The unusual role of CO transfer in molybdenum-catalyzed asymmetric alkylations

Article abstract of DOI:10.1021/ja028035h

Spectroscopic and crystallographic studies were undertaken to gain insight into the mechanism of the highly regio- and enantioselective allylic aklylation reaction catalyzed by molybdenum. The chiral ligand (L*) consisting of the mixed benzamide/picolinam

Full text of DOI:10.1021/ja028035h

Published on Web 10/05/2002
The Unusual Role of CO Transfer in Molybdenum-Catalyzed Asymmetric
Alkylations
Shane W. Krska,* David L. Hughes, Robert A. Reamer, David J. Mathre, and Yongkui Sun
Departments of Process Research, Chemical Engineering R & D, Merck and Co., Inc., Rahway, New Jersey 07065
Barry M. Trost
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received August 6, 2002
Over the past few years, the molybdenum-catalyzed asymmetric
alkylation reaction (eq 1) has been developed into a powerful
synthetic method, providing branched product 4 in high yield, ee,
and regioselectivity.1-4 Recently we reported a systematic study
groups of the ligand; the resulting anionic ligand ultimately becomes
a part of the π-allyl complex 9.
A suitable crystal of 9 was grown, and the X-ray structure is
shown in Figure 1.7 Noteworthy features of this structure include
of the effects of ligand structure on the rate and regio- and
stereoselectivity of molybdenum-catalyzed asymmetric alkylations.5
This study revealed that unsymmetrical ligands such as 6 perform
as well as (or, in some cases, better than) previously reported
symmetrical ligands such as 7 and that the ligand appears to be
binding to the metal through one pyridine ring and one or more of
the amide moieties.
While a number of ligands of varying structure have now been
successfully designed for this reaction, the nature of the catalytic
species remains unknown. Herein we describe spectroscopic and
crystallographic studies that provide definitive structures of inter-
mediates in the catalytic cycle and disclose the unusual role played
by CO transfer in catalyst turnover.
Figure 1. Crystal structure of π-allyl complex 9. Thermal ellipsoids are
drawn at the 50% probability level. Solvent (THF) and nonallylic H atoms
are omitted for clarity. Carbon atoms are shown in gray, hydrogen in white,
molybdenum in green, nitrogen in blue, and oxygen in red.
To gain more insight into the nature of the catalytic species, a
series of stoichiometric reactions designed to model various steps
in the catalytic cycle were followed by NMR. Reaction of Mo-
(CO)4(norbornadiene) with ligand 6 produced complex 8, with two-
point binding through the pyridine nitrogen and amide group.6 This
neutral Mo-ligand complex reacted with linear carbonate 2 in THF-
d8 at 50 °C in a sealed NMR tube to form the π-allyl intermediate
9. The stoichiometry of this reaction, as shown in eq 2, involves
formation of 1 equiv each of 9, MeOH, and free ligand from 2
equiv of complex 8. In addition, a significant amount (presumably
1 equiv) of Mo(CO)6 is observed by 13C NMR spectroscopy. The
methanol observed is formed, along with CO2, from the methyl
carbonate-leaving group upon deprotonation of one of the amide
the following: (1) the allyl moiety binds in an η3 fashion to Mo,
with one face clearly open for reaction with a nucleophile; (2) the
ligand is coordinated to the metal via three-point binding: the
pyridine nitrogen, the nitrogen of the deprotonated amide, and the
carbonyl oxygen of the undeprotonated amide; and (3) the complex
contains two CO ligands. The overall geometry of the complex,
including the syn orientation of the allyl moiety with respect to
the CO ligands, is similar to other structurally characterized
L2(CO)2XMo(η3-allyl) complexes.8,9 The solution structure, as
determined by multinuclear NMR, is consistent with the crystal
structure.10,11
Two important findings of the crystal structure are the depro-
tonation of the amide nitrogen,12,13 and the three-point binding of
the ligand to Mo. Both are likely key factors in providing strong
* To whom correspondence should be addressed. E-mail: shane_krska@
merck.com.
9
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10.1021/ja028035h CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
complexation and the rigidity required for producing high ee’s in
the allylic alkylation, even at temperatures of >100 °C in toluene.14
While the crystal structure indicates one face of the π-allyl moiety
is clearly open for approach of a nucleophile, attack of malonate
in this direction predicts stereochemistry opposite to that which is
observed. Thus, the π-allyl complex observed as the major species
in solution is likely not the reactive species.15
A further surprise was in store when we initiated studies on the
reactivity of 9. When 9 is formed in situ from 8 and 2, it smoothly
reacts with sodium dimethyl malonate to produce the branched
product 4 with ee >95%. However, when isolated 9 is redissolved
in THF-d8 and combined with sodium dimethyl malonate, no
reaction occurs. Since the complex formed in situ also has Mo-
(CO)6 and methanol present, we concluded one of these components
must be necessary for reactivity. Indeed, addition of Mo(CO)6 to
the reaction mixture of the isolated π-allyl complex and malonate
resulted in clean formation of the branched product 4 in 82% yield
with ee >95%. The major molybdenum-containing product of this
reaction is complex 10, formed in 90% yield (Scheme 1). The
release CO. A typical synthetic experiment using catalytic molyb-
