{(R,R)-
Binop-F}(methacrolein)]SbF6 and established, through qualita-
tive 31P NMR measurements, the preferential coordination of
crotonaldehyde over that of the nitrone N-benzylidenebenz-
ylamine N-oxide in the Cp-Ru-Binop-F system.7 Yamada and
Kanemasa used â-ketoiminato cationic cobalt(III) complexes8
and DBFOX/Ph metallic compounds9 as catalyst precursors and
no further studies have been carried out in the catalytic reaction
medium.
Chart 3. Nitrones Employed in the Catalytic Experiments
A few years ago, we demonstrated that methacrolein coor-
dinates to cationic d6 ruthenium half-sandwich moieties render-
ing active catalysts for the Diels-Alder reaction between
methacrolein and cyclopentadiene.11 As enantioselectivity of the
ruthenium system was modest, we envisaged the possibility to
investigate the related more selective d6 diphosphine moieties12
“(η5-C5Me5)M{(R)-Prophos}” (M ) Rh, Ir; (R)-Prophos ) 1,2-
bis(diphenylphosphino)propane) in the DCR of nitrones with
methacrolein. In the present paper, we report on the enantiose-
lective reaction of the acyclic N-benzylidenphenylamine N-oxide
(I) and N-benzylidenmethylamine N-oxide (II) nitrones, as well
as, the cyclic 1-pyrrolidine N-oxide (III), 2,3,4,5,-tetrahydro-
pyridine N-oxide (IV) and 3,4-dihydroisoquinoline N-oxide (V)
(Chart 3) with methacrolein employing [(η5-C5Me5)M{(R)-
Prophos}(H2O)]2+ complexes as catalyst precursors. Reactions
occur with perfect endo selectivity and excellent enantioselec-
tivity (up to 96%).
During our preliminary explorations, we realized that these
systems are well suited to study the intermediates involved in
the catalytic process. Thus, we also report here on the isolation
and crystallographic characterization of the Lewis acid-
dipolarophile compounds [(η5-C5Me5)M{(R)-Prophos}(meth-
acrolein)](SbF6)2. To obtain information about the competitive
nitrone-aldehyde Lewis acid coordination, we have spectro-
(4) (a) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007-1019. (b) Dias, L.
C. J. Braz. Chem. Soc. 1997, 8, 289-332. (c) Evans, D. A.; Johnson, J. S.
In ComprehensiVe Asymmetric Catalysis, Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds; Springer: New York, 1999; Vol II, Chapter 33.1, pp
1178-1235. (d) Carmona, D.; Lamata, M. P.; Oro, L. A. Coord. Chem.
ReV. 2000, 200-202, 717-772.
(5) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Pawda, A., Ed.;
John Wiley and Sons: New York, 1984; Chapter 9.
(6) (a) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909. (b)
Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 1449-1458.
(7) Viton, F.; Bernardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002, 124,
4968-4969.
(8) (a) Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457-
2460. (b) Ohtsuki, N.; Kezuka, S.; Kogami, Y.; Mita, T.; Ashizawa, T.;
Ikeno, T.; Yamada, T. Synthesis 2003, 1462-1466. (c) Kezuka, S.; Ohtsuki,
N.; Mita, T.; Kogami, Y.; Ashizawa, T.; Ikeno, T.; Yamada, T. Bull. Chem.
Soc. Jpn. 2003, 76, 2197-2207.
(9) Shirahase, M.; Kanemasa, S.; Oderaotoshi, Y. Org. Lett. 2004, 6, 675-
678. (b) Shirahase, M.; Kanemasa, S.; Hasegawa, M. Tetrahedron Lett.
2004, 45, 4061-4063.
(10) Ku¨ndig, E. P.; Saudan, C. M.; Bernardinelli, G. Angew. Chem., Int. Ed.
1999, 38, 1220-1223.
(11) Carmona, D.; Cativiela, C.; Elipe, S.; Lahoz, F. J.; Lamata, M. P.; Lo´pez-
Ram de V´ıu, M. P.; Oro, L. A.; Vega, C.; Viguri, F. Chem. Commun. 1997,
2351-2352.
(12) Carmona, D.; Cativiela, C.; Garc´ıa-Correas, R.; Lahoz, F. J.; Lamata, M.
P.; Lo´pez, J. A.; Lo´pez-Ram de V´ıu, M. P.; Oro, L. A.; San Jose´, E.; Viguri,
F. Chem. Commun. 1996, 1247-1248.
9
J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005 13387

A R T I C L E S
Carmona et al.
Figure 1. (a) Molecular structure of the cation of 2.SbF6. (b) Hydrogen bond system involving coordinated and solvation water molecules and the two
counteranions in 2.SbF6. Structural parameters as follows (distance D...A in Å and angle D-H...A in deg): O(1)...O(2) 2.584(4), 169(4); O(1)...F3 2.807(3),
137(7); O(2)...F(5) 2.824(4), 167(5); O(2)...F(11) 2.751(4), 163(4)
Table 1. Selected Bond Distances (Å) and Angles (deg) for the Complexes 1.BF4 and 2.SbF6
1.BF4
2.SbF6
1.BF4
2.SbF6
M-P(1)
2.3344(8)
2.3285(7)
2.198(3)
1.8533(14)
83.80(2)
80.67(8)
133.45(5)
2.3176(8)
2.3285(8)
2.169(2)
1.8679(14)
83.70(3)
81.11(7)
132.36(5)
P(1)-C(36)
P(2)-C(35)
C(35)-C(36)
C(36)-C(37)
P(2)-M-O(1)
P(2)-M-Ga
O(1)-M-Ga
1.853(3)
1.840(3)
1.535(4)
1.528(4)
89.18(8)
129.98(5)
123.38(9)
1.852(3)
1.835(3)
1.536(5)
1.539(4)
85.43(7)
131.97(5)
124.68(8)
M-P(2)
M-O(1)
M-Ga
P(1)-M-P(2)
P(1)-M-O(1)
P(1)-M-Ga
a G represents the centroid of the η5-C5Me5 ligands.
copically studied the equilibrium involved and isolated nitrone
complexes of stoichiometry [(η5-C5Me5)M{(R)-Prophos}-
(nitrone)](SbF6)2. The molecular structure of two of them
(nitrone ) 2,3,4,5,-tetrahydropyridine N-oxide, M ) Rh; nitrone
) 1-pyrrolidine N-oxide, M ) Ir) have been determined by
X-ray diffraction methods. Finally, we have been able to
elucidate the absolute configuration of the major product of the
reaction between nitrone I and methacrolein, by solving the
molecular structure of an appropriate diastereomeric derivative,
and we have detected spectroscopically the intermediate [(η5-
C5Me5)Ir{(R)-Prophos}(adduct)]2+ in which this DCR adduct
is coordinated to the iridium.
2. Rhodium complexes 1.SbF6, 1.BF4, 1.PF6, and 1.CF3SO3
were also prepared13 to study the influence of the anion on the
catalytic performance (see below). The reaction is completely
diastereoselective: only one of the two possible epimers at the
metal was spectroscopically detected in the solid state and in
solution from -90 °C to RT.
Complexes were characterized by analytical and spectroscopic
means (see Experimental Section). Assignment of the NMR
signals was verified by NOE experiments and by two-
dimensional homonuclear and heteronuclear (13C-1H, 31P-1H)
correlations. The molecular structure of the hexafluoroanti-
monate rhodium complex 1.SbF6 was previously communi-
cated.12 We have determined the crystal structures of 1.BF4 and
that of the iridium complex 2.SbF6, in search of structural
differences that may explain the different catalytic performance
often shown for different salts of the same anion.15
Crystal Structures of Complexes 1.BF4 and 2.SbF6. Figure
1a shows the molecular structure of the cationic complex of
2.SbF6; a molecular representation of the metal complex of
1.BF4 is included in the Supporting Information. At a molecular
level, both structures present very similar parameters (see Table
1). The metal atoms are pseudo-tetrahedral being coordinated
to an η5-C5Me5 ring, to the two phosphorus atoms of the (R)-
Prophos ligand and to the oxygen atom of a water molecule.
An analogous hydrogen bond system has been observed in both
structures, in which a second solvation water molecule is clearly
bonded to the metal-coordinated water moiety. Additionally,
This body of data allows us to propose a plausible catalytic
cycle for the DCR reaction between nitrones and methacrolein
catalyzed by cationic Lewis acids containing (η5-C5Me5)M{(R)-
Prophos} units. In addition, we are able to interpret the observed
selectivities on the basis of the structural data obtained for the
involved intermediates.
Part of this work has been previously communicated.13
Results and Discussion
Aquo-Compounds [(η5-C5Me5)M{(R)-Prophos}(H2O)]2+
.
Complexes [(η5-C5Me5)M{(R)-Prophos}(H2O)]A2 were pre-
pared by treating the corresponding tris(solvento) complexes14
[(η5-C5Me5)M(S)3]A2 + (R)-Prophos f
S)acetone
[(η5-C5Me5)M{(R)-Prophos}(H2O)]A2
(1)
M ) Rh (1.A), M ) Ir (2.A)
(13) For a preliminary communication see: Carmona, D.; Lamata. M. P.; Viguri.
F.; Rodr´ıguer, R.; Oro, L. A.; Balana, A. I.; Lahoz, F. J.; Tejero, T.; Merino,
P.; Franco, S.; Montesa, I. J. Am. Chem. Soc. 2004, 126, 2716-2717.
(14) White, C.; Thompson, S. J.; Maitlis, P. M. J. Chem. Soc., Dalton Trans.
1977, 1654-1661.
(15) See, for example, ref 10 or: Evans, D. A.; Murry, J. A.; von Matt, P.;
Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-
800.
