The Complete Characterization of a Rhodium Lewis Acid-Dipolarophile Complex as an Intermediate for the Enantioselective Catalytic 1,3-Dipolar Cycloaddition of C,N-Diphenylnitrone to Methacrolein

Article abstract of DOI:10.1021/ja031995z

The 1,3-dipolar cycloaddition reaction of C,N-diphenylnitrone with methacrolein is efficiently catalyzed by the rhodium diphosphine compound (S_Rh,R_C)-[(η⁵-C₅Me₅)Rh(R-Prophos)(H₂O)](SbF₆)₂ [R-Prophos = (R)-(+)-1,2-bis(diphenylphosphino)-propane, 1·SbF₆]; the asymmetric catalytic process occurs with reversal of regioselectivity, perfect endo selectivity, and up to 92% ee. The complete (NMR and X-ray analysis) characterization of the involved intermediate (S_Rh,R_C)-[(η⁵-C₅Me₅)Rh(R-Prophos)(methacrolein)](SbF₆)₂ (7·SbF₆) allows us to interpret the observed selectivity. Copyright

Full text of DOI:10.1021/ja031995z

Published on Web 02/11/2004
The Complete Characterization of a Rhodium Lewis Acid-Dipolarophile
Complex as an Intermediate for the Enantioselective Catalytic 1,3-Dipolar
Cycloaddition of C,N-Diphenylnitrone to Methacrolein
Daniel Carmona,*,† M. Pilar Lamata,† Fernando Viguri,† Ricardo Rodr´ıguez,† Luis A. Oro,†
Ana I. Balana,† Fernando J. Lahoz,† Toma´s Tejero,*,‡ Pedro Merino,‡ Santiago Franco,‡ and
Isabel Montesa‡
Departamento de Qu´ımica Inorga´nica and Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales
de Arago´n, UniVersidad de Zaragoza-Consejo Superior de InVestigaciones Cient´ıficas, 50009 Zaragoza, Spain
Received December 30, 2003; E-mail: dcarmona@unizar.es; ttejero@unizar.es
Scheme 1. 1,3-DCR between C,N-Diphenylnitrone and
Methacrolein
The 1,3-dipolar cycloaddition reaction (1,3-DCR) of nitrones with
alkenes represents one of the most useful and convenient methods
for preparing isoxazolidines (Scheme 1) that are potential precursors
for biologically important compounds such as alkaloids, amino
acids, â-lactams, and amino sugars.1 The greatest challenge for the
1,3-DCR of nitrones with alkenes is to control the enantioselectivity
of the addition. For this purpose, the use of chiral Lewis acid
transition-metal auxiliaries is one of the most promising approaches.
Coordination of the organic substrates to the metal facilitates the
addition. Additionally, this may render the reaction catalytic and
can allow for an efficient control of the enantioselectivity.2
In the case of electron-deficient alkenes (normal electron demand
reaction3), the reaction is favored by coordination of the alkene-
withdrawing substituent to the metal. In general, coordination of
the nitrone oxygen to a Lewis acid is more feasible than a
monodentate coordination of a carbonyl function.4 Therefore, while
1,3-dicarbonyl compounds, enabling a more favored bidentate
coordination, turned out to be the model system of choice for most
studies on Lewis-acid catalyzed 1,3-DCR of nitrones,2-4 examples
of one-point binding catalysts for the activation of alkenes are very
limited.5
Here, we present the first example of a rhodium-based catalytic
system successfully applied to the scarcely explored case of 1,3-
DCR of nitrones to methacrolein. The catalytic process occurs with
a reversal of regioselectivity,6 perfect endo selectivity, and up to
92% ee. Additionally, the complete characterization of the involved
intermediate allows us to interpret the observed selectivities.
A few years ago, some of us demonstrated that methacrolein
coordinates to ruthenium in a half-sandwich complex.7 This
compound and the related rhodium derivative (SRh,RC)-[(η5-C5Me5)-
Rh(R-Prophos)(H2O)](SbF6)2 [R-Prophos ) (R)-(+)-1,2-bis(diphen-
ylphosphino)propane, 1‚SbF6]8 were shown to be active catalysts
for the Diels-Alder reaction between methacrolein and cyclopen-
tadiene. As the rhodium compound gave better enantioselectivity,
we concentrated our efforts on rhodium diphosphine compounds
in search of active systems for the 1,3-DCR of nitrones with
methacrolein.