denum was followed by NMR, and both complexes 9 and 10 were
the only Mo-containing species observed, with high mass balance
in Mo conserved throughout the reaction. This confirms that 9 and
10 are the catalyst resting states under actual catalytic synthetic
conditions.
In light of the observed stereochemistry of allyl complex 9 and
the crucial role played by CO transfer in its activation toward
nucleophilic attack, questions remain as to the structure of the true
catalytic species and how that species transfers chiral information
from the ligand to the substrate. In addition, a number of features
of this reaction, such as the observed kinetic resolution and memory
effects and the high branched regioselectivity, remain to be
explained.14 Current work is focused on answering these questions
via kinetic and synthetic studies.
Acknowledgment. We thank Dr. Richard Ball and Professor
Guy Lloyd-Jones for helpful discussions.
Supporting Information Available: Synthetic procedures and
NMR characterization for 6, 9, and 10, and the crystal structure for
complex 9 are provided (PDF, CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 1
References
(1) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104-1105; Trost,
B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem. Soc. 1999, 121, 10416-
10417.
(2) Lloyd-Jones, G. C.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
462-464; Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141-144.
(3) Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg,
C. J. Org. Chem. 2000, 65, 5868-5870; Kaiser, N.-F.; Bremberg, U.;
Larhed, M.; Moberg, C.; Hallberg, A. Angew. Chem., Int. Ed. 2000, 39,
3596-3598.
(4) Malkov, A. V.; Spoor, P.; Vinader, V.; Kocovsky, P. Tetrahedron Lett.
2001, 42, 509-512; Kocovsky, P.; Malkov, A. V.; Vyskocil, S.; Lloyd-
Jones, G. C. Pure Appl. Chem. 1999, 71, 1425-1433.
(5) Trost, B. M.; Dogra, K.; Hachiya, I.; Emura, T.; Hughes, D. L.; Krska,
S.; Reamer, R. A.; Palucki, M. P.; Yasuda, N.; Reider, P. J. Angew. Chem.,
Int. Ed. 2002, 41, 1929-1932.
(6) The 15N resonances of the pyridine and one of the amide nitrogens were
shifted in complex 8 (δ 273, 133, respectively) relative to their values in
free ligand 6 (δ 304, 118, respectively). The resonance of the unbound
amide remained relatively unchanged (δ 123 in 8, vs 119 in 6).
(7) Crystallographic data for 9‚THF: C38H45MoN3O6, orange prisms, mono-
clinic, space group P2(1), a ) 10.4824(9) Å, b ) 25.322(2) Å, c )
13.7540(12) Å, R ) 90°, â ) 104.515(2)°, γ ) 90°, V ) 3534.3(5) Å3,
Z ) 4, Fcalcd ) 1.383 g cm-3, T ) 223(2) K, R(F0) ) 0.0627, wR(F02) )
0.1555, GOF ) 1.050. The THF solvent molecules were disordered.
(8) Curtis, M. D.; Eisenstein, O. Organometallics 1984, 3, 887-895.
(9) The X-ray crystal structure of a monomeric Mo allyl complex of 7
(Mo:7 ) 2:1) has been reported: Morales, D.; Pe´rez, J.; Riera, L.; Riera,
V.; Corzo-Sua´rez, R.; Garc´ıa-Granda, S.; Miguel, D. Organometallics
2002, 21, 1540-1545.
(10) Complex 9 can exist in any of four possible isomers wherein the ligand
binds in a facial, tridentate fashion in one of two geometries (defined by
either ∆ or Λ stereochemistry between the skew lines formed by the two
CO ligands and the two bound N atoms of the chiral ligand) and the π-allyl
fragment binds via its re or si face.
(11) NMR characterization data for 9 were originally discussed in ref 5 and
are included in the Supporting Information. The NOE data are consistent
either with the structure shown in Figure 1 or with the diastereomeric
structure formed by inversion of stereochemistry at both the metal center
and the π-allyl fragment (cf. compound 20 in ref 5).
reaction between isolated 9 and 3a also occurs in the presence of
1 atm CO(g) to give 4 in 80% yield and >95% ee. Under these
conditions, complex 10 is formed in 58% yield along with 13%
1
free ligand according to H NMR spectroscopy. Thus, the role of
the Mo(CO)6 is to serve as a source of CO in the reaction of the
bis(carbonyl) complex 9 to the tetra(carbonyl) complex 10. In effect,
Mo(CO)6 provides complex 9 with the necessary CO’s to enhance
its leaving-group ability in the displacement reaction.
Complex 10 was synthesized independently by reaction of 8 with
NaH. Reaction of isolated 10 with linear carbonate 2 or either
enantiomer of branched carbonate 1 cleanly generates π-allyl
complex 9 in quantitative yield according to 1H NMR spectroscopy.
The gross features of the overall catalytic scheme have now been
delineated and are shown in Scheme 1. Precatalyst 8 reacts with
carbonate 2 to generate π-allyl complex 9 according to eq 2.
Complex 9 reacts with malonate in the presence of a CO source
(e.g., Mo(CO)6) to form product 4 and molybdate complex 10.
Complex 10 reacts with carbonate 2 to regenerate complex 9 and
(12) Deprotonation of ligand 7 is precedented in metal complexes: Mulqi,
M.; Stephens, F. S.; Vag, R. S. Inorg. Chim. Acta 1981, 53, L91-L93;
Adolfsson, H.; Moberg, C. Tetrahedron: Asymmetry 1995, 6, 2023-2031.
(13) This result is in agreement with previous reactivity studies (ref 5) which
showed that deprotonating ligand 7 before catalyst formation gives typical
yields and enantioselectivities in the allylic alklyation reaction.
(14) Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider, P. J. J.
Org. Chem. 2002, 67, 2762-2768.
(15) Intramolecular attack via a ligated malonate would provide the observed
stereochemistry. However, since complex 9 is coordinatively saturated,
precomplexation of malonate seems unlikely.
JA028035H
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