[(η5-C5Me5)M(S)3]A2 in acetone with an equimolar amount of
(R)-Prophos according to eq 1. Water readily displaces coor-
dinated acetone. In fact, the presence of trace amounts of water
in the solvent is enough to afford pure aquo-complexes 1 and
9
13388 J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005

On the Origin of the Enantioselectivity
A R T I C L E S
Table 2. Selected Bond Distances (Å) and Angles (deg) for the Methacrolein Complexes 3 and 4
3
4
3
4
M-P(1)
2.3323(16)
2.3280(15)
2.175(4)
1.861(3)
1.221(8)
2.3212(13)
2.3241(14)
2.160(3)
1.876(2)
1.231(7)
P(1)-C(11)
1.814(6)
1.807(7)
1.850(6)
1.837(7)
1.811(7)
1.825(7)
1.529(10)
1.541(8)
1.811(6)
1.819(7)
1.848(5)
1.823(6)
1.822(6)
1.829(6)
1.510(10)
1.544(8)
126.4(4)
123.4(7)
114.9(7)
117.7(6)
127.3(7)
M-P(2)
P(1)-C(17)
M-O
P(1)-C(36)
M-Ga
P(2)-C(29)
O-C(38)
P(2)-C(23)
C(38)-C(39)
C(39)-C(40)
C(39)-C(41)
P(1)-M-P(2)
P(1)-M-O(1)
P(1)-M-Ga
P(2)-M-O(1)
P(2)-M-Ga
O(1)-M-Ga
1.443(9)
1.441(9)
P(2)-C(35)
1.322(12)
1.514(12)
83.53(6)
86.37(11)
133.20(10)
87.88(12)
129.63(10)
121.38(13)
1.344(11)
1.496(11)
83.79(5)
85.85(10)
133.47(8)
86.55(11)
129.87(8)
121.80(13)
C(35)-C(36)
C(36)-C(37)
Ir-O-C(38)
127.8(4)
O-C(38)-C(39)
C(38)-C(39)-C(40)
C(38)-C(39)-C(41)
C(40)-C(39)-C(41)
124.2(7)
115.6(8)
116.4(7)
127.9(8)
a G represents the centroid of the η5-C5Me5 ligands.
each hydrogen atom of these two molecules established
hydrogen bonds to three flourine atoms of the two different
anions (BF4 or SbF6) (see Figure 1b). The metal atom has S
absolute configuration16 and the M-P-C-C-P metallacycle
a λ conformation.17
[(η5-C5Me5)M{(R)-Prophos}(H2O)](SbF6)2/Methacrolein
System. We have studied, by NMR spectroscopy, the solution
behavior of mixtures of complexes 1.SbF6 or 2.SbF6 with
methacrolein. When, at RT, 28 equivalents of methacrolein were
added to a solution of [(η5-C5Me5)M{(R)-Prophos}(H2O)]2+ in
CD2Cl2,18 the new complexes [(η5-C5Me5)M{(R)-Prophos}-
Figure 2. Molecular structure of the cation of complex 4.
dinated methacrolein. To obtain additional structural information
the molecular structure of compounds 3 and 4 has been
determined by X-ray diffractometric methods.
(methacrolein)]2+ were formed according to 31P NMR measure-
ments. At this temperature both complexes are in equilibrium
in ca.. 70/30 (Rh) and 35/65 (Ir) ratio, the first percentage
corresponding to the water complex (eq 2). However, in the
presence of 4 Å molecular sieves, the equilibrium is completely
shifted to the right, the methacrolein complexes 3 and 4 being
the sole phosphorus containing compounds in the solution.19
From the solution, solids 3 and 4 can be isolated as hexafluo-
roantimonate salts. Their 1H and 13C NMR spectra show
resonances attributable to coordinated methacrolein. Notably,
the aldehyde proton is strongly shielded. It resonates at 7.06
(3) and 7.23 (4) ppm, about 2.5 ppm shifted to higher field
with respect to the corresponding free molecule resonance.
Furthermore, NOEDIFF experiments show an enhancement
pattern compatible only with an s-trans conformation for coor-
Molecular Structures of Compounds 3 and 4. Single
crystals suitable for X-ray diffraction experiments were obtained
by slow liquid-liquid diffusion of hexane into CH2Cl2 solutions.
Both structures resulted to be isostructural with analogous
structural features. Table 2 collects the most relevant structural
parameters of the complexes and Figure 2 shows an ORTEP
representation of the cation of 4 (that for 3 included in SI). As
observed in the parent water complexes, the cations are formally
pseudo-tetrahedral with metal coordinations to the C5Me5 ring,
to the quelate (R)-Prophos ligand and, in these cases, to the
oxygen atom of the methacrolein ligand. The configuration of
the metal is also S and the five membered metallacycle M-P-
C-C-P maintains a λ conformation (Cremer and Pople
parameters in 4: Q2 ) 0.780(10) A, φ2 ) -83.3(2)°).20 The
methacrolein ligand coordinates as a planar molecule with an
s-trans conformation and with an E-configuration around the
carbonylic double bond. The bond distances observed along the
methacrolein conjugated system O-C(38)-C(39)-C(40) clearly
evidence the partial delocalization of the π-electron density, with
elongations of the formal double bonds (OdC(38) 1.231(7) Å
and C(39)dC(40) 1.344(11) Å) and a shortening of the C(38)-
C(39) single bond (1.441(9) Å); mean values for these bonds
in uncoordinated organic moieties are: OdC 1.192(5), CdC
1.321(13), and C-C 1.464(18) Å.21
(16) (a) Cahn, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1966,
5, 385-415. (b) Prelog, V.; Helmchen, G. Angew. Chem., Int. Ed. Engl.
1982, 21, 567-583. (c) Lecomte, C.; Dusausoy, Y.; Protas, J.; Tirouflet,
J. Dormond, A. J. Organomet. Chem. 1974, 73, 67-76. (d) Stanley, K.;
Baird, M. C. J. Am. Chem. Soc. 1975, 97, 6598-6599. (e) Sloan, T. E.
Top. Stereochem. 1981, 12, 1.
(17) Nomenclature of Inorganic Chemistry; Leigh, G. J., Ed.; Blackwell: Oxford,
1991.
(18) An 1/28/20 catalyst precursor/methacrolein/nitrone ratio was used in the
catalytic experiments described in ref 13.
(19) In the absence of methacrolein, 31P NMR spectra, in CD2Cl2, of [(η5-C5-
Me5)M{(R)-Prophos}(H2O)]2+ treated with 4 Å molecular sieves reveals
the presence of a new (η5-C5Me5)M{(R)-Prophos} containing complex that
we tentatively assign to the dichloromethane derivative [(η5-C5Me5)M{(R)-
Prophos}(ClCD2Cl)]2+: M ) Rh, 31P NMR (161.96 MHz, CD2Cl2, -25
°C): δ ) 74.57 (dd, JRhP1 ) 130.7, JP1P2 ) 39.0 Hz, P1), 50.74. (dd, JRhP2
) 131.4, P2). M ) Ir, 31P NMR (161.96 MHz, CD2Cl2, -25 °C): δ )
46.8 (d, JP2P1 ) 11.4 Hz, P1), 29.3 (P2). For phosphorus labeling, see
Experimental Section.
(20) Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354-1358.
(21) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.;
Taylor, R. J. Chem. Soc., Perkin Trans. 1987, S1-S19.
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A R T I C L E S
Carmona et al.
Figure 3. Schematic representations of the CH/π interactions observed in 4: (a) view perpendicular to the phenyl plane; (b) view nearly parallel to the
phenyl plane.
Table 3. Selected Structural Parameters Concerning Substrate
In addition to the coordination bond angles, the relative
Coordination (Methacrolein or Nitrones) and CH/π interactions for
disposition of the methacrolein within the metal coordination
sphere could be characterized by the torsion angle C5Me5-
(centroid)-M-O-C(38), that relates its molecular plane to the
sterically demanding C5Me5 ligand; while values close to 0°
(or 180°) imply a perpendicular disposition between C5Me5 and
methacrolein planes, an approximate figure to 90° reflects a
roughly parallel disposition. The observed values, -64.6(6) (3)
and -64.1(5)° (4), indicate an intermediate situation closer to
the parallel disposition.22 A very remarkable structural feature,
in this particular conformation of the unsaturated methacrolein
ligand, is the evident CH/π attractive interaction detected
between the CHO proton, H(38), and the pro-S phenyl ring
connected to the P(1) atom of the (R)-Prophos ligand (C(17)-
C(22)) (Figure 3). This interaction is characterized by the short
H‚‚‚phenyl-plane distance (2.66 in 3, 2.83(8) Å in 4), and by
two H...C interatomic distances shorter than the usual value (3.05
Å) considered indicative for the presence of CH/π interactions
(and related to the sum of the under van der Waals radii) (see
Table 3).23
The importance of CH/π interactions in stabilizing the
structure of transition metal complexes has, in fact, been
demonstrated in a number of crystallographic determinations
in the area of enantioselective catalysis; from the early contribu-
tions of Okawa in the understanding of the stereoselective
formation of metal complexes,24 through the different stabiliza-
tion of diastereomers by the so-called ‘â-phenyl-effect’ reported
by Brunner in related half sandwich complexes,25 to the more
recent description by Noyori of the origin of enantioselectivity
in the transfer hydrogenation of acetophenone,26 the CH/π soft
acid/soft base interaction, despite its weakness, it has been
complexes 3, 4, 6, and 8a
C5Me5 vs
H‚‚‚Ph
CH‚‚‚C(17)/
complex
subs.
H‚‚‚G(Ph)
(plane)
γ
angle
C(18)
CH‚‚‚C(Ph)
3
-64.6(6) 2.84
2.66
20.3
2.70, 2.90 2.98-3.56
4b
-64.1(5) 3.05(8) 2.83(8) 22.2(6) 2.85(8), 3.19-3.80(8)
3.04(8)
6
8
-65.7(6) 3.10
-66.4(9) 2.95
2.83
2.72
24.1
22.8
2.87, 2.96 3.31-3.84
2.85, 2.76 3.20-3.66
a C5Me5 vs Subs: substrate disposition relative to the pentamethyl-
cyclopentadienyl ligand, estimated as the torsion angle C5Me5(centroid)-
M-O-C(38)/N; H‚‚‚G(Ph): separation between hydrogen atom (H(38))
and the centroid of the phenyl ring in the reported CH/π interactions;
H‚‚‚Ph(plane): distance between hydrogen atom and the phenyl plane in
CH/π interactions; γ angle: angle between the G(Ph)-H vector and the
normal to the phenyl ring; CH‚‚‚C(17)/C(18): Contact distances between
hydrogen and phenyl carbon atoms under the assumed criterium (3.05 Å)
for CH/π interactions.23 CH‚‚‚C(Ph): separations between hydrogen atom
and the rest of carbon atoms of the π-system. (Distances in Å and angles
in degrees). b H(38) has been refined as free isotropic atom for this structure.
recognized that it plays a relevant role, in particular in con-
trolling the conformation of molecules27 In our cases, this inter-
action seems to contribute to maintaining the methacrolein con-
formation observed in both the solid state and in solution as
confirmed by the strong shielding of the CHO proton detected
in the NMR spectra of both complexes (see above). The deter-
mination of this structural interaction and its effect on the stabi-
lization of a preferred conformation for the unsaturated substrate
sets up the basis for the rationalization of the catalytic outcome.