Table 1. Enantioselective 1,3-Dipolar Cycloadditions between
Methacrolein and C,N-Diphenylnitronea
c
c
entry
catalyst
T (°C)
t (h)
yield (%)b,c
4
5
ee (%)d
1
2
3
4
5
6
7
8
9
10
11e
12f
13
14
15
16
none
6
room temp
-25
-25
+5
15
10
15
15
15
15
72
15
15
15
15
15
15
15
15
20
63
96
100
30
70
63
51
53
59
66
64
65
65
63
63
63
63
63
63
1‚SbF6
1‚SbF6
1‚SbF6
1‚SbF6
1‚SbF6
1‚PF6
100
100
100
100
100
84
69
45
41
100
90
37 90/75
49 84/68
47 85/68
41 88/72
34 92/79
36 89/63
35 89/68
35 90/71
37 90/70
37 90/75
37 90/74
37 90/75
37 90/70
37 90/71
0
-15
-45
-25
-25
-25
-25
-25
-25
-25
-25
-25
1‚BF4
1‚CF3SO3
1‚SbF6
1‚SbF6
1‚SbF6
1‚SbF6
1‚SbF6
1‚SbF6
90
80
75
a 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. b Based on nitrone. c Determined by 1H NMR. d Determined by
integration of the 1H NMR signals of the diastereomeric (S)-methylbenzyl
imine derivatives. e Catalyst loading 1 mol %. f Catalyst loading 10 mol
%.
Encouraged by this result, we attempted an enantioselective
version using 1‚SbF6 as catalyst. In the presence of 1‚SbF6, the
reaction of methacrolein and nitrone 2, after 15 h at -25 °C,
afforded the corresponding 3,4- and 3,5-endo isoxazolidines in 90
and 75% ee, respectively (entry 3).10 Temperature variation from
+5 to -45 °C slightly affected both the product distribution and
the enantioselectivity, the later smoothly increasing as temperature
decreases (entries 3-7). The use of more coordinating anions,9 such
as PF6-, BF4-, or CF3SO3-, decreased the yield. However, neither
the 4/5 ratio nor the ee were significantly affected (entries 3, 8-10).
These counterion effects could be explained in terms of competition
of the anion and the substrate for the Lewis acid site.11 In this line,
conversion was also strongly affected by the solvent, especially by
good coordinating solvents, such as acetone or nitromethane, which
preclude catalysis. When the reaction was performed with only 1
mol % of catalyst, a conversion of 41% was measured after 15 h
When C,N-diphenylnitrone 2 is allowed to react with meth-
acrolein (3) (Scheme 1, Table 1), at room temperature in CH2Cl2
for 15 h in the absence of a catalyst, the 5 adduct is obtained in
63% yield (entry 1). At -25 °C, the reaction is inhibited, but in
the presence of a catalytic amount of the achiral compound [(η5-
C5Me5)Rh(dppe)(H2O)](SbF6)2 [dppe ) 1,2-bisdiphenylphosphi-
noethane, (6)],9 a 70:30 mixture of 4 and 5 adducts was obtained,
with a conversion of 96%, after 10 h in CH2Cl2 (entry 2).
† Departamento de Qu´ımica Inorga´nica.
‡ Departamento de Qu´ımica Orga´nica.
9
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J. AM. CHEM. SOC. 2004, 126, 2716-2717
10.1021/ja031995z CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Equilibrium between 1 and 7
occur through the methacrolein Si-face, and an exo approach of
the nitrone would be disfavored due to repulsive interactions
between the nitrogen substituent and the methyl R-Prophos group.
Therefore, the configuration of the two major isomers obtained will
be 3S,4S for 4 and 3S,5S for 5.
To summarize, we present here a rhodium-based system in which
the formation of the dipolarophile/catalyst complex is favored with
respect to nitrone coordination. Therefore, it represents a rare
example of efficient activation of electron-deficient monofunction-
alized alkenes toward the 1,3-dipolar cycloaddition reaction of
nitrones. In addition, this activation leads to 3,4-isoxazolidines as
major regioisomers with enantioselectivities up to 92%. The
characterization of the enal coordinated intermediate 7 sheds
significant light on the nature of the catalytic outcome. Notably,
the catalyst can be recovered and reused at least up to four times
without significant loss of either activity or selectivity. Further
studies to establish the scope of the catalytic reaction and to explore
the activity of related half-sandwich platinum group metal com-
plexes are in progress.
of treatment without significant changes in the ee values (entry
11). Increasing the catalyst loading did not improve the enantio-
selectivity (entry 12). Notably, despite it being a homogeneous
system, the catalyst can be easily recovered and reused. Consecutive
catalyst runs of up to four more times were possible, producing
very similar results (entries 13-16).
31P NMR studies revealed that water is partially displaced from
1 by methacrolein. At room temperature, in CD2Cl2, a mixture of
complex 1‚SbF6 and 28 equiv of methacrolein consists of 68% of
1 and 32% of 7 (Scheme 2). The equilibrium is completely shifted
to the right in the presence of 4 Å MS. In fact, pure complex 7‚
SbF6 can be isolated from this solution, and single crystals, suitable
for X-ray diffraction analysis, were obtained from CH2Cl2/n-hexane
solutions (for spectroscopic and X-ray data, see the Supporting
Information).