[(η5-C5Me5)M{(R)-Prophos}(methacrolein)]2+/Nitrone Sys-
tem. In the NED reaction of nitrones with electron-poor alkenes,
coordination of the alkene to the catalyst must occur to the
detriment of nitrone coordination. To test the viability of our
system as a catalyst we have studied, by NMR spectroscopy,
the system generated after the addition of a nitrone to the
preformed catalyst [(η5-C5Me5)M{(R)-Prophos}(methacrolein)]2+.
Depending on the nitrone two different behaviors have been
encountered. While acyclic nitrones I and II (Chart 3) do not
displace the coordinated dipolarophile, the cyclic ones III-V
readily substitute the coordinated alkene, even at low temper-
ature. As representative examples, the 31P NMR spectrum of a
(22) It is interesting to point out that in the only two previously reported examples
of chiral Lewis acid-methacrolein complexes, the methacrolein plane is
roughly perpendicular to the ring (Cp10 or p-MeC6H4 Pr11) plane.
i
(23) (a) Suezawa, H.; Yoshida, T.; Umezawa, Y.; Tsuboyama, S.; Nishio, M.
Eur. J. Inorg. Chem. 2002, 3148-3155. (b) Umezawa, Y.; Tsuboyama,
S.; Honda, K.; Uzawa, J.; Nishio, M. Bull. Chem. Soc. Jpn. 1998, 71, 1207-
1213.
(24) (a) Okawa, H.; Numata, Y.; Mio, A.; Kida, S. Bull. Chem. Soc. Jpn. 1980,
53, 2248-2251. (b) Okawa, H.; Ueda, K.; Kida, S. Inorg. Chem. 1982,
21, 1594-1598.
(25) (a) Brunner, H. Angew. Chem., Int. Ed. Engl. 1999, 38, 1195-1208. (b)
Brunner, H.; Oeschey, R.; Nuber, B. J. Chem. Soc., Dalton Trans. 1996,
1499-1508. (c) Brunner, H. Angew. Chem., Int. Ed. Engl. 1983, 22, 987-
1012.
(26) (a) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001,
40, 2818-2821. (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc.
2000, 122, 1466-1478.
(27) (a) Nishio, M. CrystEngComm. 2004, 6, 130-158. (b) Nishio, M.; Hirota,
M.; Umezawa, Y. In The CH/π Interaction. EVidence, Nature, and
Consequences; Wiley-VCH: New York, 1998.
9
13390 J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005

On the Origin of the Enantioselectivity
A R T I C L E S
Figure 4. (a) Molecular drawing of the cationic metal complex of 6. (b) Schematic representation of the CH/π interactions observed in 6 (only the ipso
carbon of two phenyl groups have been represented for clarity).
Chart 4. Canonical Structures for the Nitrone Function
CD2Cl2 solution of complex 3 prepared as above remains
unchanged for hours, in the -90 °C to RT range of temperatures,
after the addition of 20 equivalents of the nitrone I.18 Simul-
taneously, it was observed that the DCR is taking place,
according to 1H NMR data.28 However, immediately after
addition, at -60 °C, of the same amount of the cyclic nitrone
molar ratio for the iridium complex 8, according to NMR
V, the 31P NMR signals of complex 3 disappeared and a new
spectrocopic data. In dichloromethane, irreversible and complete
two double doublet pattern, characteristic for Rh(R)-Prophos
epimerization occurs to yield the thermodynamic isomer, which
containing complexes, appeared. The new signals correspond
is the sole isomer obtained if the preparation is carried out at
to the nitrone complex [(η5-C5Me5)Rh{(R)-Prophos}(V)]2+ that
was completely characterized as hexafluoroantimonate salt
(compound 7, see below). Obviously, the NED reaction is
room temperature.
The IR spectra of complexes 5-8 exhibit an intense ν(CN)
stretching band in the range 1617-1648 cm-1 30
This band is
.
precluded in these conditions. However, we realized that
addition of only one equivalent of nitrone V, per equivalent of
complex 3, afforded, at the same temperature, only 57% of the
nitrone complex 7. More interestingly, we observed, by 1H NMR
spectroscopy, that the DCR of nitrone V with methacrolein was
taking place at this low temperature.29 These experiments clearly
established that our M(R)-Prophos systems can actively catalyze
the DCR of both types of nitrones at low temperatures provided
the cyclic nitrones are added slowly.
shifted about 25 cm-1 toward higher frequency with respect to
the free ligands, indicating that, after coordination to the metal,
the contribution of the resonance I with a CN double bond
increases.
In all cases, the NdCH proton of the coordinated nitrones is
strongly shielded as was the CHO proton of the coordinated
methacrolein of compounds 3 and 4 (see above). ∆δ’s between
1.50 and 2.00 ppm were observed. Again, a relative disposition
of the pro-S phenyl ring and the NdCH proton, comparable to
that shown for compound 4 in Figure 3, accounts for the
observed shielding. The molecular structures of complexes 6
and 8 clearly established this feature.
Detection of complex 7 prompted us to attempt the synthesis
of metal nitrone complexes. In fact, compounds of stoichiometry
[(η5-C5Me5)M{(R)-Prophos} (nitrone)](SbF6)2 can be isolated
Molecular Structures of Compounds 6 and 8. Although it
has been anticipated that nitrone coordination is more feasible
than coordination of enals through its oxygen atom, examples
of metal nitrone complexes are very scarce. In some instances,
[(η5-C5Me5)M{(R)-Prophos}(H2O)](SbF6)2 + nitrone 4ÅMS8
[(η5-C5Me5)M{(R)-Prophos}(nitrone)](SbF6)2
(3)
M ) Rh; nitrone ) III (5), IV (6), V (7)
nitrone ligands also contain a chelating group (usually pyridyl30a,31
)
M ) Ir; nitrone-III (8)
to enhance complexation. In fact, the only examples of simple
nitrones η1-O coordinated to transition metals are the diiron
complex [Fe(hfac)2(M3PO)]2(µ-O) (hfac ) hexafluoroacetylac-
etonate; M3PO ) 2,5,5-trimethyl-1-pyrroline-N-oxide),31a the
rhodium compound [RhCl(CO)2(I)],30c and the ruthenium or
osmium porphyrin complexes [M(oep)(CO)(M2PO)] (M ) Ru,
by addition of the appropriate nitrone to the water complexes
[(η5-C5Me5)M{(R)-Prophos}(H2O)]2+ in the presence of 4Å
molecular sieves, according to eq 3. The new compounds have
been characterized by the usual analytical and spectroscopic
means. Additionally, the molecular structures of compounds 6
and 8 have been determined by diffractometric methods.
Complexes were prepared at -25 °C and, at this temperature,
while only one isomer was obtained for the rhodium compounds
5-7, the two epimers at the metal were isolated in ca. 50/50
(30) (a) Hutchison, J. R.; La Mar, G. N.; Horrocks, W. D., Jr. Inorg. Chem.
1969, 8, 126-131. (b) Sivasubramanian, S.; Manisankar, P.; Palaniandavar,
M.; Arumugan, N. Transition Met. Chem. 1982, 7, 346-349. (c) Das, P.;
Boruah, M.; Kumari, N.; Sharma, M.; Konwar, D.; Dutta, D. K. J. Mol.
Catal. A: Chem. 2002, 178, 283-287.
(31) (a) Villamena, F. A.; Dickman, M. H.; Crist, D. R. Inorg. Chem. 1998, 37,
1446-1453. (b) Ibid, 1454-1457. (c) Merino, P.; Tejero, T.; Laguna, M.;
Cerrada, E.; Moreno, A.; Lo´pez, J. A. Org. Biomol. Chem. 2003, 2336-
2342. (d) Ade, A.; Cerrada, E.; Contel, M.; Laguna, M.; Merino, P.; Tejero,
T. J. Organomet. Chem. 2004, 689, 1788-1795.
(28) Ca. 2% conversion, based on the nitrone, after 1 h at -50 °C.
(29) Three hours after the nitrone addition, a conversion to the 3, 4-endo DCR
adduct of ca. 77% of the nitrone had occurred, with 20% forming complex
7, and 3% of the nitrone remained free.
9
J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005 13391

A R T I C L E S
Carmona et al.
Table 4. Selected Bond Distances (Å) and Angles (deg) for the Metal Nitrone Complexes 6 and 8
6
8
6
8
M-P(1)
2.323(2)
2.346(3)
2.111(7)
1.860(4)
1.856(9)
1.827(10)
1.528(15)
1.509(13)
83.93(9)
86.2(2)
2.305(4)
2.349(4)
2.135(10)
1.864(7)
1.878(15)
1.833(18)
1.50(2)
1.51(2)
83.82(14)
86.1(3)
O-N
1.355(10)
1.250(13)
1.473(13)
1.497(14)
1.521(18)
1.52(2)
1.313(16)
1.30(2)
1.47(2)
1.49(2)
1.56(3)
1.51(3)
M-P(2)
N-C(38)
M-O
N-C(42)a
M-Gb
C(38)-C(39)
C(39)-C(40)
C(40)-C(41)
C(41)-C(42)#
P(1)-C(36)
P(2)-C(35)
C(35)-C(36)
C(36)-C(37)
P(1)-M-P(2)
P(1)-M-O(1)
P(1)-M-Gb
P(2)-M-O(1)
P(2)-M-Gb
O(1)-M-Gb
1.540(17)
M-O-N
132.7(6)
129.3(9)
O-N-C(38)
125.0(9)
108.5(8)
126.5(9)
121.3(10)
113.7(10)
131.0(15)
114.9(13)
113.9(15)
112.1(18)
102.8(16)
133.41(16)
79.6(2)
128.61(16)
127.1(3)
133.3(3)
80.2(3)
129.3(3)
126.4(4)
O-N-C(42)a
C(38)-N-C(42)a
N-C(38)-C(39)
N-C(42)-C(41)a
a The labeling scheme used in both complexes is analogous; as the nitrone in 8 has a five-membered ring, the carbon labeling ends with C(41). b G
represents the centroid of the η5-C5Me5 ligands.
Table 5. Enantioselective 1,3-Dipolar Cycloadditions of
Methacrolein with Nitrones I-V
Os; oep ) octaethylporphyrinato dianion; M2PO ) 5,5-
trimethyl-1-pyrroline-N-oxide),32 the diiron and ruthenium
T
yield
(%)b,c
compounds being the only ones characterized by X-ray diffrac-
tion methods.
entry
complex
nitrone
(
°
C)
t (h)a
3,4-endob 3,5-endob
ee (%)d
1e 1.SbF6
2e 2.SbF6
I
I
II
II
-25 15 100
-25 10 100
63
82
2
37
18
98
90/75
95/85.5
- -/92
- -/93
86
86
91
92
81
We have determined the molecular structures of the nitrone
compounds 6 and 8 by X-ray crystallography. Figure 4a shows
a molecular view of the complex cation of 6 (a similar drawing
of complex 8 is included in the Supporting Information). The
molecular structures of these complexes are analogous to those
previously described for the methacrolein derivatives; in these
complexes the nitrone ligand, linked η1 through the oxygen
atom, substitutes the coordination position of the methacrolein.
The metal exhibits an S configuration and the M-P-C-C-P
five-membered metallacycle adopts a λ conformation. The
structural parameters determined for the coordinated nitrones,
in particular the planarity observed around the nitrogen atom
together with the bond lengths N-O 1.355(10), N-C(38)
1.250(13) and N-C(42) 1.473(13) Å in 6 (1.313(16), 1.30(2)
1.47(2) Å in 8, respectively), strongly suggest an important
contribution of the resonance form I depicted in Chart 4, in
good agreement with the IR data. Quite surprisingly, in both
complexes, the planar nitrone moiety (O-N-C(38)) adopts an
identical disposition, relative to the C5Me5 group, to those
observed in the methacrolein analogues 3 and 4, the torsion
angles C5Me5(centroid)-M-O-C(38) being -65.7(6) in 6 and
-66.4(9)° in 8. This disposition is appropriate -as it occurs in
the methacrolein derivatives- for the formation of a clear CH/π
interaction between the hydrogen atom of the Csp2 atom (C(38)
in the structural labeling) and the pro-S phenyl ring (C(17)-
C(22)) of the (R)-Prophos ligand. Table 3 collects the detailed
structural parameters that corroborate the existence, in both
complexes, of this particular interaction, which is already
suggested, as commented above, by the proton NMR shielding
observed for these atoms.33
3
4
5
6
7
8
9
1.SbF6
2.SbF6
1.SbF6
2.SbF6
1.SbF6
2.SbF6
1.SbF6
-10 24
-10 24
75
78
2
98
III -25 15 100
III -25 15 100
IV
IV
V
- -
- -
- -
- -
- -
- -
- -
- -
>99
100
>99
>99
100
100
>99
>99
-25 15
99
-25 15 100
-25 24
-25 15 100
57.5
10 2.SbF6
11e 1.SbF6
12e 2.SbF6
V
93
80
76
III -25 15
III -25 16
50
75
Reaction conditions: catalyst 0.06 mmol (5.0 mol %), methacrolein 8.4
mmol, 100 mg of 4Å molecular sieves, and nitrone 1.2 mmol in 6 mL of
CH2Cl2. a Total reaction time; addition of the cyclic nitrones III-V was
accomplished over 10 h (15 h in entry 9). b Based on nitrone. c Determined
by 1H NMR. d Determined by integration of the 1H NMR signals of the
diastereomeric (S)-methylbenzylimine (nitrone I), (R)-methylbenzylimine
(nitrone II) or (S)-(+)-mandelic acid (nitrone IV) derivatives or with the
use of the chiral shift reagent Eu(hfc)3 (nitrones III and V). e Catalyst 0.06
mmol (5.0 mol %), methacrolein 1.68 mmol, 50 mg of 4Å molecular sieves,
and nitrone 1.2 mmol in 5 mL of CH2Cl2.
[(η5-C5Me5)M{(R)-Prophos}(methacrolein)]2+ were the sole
metallic complexes present in solution (see above). Otherwise,
complexes 1 and 2 could catalyze the hydrolysis of the nitrone.34
Although both rhodium and iridium systems perform similarly,
the iridium system is a little more reactive and selective. Usually,
quantitative conversions are obtained after a few hours at a
typical temperature of -25 °C. Ee’s greater than 90% were
achieved in most cases. A greater excess of methacrolein
improves both rate and enantioselectivity (compare entries 11
and 12 with a catalyst/methacrolein/nitrone ratio of 1/28/20 with
(33) We would also like to remark the presence of short contact distances for
protons belonging to carbons adjacent to the CdN functionality (C(38)
and C(42) for complex 6 and C(38) and C(41) for complex 8). Correspond-
ingly, shieldings from 0.48 to 0.79 ppm were observed for these protons.
From these parameters, we suggest that additional CH/π interactions,
concerted with the main CH/π interactions detailed in Table 3, could be
taking place.
Catalytic Reactions. The water complexes (SM,RC)-[(η5-C5-
Me5)M{(R)-Prophos}(H2O)]2+ (M ) Rh (1), Ir (2)) efficiently
catalyze the cycloaddition reaction of methacrolein with nitrones
I-V. Table 5 lists a selection of the results together with the
reaction conditions employed. The collected results are the
average of at least two comparable reaction runs. Catalyst
precursors have to be treated with methacrolein in the presence
of 4 Å MS before the addition of the nitrone. In these conditions,
(34) Nitrone I is stable in water for hours. However, the 31P NMR spectrum of
a mixture of 1.SbF6 and 20 equiv. of I showed the expected two doublet
of doublets system centered at 51.9 (JRhP1) 131.5 Hz, JP1P2 ) 40.7 Hz)
and 77.8 ppm (JRhP2 ) 131.1 Hz), assigned to the nitrone complex [(η5-
C5Me5)Rh{(R)-Prophos}(I)]2+, along with two humps centered at 62 and
79 ppm and a poorly resolved weak multiplet at 51 ppm. The spectrum of
a mixture of 1.SbF6 and the products of the hydrolysis of I, phenylhy-
droxylamine and benzaldehyde, presents the three later signals. Therefore,
we concluded that complex 1.SbF6 catalyzes the hydrolysis of nitrone I.
(32) Lee, J.; Twamley, B.; Richter-Addo, G. B. Chem. Commun. 2002, 380-
381.
9
13392 J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005

On the Origin of the Enantioselectivity
A R T I C L E S
Table 6. Effect of the Temperature
Table 7. Effect of the Anion, Solvent, and Catalyst Loading, and
Reutilization of the Catalyst in the 1,3-Dipolar Cycloaddition
between Methacrolein and Nitrone I, at - 25 °C
yield
(%)
entry
complex
nitrone
T (°
C)
t (h)
3,4-endo
3,5-endo
ee (%)
entry
complex
t (h)
yield (%)
3,4-endo
3,5-endo
ee (%)
1a 1.SbF6
2a 1.SbF6
3a 1.SbF6
4a 1.SbF6
5a 1.SbF6
I
I
I
I
+5 15 100
15 100
-15 15 100
-25 15 100
-45 72 100
51
53
59
63
66
49
47
41
37
34
>99
100
42
29
22
84/68
85/68
88/72
90/75
92/79
92
1
2
3
1.SbF6
1.PF6
1.BF4
15
15
15
15
15
15
15
15
15
15
15
15
15
20
100
84
69
45
83
6
63
64
65
65
72
60
- -
63
63
63
63
63
63
63
37
36
35
35
28
40
- -
37
37
37
37
37
37
37
90/75
89/63
89/68
90/71
87/75
- -/- -
- -
90/70
90/75
90/75
90/74
90/75
90/70
90/71
0
4
1.CF3SO3
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
1.SbF6
I
5a
6
7
8
1.SbF6
1.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
2.SbF6
IV
IV
I
I
I
-25 15
99
6b
-45 45 100
95
7c
0
+5
-5
6
7
8
100
100
100
58
71
78
82
86.5
5
85/79
91/81
93.5/82
95/85.5
8d
41
100
100
90
90
80
75
9
9e
10
11
12
13
14
15
16
17
18
-15
10.1
10.2
10.3
10.4
10.5
I
I
-25 10 100
18
-35 24 100
13.5 96/87
95
98
100
100
>99
100
II
II
III
III
V
V
0
15
78
78
- -/88
- -/93
86
91
93
-10 24
2
-25 15 100
-35 24 55
-25 15 100
-35 24 53
Reaction conditions: catalyst 0.03 mmol (5.0 mol %), methacrolein 0.84
mmol, 50 mg of 4 Å molecular sieves, and nitrone 0.6 mmol in 5 mL of
CH2Cl2. a In dichloromethane/toluene, 1/1 v/v. b In acetone. c In ni-
tromethane. d Catalyst loading 1 mol %. e Catalyst loading 10 mol %. For
other conditions see footnote of Table 5.
95
For conditions see footnote of Table 5. a See paragraph e in footnote of
Table 5.
catalysis (entries 5-7). When the reaction was performed with
only 1 mol % of catalyst, a conversion of 41% was measured
after 15 h of treatment without significant changes in the ee
values (entry 8). Increasing the catalyst loading did not improve
the enantioselectivity (entry 9). Notably, despite being an
homogeneous system, the catalyst can be easily recovered and
reused. Consecutive catalyst runs of up to 4 more times were
possible, producing very similar results (entries 10.1-10.5).
entries 5 and 6 (1/140/20 ratio), respectively). The acyclic
nitrone II generates the less active system but, even so,
conversions of 75 and 78% were achieved after 24 h at -10
°C (entries 3 and 4). To avoid undesired nitrone coordination,
cyclic nitrones were added over a 10-15 h period (see above).