Acknowledgment. We thank the DGICYT (Spain) for financial
At -90 °C, in the catalytic conditions, the NMR spectra revealed
the presence of 7 and free nitrone both remaining unchanged for
hours. At -50 °C, while the 31P NMR spectrum did not change,
the 1H NMR spectrum showed the presence of the 4 and 5
cycloaddition adducts (ca. 2% conversion, based on the nitrone,
after 1 h at -50 °C). At -25 °C, the sole significant spectral change
was the progressive increasing of the adducts signals. These
measurements strongly indicate that, in the catalytic conditions, (i)
coordinated methacrolein is not displaced by nitrone 2, (ii) most
probably, the reaction occurs through attack of the nitrone to the
activated enal, and (iii) the rate-determining step is the nitrone attack
to the methacrolein complex 7. It is worth mentioning that, from
-90 °C to room temperature, only one epimer at the metal has
been detected.
support (Grants PB96/0845, BQU2000/0907, BQU2001/2428).
Supporting Information Available: Selected spectroscopic data
for complexes 1‚PF6, 1‚BF4, 1‚CF3SO3, 6, and 7 (PDF), and details of
the crystal structure analysis of 7 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.;
Wiley and Sons: Hoboken, NJ, 2003. (b) Frederickson, M. Tetrahedron
1997, 53, 403-425.
(2) Gothelf, K. V.; Jorgensen, K. A. Chem. ReV. 1998, 98, 863-909.
(3) For a definition on normal and inverse-demand 1,3-DCR, see: Gothelf,
K. V. In Cycloaddition Reactions in Organic Synthesis; Kobayashi, S.,
Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2002; pp 211-247.
(4) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 1449-1458.
(5) (a) Viton, F.; Bernardinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002,
124, 4968-4969. (b) Kanemasa, S. In Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim,
2002; pp 249-300. (c) Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org.
Lett. 2002, 4, 2457-2460. (d) Ohtsuki, N.; Kezuka, S.; Kogami, Y.; Mita,
T.; Ashizawa, T.; Ikeno, T.; Yamada, T. Synthesis 2003, 1462-1466.
(6) Methacrolein usually gives rise to 3,5-regioisomers preferentially. See refs
5a and 5b.
The X-ray analysis of compound 7‚SbF6 showed that the rhodium
atom has an absolute S configuration. The methacrolein molecule
adopts an s-trans conformation, and it maintains its planar structure
upon coordination. In the only two previously reported examples
of related chiral Lewis acid-methacrolein complexes,7,11b the
methacrolein lies in a plane roughly perpendicular to the ring (p-
i
(7) 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.
MeC6H4 Pr or Cp) plane. Interestingly, in compound 7, the
methacrolein plane forms an angle of only 27.36(27)° with the C5
ring plane. Additionally, the CHO proton points to the pro-S phenyl
group of the Ph2PC(CH3)H fragment being only 2.7 and 3.0 Å apart
from their ipso and ortho carbons, respectively. In this disposition,
the Re-face of the methacrolein is shielded by the C5Me5 methyls.
The NMR data at -25 °C are consistent with the retention of
the stereochemistry in solution. In particular, the strong shielding
of the CHO methacrolein proton upon coordination (about 2.5 ppm)
strongly indicates that it is pointing to a phenyl group, in such a
way that it is shielded by the anisotropic ring current.12 Selective
ROESY experiments are also in good agreement with this stereo-
chemistry.
(8) 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) Compounds 1‚PF6, 1‚BF4, 1‚CF3SO3, and 6 were prepared following the
same method reported for 1‚SbF6 in ref 8. For selected spectroscopic data,
see the Supporting Information.
(10) Complex 1‚SbF6 catalyzes the hydrolysis of nitrone 2. To avoid this side
reaction, it was pretreated with methacrolein, in the presence of 4 Å MS,
in CH2Cl2 during 30 min, before the addition of the nitrone.
(11) (a) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S.
J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798-800. (b) Ku¨ndig, E. P.;
Saudan, C. M.; Bernardinelli, G. Angew. Chem., Int. Ed. 1999, 38, 1220-
1223.
(12) In free methacrolein, δ(CHO), 9.59 ppm; in compound 7, δ(CHO), 7.06
ppm. Previously reported data for coordinated methacrolein: δ(CHO),
9.76,11b 9.1013 ppm.
The structural characterization of this intermediate permits us
to propose the absolute configuration of the adducts and to interpret
the observed endo preference. The nitrone attack would preferably
(13) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Garratt, S. A.; Russell, D. R.
J. Chem. Soc., Dalton. Trans. 2000, 4432-4441.
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