Ab initio calculations carried out by Tanaka and Kanemasa
on the model reaction between nitrone CH2dN(O)H and
acrolein (CH2dCHCHO) in the presence of BH3 or BF3 catalysts
conclude that under Lewis acid-catalyzed conditions the forma-
tion of endo-cycloadducts is preferred and that the attack of
nucleophilic nitrone oxygen should become more favored to
occur at the â-position of the enal rendering 3,4-cycloadducts.35
In our system, endo preference is showed in all cases and
reactions occur with perfect endo selectivity. With respect to
the regioselectivity, while the uncatalyzed reaction of nitrone I
with methacrolein gives the 3,5-endo adduct, the major product
of the catalyzed reaction is the 3,4-endo cycloadduct (entries 1
and 2, Table 5), according to the Kanemasa studies. On the
other hand, cyclic nitrones III-V, which are more sterically
demanding in their endo-approach to coordinated methacrolein,
render 3,5-cycloadducts in all cases. These results are in good
agreement with previous experimental work.7,36
Catalytic Cycle. Taking together all the above observations
we propose the catalytic cycle depicted in Scheme 2. Repre-
sentative examples of the [M]-OH2, [M]-methacrolein and
[M]-nitrone intermediates have been spectroscopically and
crystallographically characterized. Examples of the remaining
[M]-adduct species have also been spectroscopically detected
when, at around -45 °C, the reaction between nitrone I and
methacrolein, catalyzed by the iridium compound 2.SbF6, was
monitored by NMR spectroscopy. Thus, 90 min after the
addition of 20 equiv. of nitrone I to a mixture of 2.SbF6 and 6
equiv. of methacrolein, in the presence of molecular sieves, the
31P NMR spectrum shows, along with peaks of the methacrolein
iridium complex 4 (33.5%), the formation of two not previously
observed (R)-Prophos containing compounds. Their resonances
appear as a pair of corresponding broad singlets centered at
48.70 and 28.44 ppm (47%) and at 49.27 and 29.72 ppm
(19.5%). Simultaneously, the proton NMR spectrum revealed
the formation of the cycloadduct products. Interestingly, when
6 equiv. of a mixture of adduct, preformed according to entry
12, Table 6, were added to a solution of 2.SbF6, in the presence
of 4Å MS, the 31P NMR spectrum, at -50 °C, showed the
presence of the iridium methacrolein complex 4, two doublets
at 46.88 (JP1P2 ) 12.9 Hz) and at 21.53 ppm, that we assign to
the nitrone complex [(η5-C5Me5)Ir{(R)-Prophos}(nitrone I)]2+
and the pair of broad singlets of the new minor compound
above-mentioned. Therefore, we tentatively assign the new
resonances to the two adduct containing compounds [(η5-C5-
Me5)Ir{(R)-Prophos}(3,4-endo adduct)]2+ and [(η5-C5Me5)Ir-
Temperature variation slightly affected both product distribu-
tion, and enantioselectivity, the later smoothly increasing as
temperature decreases (Table 6).
The effect of the anion, solvent, catalyst loading, as well as
the reutilization of the catalyst was studied for the methacrolein/
nitrone I/1.SbF6 system (Table 7). The use of more coordinating
anions, such as PF6-, BF4-, or CF3SO3-, decreased the yield.
However, neither the 3,4-endo/3,5-endo ratio nor the ee were
significantly affected (entries 1-4). In this respect, no anion-
cation interactions have been found in the crystal structures of
the catalysts 3 and 4. Thus, most probably, these counterion
effects are due to competition of the anion and the substrate
for the Lewis acid site.10,15 In this line, conversion was also
strongly affected by the solvent, especially by good coordinating
solvents, such as nitromethane or acetone, which preclude
{(R)-Prophos}(3,5-endo adduct)]2+ 37
.
At -25 °C, the resting state of the catalyst is the [M]-
methacrolein complex. According to Scheme 2, it is the true
catalyst. Its reaction with the nitrone is the key step of the
(35) Tanaka, J.; Kanemasa, S. Tetrahedron 2001, 57, 899-905.
(36) Ali, S. A.; Khan, J. H.; Wazeer, M. I. M. Tetrahedron 1988, 44, 5911-
5920.
9
J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005 13393

A R T I C L E S
Carmona et al.
Scheme 2. Proposed Catalytic Cycle
Scheme 3. Absolute Configuration of the Major Adducts Derived
from Nitrones I and III-V
productive cycle A: it is the rate and enantioselectivity
determining step, at this temperature. For cyclic nitrones, path
B becomes operative diminishing the concentration of the active
species and, therefore, decreasing the rate. Lowering nitrone
concentration (slow addition) avoids this undesired side reaction
and, although it also slows down the rate of formation of the
[M]-adduct intermediate, overall it favors the catalytic process.
It has been experimentally shown that the catalytic rate
increases when methacrolein concentration increases. Scheme
2 explains this effect because increasing this concentration favors
the adduct elimination in path A and it recuperates the inactive
metallic concentration, present as [M]-nitrone in path B,
shifting the [M]-nitrone/[M]-methacrolein equilibrium toward
the enal complex which restarts the cycle.
Determination of the Absolute Configuration. The absolute
configuration of the 3,5-endo adducts derived from nitrones
III-V has been established by comparison of their optical
properties with those reported in the literature.7 From circular
dichroism and polarimetric data38 it was concluded that the
major isomer obtained has 3R,5R configuration for compounds
10 and 11 and 3S,5R for compound 12 (Scheme 3). The
configuration of 9 was determined as depicted in Scheme 4.
Mixtures of 3,4-endo and 3,5-endo isoxazolidines, obtained from
cycloaddition with nitrone I, were separated by radial chroma-
tography. The isolated enantioenriched compounds were con-
verted into diastereomeric mixtures of amines through conden-
sation with (S)-(-)-R-methylbenzylamine followed by in situ
reduction of the resulting imine with sodium borohydride in
methanol. To confirm the absolute configuration of the major
adduct 3,4-endo-9, the corresponding derived amine was purified
by radial chromatography and treated with hydrochloric acid
to form the corresponding hydrochloride. Crystals suitable for
X-ray analysis were obtained and its molecular structure was
determined. Figure 5 shows a view of the cation and an ORTEP
representation is included in the SI. The absolute configuration
of the stereogenic centers was established unambiguously as
3R,4R, corresponding to the 3R,4R catalytic adduct, in contrast
to our previous assignment.13
Origin of the Enantioselectivity. Our (η5-C5Me5)M{(R)-
Prophos} system is very selective for the DCR of nitrones and
methacrolein with enantioselectivity up to 96% ee. In this
respect, there are a few structural features that deserve some
comments. First, despite (R)-Prophos being a C1 symmetric
(37) From the spectroscopic measurements, it seems that, in the absence of
methacrolein, (η5-C5Me5)Ir{(R)-Prophos} species efficiently catalyze the
decomposition of the cycloadducts to the corresponding nitrone and
methacrolein, in this way generating the observed iridium-nitrone I and
iridium-methacrolein complexes.
(38) Compound 10 (ee ) 85%): [R]D,26°C ) +29 (c ) 0.84, CH2Cl2); CD (CH2-
Cl2, 9.7 × 10-3 M, 20 °C): λ (∆ꢀ) 266 (+ 0.12), 303 (-0.20). Compound
11 (ee ) 95%): [R]D,25°C ) -142 (c ) 0.84, CH2Cl2); CD (CH2Cl2, 1.7 ×
10-3 M, 20 °C): λ (∆ꢀ) 238 (+ 4.05), 310 (-3.33). Compound 12 (ee )
93%): [R]D,25°C ) -81 (c ) 0.87, CH2Cl2); CD (CH2Cl2, 1.5 × 10-3 M,
20 °C): λ (∆ꢀ) 246 (+ 1.73), 306 (-2.00).
9
13394 J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005

On the Origin of the Enantioselectivity
A R T I C L E S
Figure 5. View of the cation of the reductive amination derivative.
Scheme 4. Derivatization of Isoxazolidines 9 (only the endo-3,4
Adduct is Shown)
Figure 6. Space filling diagram of the chiral pocket configured by C5Me5
and the (R)-Prophos Ligand in the Iridium Catalyst 4 (violet: iridium;
orange: phosphorus; dark gray: carbon; light gray: hydrogen).
partial double bond character of the C(38)-C(39) bond, and,
according to spectroscopic data, it is retained in catalytic
conditions. Fourth, the CH/π attractive interactions between the
CHO aldehyde proton and the pro-S phenyl ring establish the
methacrolein rotamer around the M-O bond both in the solid
state and in solution. Overall, the geometry of the methacrolein
is set and, in the chiral environment in which it is located,
despite the presence of the bulky C5Me5 group, its Re-face
becomes much more accessible to the nitrone than its Si-face,
which is shielded by the phenyl rings of the (R)-Prophos ligand.
This situation seems also to apply for the transition-state
assembly of the 1,3-dipolar cycloaddition reaction; hence, the
outcome of the enantioselective catalysis can be rationalized
on the basis of the precedent arguments: nitrone attack occurs
preferentially to the Re-face of the coordinated methacrolein.
Concluding Remarks
We have developed a catalytic system based on the (η5-C5-
Me5)M{(R)-Prophos} fragment which is well suited for the DCR
between nitrones and methacrolein. The remarkable stereoelec-
tronic properties of this fragment establish the chiral bias of its
single binding pocket. Notably, methacrolein coordinates to the
metallic fragment in a completely diastereoselective way and
adopts a fixed geometry. Typically, perfect regio- and diaste-
reoselectivity and good to excellent enantioselectivity are
achieved. The characterization of most of the intermediates
involved in the catalytic process allow us to propose a plausible
catalytic cycle, which accounts for all the experimental observa-
tions, and to rationalize the achieved selectivities. From all these
data, along with the assignment of the absolute configuration
to the adducts, the origin of the enantioselectivity can be
conveniently explained. Finally, the structure of the nitrone
complexes [(η5-C5Me5)M{(R)-Prophos}(nitrone)](SbF6)2 shows
that the geometry of the nitrone inside the chiral (η5-C5Me5)M-
{(R)-Prophos} pocket is also established through CH/π interac-
tions. This feature opens the door to new and interesting catalytic
processes that are currently under investigation in our laboratory.
ligand, the S metal epimer of the [(η5-C5Me5)M{(R)-Prophos}-
(methacrolein)]2+ catalysts is formed with complete diastereo-
selectivity. Moreover, although, in some instances, epimerization
at the metal in chiral half-sandwich transition metal complexes
is a low-demanding energy process,39 we have not detected it
in our system. Second, all the diffractometric and spectroscopic
data support a λ conformation for the M-P-C-C-P five-
membered metallacycle formed on coordination of the (R)-
Prophos ligand. The bulky C5Me5 ring constrains this confor-
mation forcing the methyl substituent to occupy the less hindered
pseudoequatorial position. This conformation, together with the
S configuration at the metal, determines the chiral bias of the
catalyst pocket in which catalysis takes place (Figure 6). Third,
methacrolein coordinates to the metallic fragment in the E
geometry and it adopts an s-trans conformation.10,11,40 This
conformation, which is also preferred for uncomplexed meth-
acrolein,41 is reinforced by coordination as evidenced by the
Experimental Section
General Methods. All solvents were dried over appropriate drying
agents, distilled under argon, and degassed prior to being used. All
(40) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Garrat, S. A.; Russell, D. R.
J. Chem. Soc., Dalton Trans. 2000, 4432-4441.
(41) Ishihara, K.; Qingzhi, G.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
10412-10413.
(39) Brunner, H. Eur. J. Inorg. Chem. 2001, 905-912.
9
J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005 13395

A R T I C L E S
Carmona et al.
Chart 5. Labeling of (R)-Prophos for NMR Assignments
-25 °C): δ ) 209.71 (s, CHO), 149.40 (s, CHOC(CH3)CHH), 146.07
(s, CHOC(CH3)CHH), 139-121 (Ph), 109.02 (dt, JRhC ) 5.6, JPC
)
1.8 Hz, C5Me5), 35.50 (dd, JPC ) 34.6, JPC ) 15.8 Hz, Ctc), 32.82 (dd,
JPC ) 31.4, JPC ) 10.3 Hz, CMe), 17.77 (dd, JPC ) 17.9, JPC ) 5.2 Hz,
Me) 11.19 (C5Me5). 31P NMR (161.96 MHz, CD2Cl2, -25 °C): δ )
76.18 (dd, JRhP1 ) 131.3 Hz, JP2P1 ) 37.9 Hz, P1), 52.00 (dd, JRhP2
)
134.2 Hz, P2). IR (KBr pellets, cm-1): ν(CO) 1599s, ν(SbF6) 658vs.
Anal. Calcd for C42H49Cl2F12OP2RhSb2: C, 39.5; H, 3.8. Found: C,
39.3; H, 3.7.
4: 1H NMR (400 MHz, CD2Cl2, -25 °C): δ ) 7.95-7.2 (m, 20H,
Ph), 7.23 (s, 1H, CHO), 6.26 (s, 1H, CHOC(CH3)CHH), 5.69 (s, 1H,
CHOC(CH3)CHH), 3.55 (dddd, J ) 48.3, 15.4, 11.1, 4.6 Hz, 1H, Hc/t),
2.79 (m, 1H, Hg), 2.65 (m, 1H, Ht/c), 1.40 (st, JPH ) 2.1 Hz, 15H,
C5Me5), 1.38 (Me, overlapped with the C5Me5 triplet), 1.10 (s, 3H,
CHOC(CH3)CHH). 13C NMR (100.62 MHz, CD2Cl2, -25 °C): δ )
209.29 (s, CHO), 149.09 (s, CHOC(CH3)CHH), 144.26 (s, CHOC(CH3)-
CHH), 135-118 (Ph), 101.26 (st, JPC ) 1.9 Hz, C5Me5), 34.20 (dd,
JPC ) 41.0, JPC ) 11.7 Hz, Ctc), 31.47 (dd, JPC ) 37.0, JPC ) 7.7 Hz,
preparations have been carried out under an argon atmosphere. Infrared
spectra were recorded on a Perkin-Elmer 1330 spectrophotometer.
Carbon, hydrogen, and nitrogen analyses were performed using a
Perkin-Elmer 240C microanalyzer. NMR spectra were recorded on a
Bruker AV-400.(400.16 MHz) spectrometer. Chemical shifts are
expressed in ppm upfield from SiMe4 and 85% H3PO4 (31P). NOEDIFF
and 13C, 31P, 1H correlation spectra were obtained using standard
procedures. CD spectra were determined in dichloromethane (ca. 5 ×
10-4 mol L-1 solutions) in a 1 cm path length cell by using a Jasco-
710 apparatus. Optical rotations were recorded on a Perkin-Elmer-241
polarimeter (10 cm cell, 589 nm).
C
Me), 15.18 (dd, JPC ) 17.6, JPC ) 4.4 Hz, Me). 31P NMR (161.96
MHz, CD2Cl2, -25 °C): δ ) 48.47 (d, JP2P1 ) 8.4 Hz, P1), 27.75 (d,
P2). IR (KBr pellets, cm-1): ν(CO) 1583m, ν(SbF6) 658s. Anal. Calcd
for C41H47F12IrOP2Sb2: C, 38.4; H, 3.7. Found: C, 38.05; H, 4.0. [(η5-
C5Me5)Rh{(R)-Prophos}(III)](SbF6)2 (5). At -25 °C, under argon,
a solution of [(η5-C5Me5)Rh{(R)-Prophos}(H2O)](SbF6)2 (150.0 mg,
0.131 mmol) in CH2Cl2 (4 mL) was stirred with 4 Å molecular sieves
(200.0 mg) for 20 min. Then, 12.3 mg (0.145 mmol) of nitrone III
were added and the suspension was stirred for 20 min. Addition of 20
mL of hexanes caused the precipitation of a solid. The solvents were
separated by decantation and the residue washed with 3 × 20 mL of
hexanes. After washing the residue was extracted with 5 mL of CH2-
Cl2. Addition of 20 mL of hexanes to the resulting solution gave an
orange-red solid which was washed with hexanes and vacuum-dried
(144.9 mg, 91.2%). The related compounds 6-8 were prepared similarly.
Yield: 6, 94.0%; 7, 92.4%; 8, 91.1%.
[(η5-C5Me5)Ir{(R)-Prophos}(H2O)](SbF6)2 (2). To a suspension of
[{(η5-C5Me5)IrCl}2(µ-Cl)2] (150.0 mg, 0.188 mmol) in acetone (7 mL)
AgSbF6 (258.8 mg, 0.753 mmol) was added. The resulting suspension
was stirred at room temperature for 3 h. The mixture was filtered over
kieselguhr and the precipitate washed with 3 × 1 mL of acetone. The
filtrate was concentrated to ca. 5 mL and cooled to -50 °C. Solid (R)-
Prophos (155.3 mg, 0.376 mmol) was added. The solution was stirred
at -50 °C for 20 min and 20 mL of hexanes was then added. The
resulting yellow oil was stirred at room temperature until it converts
1
to a yellow solid (416.6 mg, 88.8%). H NMR (400 MHz, CD2Cl2, 0
°C): δ ) 7.98-7.23 (m, 20H, Ph), 3.79 (brs, 2H, H2O), 3.23 (dddd, J
) 48.3, 15.4, 11.3, 4.8 Hz, 1H, Hc), 2.80 (m, 1H, 1H, Hg), 2.35 (m,
1H, Ht), 1.48 (st, J ) 2.2 Hz, 15H, C5Me5), 1.31 (dd, J ) 14.3, 6.6
Hz, 3H, Me). 13C NMR (100.62 MHz, CD2Cl2, 0 °C): δ ) 136-118
(Ph), 99.76 (br, C5Me5), 31.1 (m, Ctc), 30.8 (m, CMe), 13.83 (dd, J )
17.6, 4.4 Hz, Me), 8.74 (s, C5Me5). 31P NMR (161.96 MHz, CD2Cl2,
-25 °C): δ ) 47.61 (d, JP2P1 ) 12.9 Hz, P1), 22.72 (d, P2). IR (KBr
pellets, cm-1): ν(SbF6) 659s. Anal. Calcd for C37H45F12IrO2P2Sb2: C,
35.6; H, 3.6. Found: C, 35.7; H 3.6.
[(η5-C5Me5)Ir{(R)-Prophos}(methacrolein)](SbF6)2 (4). At -25
°C, under argon, to a solution of [(η5-C5Me5)Ir{(R)-Prophos}(H2O)]-
(SbF6)2 (150.0 mg, 0.120 mmol) in CH2Cl2 (4 mL) methacrolein (33.0
µL, 0.395 mmol) and 4 Å molecular sieves (200.0 mg) were added.
The solution was stirred for 20 min and then the solvent was vacuum-
evaporated. The residue was extracted with 3 × 2 mL of CH2Cl2, at
-25 °C. The addition of 20 mL of dry hexane to the yellow filtrate
afforded a yellow solid that was filtered off, washed with hexane and
vacuum-dried (140.7 mg, 91.3%). The rhodium analogue 3 was prepared
similarly (yield: 91.2%).
5: 1H NMR (400 MHz, CD2Cl2, -50 °C): δ ) 7.1-7.9 (m, 20H,
Ph), 4.94 (s, 1H, H1), 3.17 (m, 3H, Hc, H41, H42), 2.99 (m, 1H, Hg),
2.53 (m, 1H, H22), 2.29 (m, 1H, Ht), 2.21 (m, 1H, H21), 1.97 (m, 2H,
H31, H32), 1.36 (st, JPH ) 3.4 Hz, 15H, C5Me5), 1.18 (dd, JPH ) 12.8,
JPH ) 5.1 Hz, 3H, Me). 13C NMR (100.62 MHz, CD2Cl2, -50 °C): δ
) 148.11 (C1), 136-120 (Ph), 104.16 (C5Me5), 63.33 (C4), 31.53 (dd,
J ) 31.5, 13.5 Hz, Ctc), 30.45 (C2), 29.75 (dd, J ) 32.4, 10.8 Hz,
CMe), 18.60 (C3), 15.15 (dd, J ) 17.7, 5.2 Hz, Me), 10.11 (C5Me5). 31
P
NMR (161.96 MHz, CD2Cl2, -50 °C): δ ) 73.16 (dd, JRhP1 ) 128.8
Hz, JP2P1 ) 43.0 Hz, P1), 48.93 (dd, JRhP2 ) 132.4 Hz, P2). IR (KBr
pellets, cm-1): ν(CN) 1618m, ν(SbF6) 658vs. Anal. Calcd for C41H48F12-
NOP2RhSb2: C, 40.6; H, 4.3; N, 1.3. Found: C, 40.8; H, 4.0; N, 1.2.
6: 1H NMR (400 MHz, CD2Cl2, -25 °C): δ ) 7.1-7.9 (m, 20H,
Ph), 5.57 (bs, 1H, H1), 3.16 (m, 1H, Hc), 3.10 (m, 1H, Hg), 2.91 (m,
2H, H51, H52), 2.33 (m, 1H, Ht), 2.25, 1.62 (m, 2H, H21, H22), 1.69 (m,
2H, H41, H42), 1.45 (partially overlapped) (m, 2H, H31, H32), 1.43 (st,
JPH ) 3.4 Hz, 15H, C5Me5), 1.22 (dd, JPH ) 13.4, JPH ) 6.4 Hz, 3H,
Me). 13C NMR (100.62 MHz, CD2Cl2, -25 °C): δ ) 147.82 (C1),
136-120 (Ph), 103.87 (st, JPC ) 2.7 Hz, C5Me5), 57.44 (C5), 30.94
(dd, J ) 32.9, 14.6 Hz, Ctc), 29.43 (dd, J ) 32.3, 10.4 Hz, CMe), 26.05
(C2), 21.65 (C4), 15.57 (C3), 14.70 (dd, J ) 17.7, 5.5 Hz, Me), 9.76
3: 1H NMR (400 MHz, CD2Cl2, -25 °C): δ ) 7.9-7.2 (m, 20H,
Ph), 7.06 (s, 1H, CHO), 6.27 (s, 1H, CHOC(CH3)CHH), 5.63 (s, 1H,
CHOC(CH3)CHH), 3.53 (m, 1H, Hc/t), 2.75 (m, 2H, Hg, Ht/c), 1.34 (st,
JPH ) 3.0 Hz, 15H, C5Me5), 1.28 (dd, JPH ) 13.9, JPH ) 6.1 Hz, 3H,
Me), 1.06 (s, 3H, CHOC(CH3)CHH). 13C NMR (100.62 MHz CD2Cl2,
Chart 6. Labeling for NMR Assignments.
9
13396 J. AM. CHEM. SOC. VOL. 127, NO. 38, 2005

On the Origin of the Enantioselectivity
A R T I C L E S
(C5Me5). 31P NMR (161.96 MHz, CD2Cl2, -25 °C): δ ) 72.15 (dd,
JRhP1 ) 131.9 Hz, JP2P1 ) 41.7 Hz, P1), 48.70 (dd, JRhP2 ) 128.3 Hz,
P2). IR (KBr pellets, cm-1): ν(CN) 1649m, ν(SbF6) 658vs. Anal. Calcd
for C42H50F12NOP2RhSb2: C, 41.1; H, 3.9; N, 1.0 Found: C, 41.3; H,
4.1; N, 1.15.
7: 1H NMR (400 MHz, CD2Cl2, -25 °C): δ ) 7.2-7.9 (m, 24H,
Ph, C3-C6), 6.58 (d, JHH ) 7.6 Hz, 1H, H3), 5.97 (bs, 1H, H1), 3.29
(m, 1H, Hc), 3.21 (m, 3H, Hg, H91, H92), 3.00 (m, 2H, H81, H82), 2.36
organic layer was separated, washed with brine (1 × 10 mL), dried
over MgSO4 and evaporated under reduced pressure. The residue was
purified by radial chromatography (hexane/ethyl acetate, 80:20) to give
pure 14a and 14b.
(3R,4R)-14a: 1H RMN (400 MHz, CDCl3, 25 °C) δ 0.62 (s, 3H,
C4-CH3), 1.22 (d, J ) 6.6 Hz, 3H, NH-CHCH3Ar), 1.28 (bs, 1H,
NH), 2.43 (d, J ) 11.9 Hz, 1H, NH-CH2a-C4), 2.51 (d, J ) 11.9 Hz,
1H, NH-CH2b-C4), 3.60 (q, J ) 6.6 Hz, 1H, NH-CHCH3Ar), 3.73
(d, J ) 8.2 Hz, 1H, H5a), 3.90 (d, J ) 8.2 Hz, 1H, H5b), 4.32 (s, 1H,
H3), 6.73-7.38 (15H, Ar).
(m, 1H, Ht), 1.46 (st, JPH ) 3.4 Hz, 15H, C5Me5), 1.24 (dd, JPH
)
12.9, JPH ) 6.1 Hz, 3H, Me). 13C NMR (100.62 MHz, CD2Cl2, -25
°C): δ ) 142.28 (C1), 135-120 (Ph, C2-C7), 103.92 (st, JPC ) 2.6
Hz, C5Me5), 56.73 (C9), 30.69 (dd, J ) 32.6, 15.0 Hz, Ctc), 29.53 (dd,
J ) 31.1, 9.9 Hz, CMe), 26.20 (C8), 14.70 (dd, J ) 18.0, 5.5 Hz, Me),
9.91 (C5Me5). 31P NMR (161.96 MHz, CD2Cl2, -25 °C): δ ) 72.45
(dd, JRhP1 ) 132.2 Hz, JP2P1 ) 42.6 Hz, P1), 49.2 (dd, JRhP2 ) 128.3
Hz, P2). IR (KBr pellets, cm-1): ν(CN) 1617m, ν(SbF6) 659vs. Anal.
Calcd for C46H50F12NOP2RhSb2: C, 43.3; H, 4.0; N, 1.0 Found: C,
43.5; H, 4.0; N, 1.1.
(3S,4S)-14b: 1H RMN (400 MHz, CDCl3, 25 °C) δ 0.64 (s, 3H,
C4-CH3), 1.19 (d, J ) 6.6 Hz, 3H, NH-CHCH3Ar), 1.28 (bs, 1H,
NH), 2.37 (d, J ) 11.9 Hz, 1H, NH-CH2a-C4), 2.55 (d, J ) 11.9 Hz,
1H, NH-CH2b-C4), 3.56 (q, J ) 6.6 Hz, 1H, NH-CHCH3Ar), 3.77
(d, J ) 8.1 Hz, 1H, H5a), 3.84 (d, J ) 8.1 Hz, 1H, H5b), 4.30 (s, 1H,
H3), 6.73-7.38 (15H, Ar).
Synthesis of the Hydrochloride Salts of 15a and 15b. The
corresponding pure compound 14 (37 mg, 0.1 mmol) was dissolved in
diethyl ether and the resulting solution was treated with 2 N HCl in
the same solvent. A white solid precipitated immediately. The
precipitate was filtered, washed with ether, and dried to yield the pure
hydrochloride salt of 15.
15a: 1H RMN (400 MHz, CD3OD, 25°C) δ 0.68 (s, 3H, C4-CH3),
1.64 (d, J ) 6.9 Hz, 3H, NH2-CHCH3Ar), 2.80 (d, J ) 13.1, 1H,
NH2-CH2a-C4), 3.16 (d, J ) 13.1 Hz, 1H, NH2-CH2b-C4), 3.89 (d,
J ) 8.9 Hz, 1H, H5a), 4.02 (d, J ) 8.9 Hz, 1H, H5b), 4.17 (s, 1H, H3),
4.37 (q, J ) 6.8 Hz, 1H, NH2-CHCH3Ar), 6.69-7.43 (15H, Ar).
15b: 1H RMN (400 MHz, CD3OD, 25 °C) δ 0.74 (s, 3H, C4-CH3),
1.64 (d, J ) 6.9 Hz, 3H, NH2-CHCH3Ar), 2.86 (d, J ) 13.1 Hz, 1H,
NH2-CH2a-C4), 3.07 (d, J ) 13.1 Hz, 1H, NH2-CH2b-C4), 3.84 (d, J
) 4.1 Hz, 1H, H5a), 4.02 (d, J ) 8.9 Hz, 1H, H5b), 4.13 (s, 1H, H3),
4.31 (q, J ) 6.8, 4.6 Hz, 1H, NH2-CHCH3Ar), 6.69-7.43 (15H, Ar).
Suitable crystals for X-ray of compound 15a were obtained by slow
crystallization from methanol/isopropyl ether.
Structural Analysis of Complexes 1.BF4, 2.SbF6, 3, 4, 6, and 8.
X-ray data were collected for all complexes at low temperature (1.BF4
at 150(2) K and all the rest at 100(2) K) on Daresbury SRS Station 9.8
with silicon monochromated synchrotron radiation (λ ) 0.693 40 Å)
(1.BF4) or in a Bruker SMART APEX CCD diffractometer with
graphite monochromated Mo KR radiation (λ ) 0.71073 Å) (2.SbF6,
3, 4, 8, and 10) using in all cases ω scans. Data were corrected for
absorption by using a multiscan method applied with the SADABS
program.42
The structures were solved by direct methods with SHELXS-86.43
Refinement, by full-matrix least squares on F2 with SHELXL97,43 was
similar for all complexes, including isotropic and subsequently aniso-
tropic displacement parameters for all non-hydrogen nondisordered
atoms. Particular details concerning the presence of solvent, static
disorder and hydrogen refinement are listed below. All the highest
electronic residuals were observed in close proximity of the metal or
Sb atoms and have no chemical sense. In all structures, additionally to
the internal configuration reference of the (R)-Prophos ligand, the Flack
parameter was refined as a check of a correct absolute configuration
determination.44
Crystal data for 1.BF4: C37H43B2F8OP2Rh‚H2O‚CH2Cl2, M )
945.13; yellow needle, 0.200 × 0.040 × 0.010 mm3; monoclinic, P21;
a ) 10.0890(13), b ) 9.6210(12), c ) 22.019(3) Å, â ) 102.170(3)°;
Z ) 2; V ) 2089.3(5) Å3; Dc ) 1.502 g/cm3; µ ) 0.682 mm-1, min &
max transmission factors 0.876 and 0.993; 2θmax ) 60.92°; 14 790
reflections collected, 10 466 unique [R(int) ) 0.0203]; number of data/
restrains/parameters 10 466/1/518; final GoF 1.066, R1 ) 0.0414
8: SIr,RC isomer: 1H NMR (400 MHz, CD2Cl2, 0 °C): δ ) 7.1-
7.9 (m, 20H, Ph), 5.27 (bs, 1H, H1), 3.34 (m, 2H, H41, H42), 3.16 (m,
1H, Hc), 3.01 (m, 1H, Hg), 2.62, 2.20 (m, 2H, H21, H22), 2.34 (m, 1H,
Ht), 2.08 (m, 2H, H31, H32), 1.48 (st, JPH ) 2.3 Hz, 15H, C5Me5), 1.30
(dd, JPH ) 13.9, JPH ) 5.3 Hz, 3H, Me). 13C NMR (100.62 MHz, CD2-
Cl2, 0 °C): δ ) 149.50 (C1), 119.5-137.0 (Ph), 98.24 (C5Me5), 62.28
(C4), 31.47 (dd, J ) 38.7, 11.3 Hz, Ctc), 30.06 (dd, J ) 32.4, 10.8 Hz,
CMe), 30.00 (C2), 18.46 (C3), 13.70 (dd, J ) 17.1, 4.55 Hz, Me), 9.23
(C5Me5). 31P NMR (161.96 MHz, CD2Cl2, 0 °C): δ ) 44.77 (d, JP2P1
) 11.7 Hz, P1), 24.67 (d, P2). IR (KBr pellets, cm-1): ν(CN) 1624m,
ν(SbF6) 658vs. Anal. Calcd for C41H48F12IrNOP2Sb2: C, 38.1; H, 3.8;
N, 1.0. Found: C, 38.0; H, 3.7; N, 1.1. RIr,RC isomer: 1H NMR (400
MHz, CD2Cl2, -25 °C): δ ) 7.0-8.0 (m, 20H, Ph), 6.40 (bs, 1H,
H1), 3.93, 3.30 (m, 2H, H41, H42), 3.25 (m, 1H, Hg), 3.21 (m, 1H, Hc),
2.76, 1.97 (m, 2H, H21, H22), 2.63 (m, 1H, Ht), 2.15, 1.80 (m, 2H, H31,
H32), 1.19 (st, JPH ) 2.2 Hz, 15H, C5Me5), 1.16 (dd, JPH ) 6.2 Hz, 3H,
Me). 13C NMR (100.62 MHz, CD2Cl2, -25 °C): δ ) 149.93 (C1),
119-135 (Ph), 100.81 (C5Me5), 62.32 (C4), 39.91 (dd, J ) 39.8, 10.2
Hz, CMe), 34.13 (dd, J ) 41.0, 10.2 Hz, Ctc), 29.01 (C2), 19.49 (C3),
14.74 (dd, J ) 17.1, 4.6 Hz, Me), 8.52 (C5Me5). 31P NMR (161.96
MHz, CD2Cl2, -25 °C): δ ) 29.56 (d, JP2P1 ) 10.9 Hz, P1), 22.50 (d,
P2).
Catalytic Procedure. The metallic complex [(η5-C5Me5)M{(R)-
Prophos}(H2O)]A2 (0.06 mmol, 5 mol %) was dissolved in CH2Cl2 (3
mL) at -25 °C. Freshly distilled methacrolein (0.70 mL, 8.40 mmol)
and 100.0 mg of activated 4Å molecular sieves were added and the
suspension stirred for 30 min. A solution of the corresponding nitrone
(1.20 mmol) in CH2Cl2 (3 mL) was added. For nitrones III-V, the
nitrone solution was added dropwise with a syringe pump for 10-15
h. After stirring at -25 °C for the appropriate reaction time, 20 mL of
hexanes were added. After filtration over diatomaceous earth, the
solution was evaporated to dryness. The residue was purified by
chromatography (SiO2) to provide a mixture of the corresponding
1
isomers. Regioselectivity was determined on the crude mixture by H
NMR analysis in C6D6 (nitrones I, II, and V) or CDCl3 (nitrones III
and IV). Enantioselectivity was determined as indicated in the footnote
of Table 5.
Synthesis of (1S)-N-((4-methyl-2,3-diphenylisoxazolidin-4-yl)-
methyl)-1-phenyl ethanamines 14. The corresponding mixtures of
adducts 9 (120 mg, 0.45 mmol) were dissolved in bencene (10 mL)
and treated with (S)-(-)-R-methylbenzylamine (73 mg, 0.60 mmol).
The resulting mixture was stirred at ambient temperature for 24 h at
which time the solvent was evaporated under reduced pressure. The
residue was taken up in methanol (10 mL) and treated with NaBH4
(19 mg, 0.5 mmol) at 0 °C. After 10 min, the reaction was quenched
with methanolic HCl (1 mL, 0.1M). The solvent was evaporated under
reduced pressure and the residue was partitioned between ethyl acetate
(10 mL) and saturated aqueous ammonium chloride (10 mL). The
(42) Blessing, R. H. Acta Crystallogr. 1995, A51, 33-38. SADABS: Area-
detector absorption correction, 1996, Bruker-AXS, Madison, WI.
(43) SHELXTL Package v. 6.10, 2000, Bruker AXS, Madison, WI. Sheldrick,
G. M. SHELXS-86 and SHELXL-97; University of Go¨ttingen: Go¨ttingen,
Germany, 1997.
(44) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
9
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A R T I C L E S
Carmona et al.
[10 313 reflections, I > 2σ(I)], wR2 ) 0.1083 for all data; Flack
parameter x ) 0.03(2); largest difference peak 2.558. A solvation
dichloromethane molecule was observed in the crystal structure; its
non-hydrogen atoms were refined anisotropically. A second crystal-
lization water molecule was at this point evident in the refinement.
Hydrogen atoms were partially observed in the difference Fourier maps,
but eventually included in calculated positions -with riding position
and thermal parameterssfor organic ligands and for the dichlo-
romethane solvent molecule. Hydrogens for the two water molecules
were included in the refinement from observed positions and refined
as free isotropic atoms. The four electron residuals over 1 e/Å3 were
situated close to the rhodium metal.
Crystal Data for 2.SbF6: C37H43F12IrOP2Sb2‚H2O, M ) 1247.37;
yellow needle, 0.459 × 0.095 × 0.048 mm3; orthorhombic, P212121; a
) 10.6154(8), b ) 15.8025(12), c ) 25.0896(19) Å; Z ) 4; V )
4208.8(6) Å3; Dc ) 1.969 g/cm3; µ ) 4.590 mm-1, min & max
transmission factors 0.227 and 0.810; 2θmax ) 57.44°; 51822 reflections
collected, 10191 unique [R(int) ) 0.0285]; number of data/restrains/
parameters 10191/0/685; final GoF 1.093, R1 ) 0.0209 [10034
reflections, I > 2σ(I)], wR2 ) 0.0493 for all data; Flack parameter x
) -0.004(2); largest difference peak 1.746. A water molecule was
observed as crystallization solvent in the structure. The organic
hydrogen atoms were included in observed positions and refined as
free isotropic atoms. At this stage of refinement the hydrogen atoms
of both water molecules were clearly observed in the difference Fourier
map. These four atoms were also included in the refinement as free
isotropic atoms. Five residual maxima above 1 e/Å3 were observed
around the Ir metal at distances shorter than 1.16 Å.
Crystal Data for 3: C41H47F12OP2RhSb2‚CH2Cl2, M ) 1277.06;
orange irregular block, 0.245 × 0.153 × 0.125 mm3; tetragonal, P41212;
a ) 13.6002(14), c ) 51.477(10) Å; Z ) 8; V ) 9521(2) Å3; Dc )
1.782 g/cm3; µ ) 1.728 mm-1, min & max transmission factors 0.677
and 0.813; 2θmax ) 56.72°; 118 669 reflections collected, 11785 unique
[R(int) ) 0.0490]; number of data/restrains/parameters 11 785/1/569;
final GoF 1.335, R1 ) 0.0515 [11 535 reflections, I > 2σ(I)], wR2 )
0.1158 for all data; Flack parameter x ) 0.02(3); largest difference
peak 1.344 e/Å3. All non-hydrogen atoms, except the atoms of a
solvation dichloromethane molecule, were refined anisotropically. This
solvent molecule was observed as disordered and interpreted to be
distributed in two isotropically refined positions. The hydrogens of the
non disordered atoms were included in calculated positions and refined
riding on carbon atoms.
chloride atoms of a the dichloromethane molecule, were refined
anisotropically. Hydrogens of the non disordered atoms were included
in calculated positions and refined riding on carbon atoms with free
displacement parameters.
Crystal Data for 6: C42H50F12NOP2RhSb2‚CH2Cl2, M ) 1304.09;
amber block, 0.175 × 0.172 × 0.147 mm3; tetragonal, P41212; a )
13.6725(3), c ) 52.004(3) Å); Z ) 8; V ) 9721.5(6) Å3; Dc ) 1.782
g/cm3; µ ) 1.695 mm-1, min & max transmission factors 0.741 and
0.774; 2θmax ) 54.26°; 63 220 reflections collected, 10 742 unique
[R(int) ) 0.0636]; number of data/restrains/parameters 10 742/0/571;
final GoF 1.204, R1 ) 0.0705 [9979 reflections, I > 2σ(I)], wR2 )
0.1658 for all data; Flack parameter x ) 0.02(4). All non-hydrogen
atoms, except a dichloromethane molecule, were refined anisotropically.
The hydrogen atoms were included in calculated positions and refined
riding on carbon atoms.
Crystal Data for 8: C41H48F12IrNOP2Sb2‚CH2Cl2, M ) 1381.37;
yellow irregular block, 0.146 × 0.080 × 0.024 mm3; tetragonal, P41212;
a ) 13.6029(4), c ) 51.708(3) Å; Z ) 8; V ) 9567.9(7) Å3; Dc )
1.918 g/cm3; µ ) 4.156 mm-1, min. & max. transmission factors 0.588
and 0.916; 2θmax ) 50.08°; 53198 reflections collected, 8460 unique
[R(int) ) 0.1060]; number of data/restrains/parameters 8460/12/577;
final GoF 1.075, R1 ) 0.0702 [7055 reflections, I > 2σ(I)], wR2 )
0.1602 for all data; Flack parameter x ) 0.054(13); largest difference
peak 4.375 e/Å3. The hydrogen atoms were included in calculated
positions and refined riding on carbon atoms.
Crystal Data for 9: C25H29ClN2O, M ) 408.95; colorless prismatic
block, 0.447 × 0.144 × 0.093 mm3; monoclinic, P21; a ) 11.3849(8),
b ) 7.4838(5), c ) 13.4086(9) Å, â ) 105.204(1)°; Z ) 2; V )
1102.46(13) Å3; Dc ) 1.232 g/cm3; µ ) 0.191 mm-1, min. & max.
transmission factors 0.919 and 0.982; 2θmax ) 56.56°; 13 511 reflections
collected, 5203 unique [R(int) ) 0.0264]; number of data/restrains/
parameters 5203/1/378; final GoF 1.036, R1 ) 0.0305 [5016 reflections,
I > 2σ(I)], wR2 ) 0.0751 for all data; Flack parameter x ) -0.03(4).
The hydrogen atoms were included in calculated positions and refined
as free isotropic atoms atoms.
Acknowledgment. We thank Ministerio de Ciencia y Tec-
nolog´ıa (MCyT, Spain) for financial support (Grants BQU2003/
01096 and BQU2004/021). R. R. acknowledges MCyT for a
predoctoral fellowship. Authors thank CCLRC Daresbury
Laboratory for allocation of synchrotron beam time (AP41) for
the X-ray measurement of complex 1.BF4.
Crystal Data for 4: C41H47F12IrOP2Sb2‚CH2Cl2, M ) 1366.35;
yellow regular prism, 0.403 × 0.263 × 0.131 mm3; tetragonal, P41212;
a ) 13.6161(3), c ) 51.580(2); Z ) 8; V ) 9562.8(5) Å3; Dc ) 1.898
g/cm3; µ ) 4.156 mm-1, min & max transmission factors 0.285 and
0.612; 2θmax ) 56.66°; 117464 reflections collected, 11788 unique
[R(int) ) 0.0386]; number of data/restrains/parameters 11 788/0/628;
final GoF 1.009, R1 ) 0.0355 [11 447 reflections, I > 2σ(I)], wR2 )
0.0818 for all data; Flack parameter x ) 0.022(4); largest difference
peak 1.578 e/Å3. All non-hydrogen atoms, except two disordered
Supporting Information Available: A crystallographic in-
formation file containing full details of the structural analysis
of the structures 1.BF4, 2.SbF6, 3, 4, 6, 8, and 15b (CIF format);
molecular representations (ORTEP style) of compounds 1.BF4,
3, 8, and 15b. This material is available free of charge via
Internet at http://pubs.acs.org.
JA0539443
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