Non-carbonyl-stabilized metallocarbenoids in synthesis: The development of a tandem rhodium-catalyzed bamford-stevens/thermal aliphatic claisen rearrangement sequence

Article abstract of DOI:10.1021/ja028020j

A tandem rhodium-catalyzed Bamford-Stevens/Claisen rearrangement is presented. The tandem reaction uses Eschenmoser hydrazones for the in situ generation of non-carbonyl-stabilized diazo alkanes, which are presumably intercepted by Rh(II) catalysts to induce a 1,2-hydride migration. This sequence provides high levels of stereocontrol for the generation of simple acyclic (Z)-enol ethers. These enol ethers undergo either thermal or Lewis acid accelerated Claisen rearrangements to provide products of high diastereopurity. Also presented are cascade reactions, wherein a third chemical step occurs after the initial tandem sequence (i.e., Bamford-Stevens/Claisen/ene and Bamford-Stevens/Claisen/Cope). Copyright

Full text of DOI:10.1021/ja028020j

Published on Web 10/01/2002
Non-Carbonyl-Stabilized Metallocarbenoids in Synthesis: The Development
of a Tandem Rhodium-Catalyzed Bamford-Stevens/Thermal Aliphatic Claisen
Rearrangement Sequence
Jeremy A. May and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received August 5, 2002
Scheme 1
Of the transformations available to synthetic chemists, the Claisen
rearrangement arguably stands alongside the Diels-Alder and aldol
reactions as one of the most powerful, well-characterized, and
elegant protocols for the construction of carbon-carbon bonds.1
The ability to control and predict stereochemical issues in these
reactions, and the acceleration of all three reactions with Lewis
Scheme 2
acid catalysis, has led to significant accomplishments in the area
of asymmetric synthesis.2 Although numerous modifications to the
Claisen rearrangement exist, the classic allylic enol ether variant
is often overlooked due to the difficulty associated with the
stereoselective preparation of allylic enol ethers as a single
stereoisomer. In particular, the (Z)-isomer has proven exceptionally
challenging to access reliably. In conjunction with a general program
aimed toward the preparation and utilization of non-carbonyl-
stabilized diazo compounds,3 we have discovered a novel generation
of such acyclic (Z)-enol ethers via rhodium-catalyzed elimination
of diazo alkanes prepared in situ from N-aziridinyl imines.4
Additionally, we have found that in the case of allylic enol ethers,
a subsequent thermal Claisen rearrangement occurs in good yield
and with high levels of diastereoselectivity. The result is the
development of a highly stereoselective tandem rhodium-catalyzed
Bamford-Stevens/Claisen reaction (Scheme 1).5,6
Stevens elimination reaction, we turned our attention to the
As a general method to prepare non-carbonyl-stabilized diazo
compounds in situ, we chose to investigate the decomposition of
N-aziridinyl imines (also known as Eschenmoser hydrazones) in
the presence of standard rhodium(II) catalysts.7,8 This overall
transformation would potentially render any ketone as a carbenoid
precursor.9 To test for the influence of Rh(II) catalysts on the in
situ generated non-carbonyl-stabilized diazo compound, we carried
out a control experiment on hydrazone 3a. As illustrated in Scheme
2, discrete reaction pathways were observed in the presence or
absence of the Rh2(OAc)4 catalyst. Without catalyst, multiple
decomposition products resulted from what would be considered
highly reactive carbene chemistry. Alternatively, in the presence
of Rh2(OAc)4, catalyst-mediated de-diazotization most likely
produces a rhodium-carbenoid intermediate, which attenuates the
reactivity of the species and results in a more selective carbenoid
type reaction. In the particular case of hydrazone 3a, a 1,2-hydride
migration occurs to form enol ether 6a in high yield and excellent
stereoselectivity. These results are in full accord with previous
examples of carbene and metallocarbenoid hydride migrations,
wherein high levels of (Z)-olefin selectivity are also found.10
Interestingly, it appears that the stereoselectivity observed is general
across a range of substrates, including those that generate acyclic
trisubstituted enol ethers (e.g., 6b).
development of a conceptually novel tandem process. We reasoned
that rhodium-mediated stereoselective hydride migration of the
derived diazoalkane from an allyloxy hydrazone such as 1 would
produce a 1,5-diene poised for Claisen rearrangement. To our
delight, treatment of hydrazone 1 with Rh2(OAc)4 in 1,2-dichlo-
roethane at 80 °C resulted in a tandem process proceeding via (A)
thermal decomposition of the aziridine, (B) rhodium-mediated de-
diazotization, (C) stereoselective 1,2-hydride migration (>20:1 Z:E
selectivity), and finally (D) thermal aliphatic Claisen rearrangement
(i.e., Scheme 1, 1 f 2).11
With this new tandem process in hand, we have examined the
scope of the rearrangement and found that the reaction is quite
general (see Tables 1 and 2). The tandem sequence tolerates
aromatic, alkyl, and alkenyl substitution adjacent to the hydrazone
functionality. The allylic portion can be modified with numerous
substituents that produce a wide range of Claisen products. In
relevant cases, high levels of diastereoselectivity are generally
observed, and the sense of stereoinduction is consistent with the
intermediacy of a (Z)-enol ether proceeding through a chairlike
transition state. For example, rearrangement of hydrazone 7 results
in the formation of aldehyde 8 in greater than 20:1 anti:syn
diastereoselectivity (Table 1, entry 1). In some cases (i.e., Table 1,
entries 5 and 7), thermal Claisen rearrangement of the intermediate
enol ether was sluggish; however, the rearrangement could be
accelerated at low temperature (-40 °C) by addition of Me2AlCl
to the cooled reaction mixture.12
Having established the carbenoid reactivity profile of our in situ
prepared diazo compounds, as well as the catalytic Bamford-
* To whom correspondence should be addressed. E-mail: stoltz@caltech.edu.
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C O M M U N I C A T I O N S
Table 1. The Tandem Bamford-Stevens/Claisen Reactiona
cyclohexanols 28 and 30 with excellent diastereoselectivity.13
Alternatively, using reductive conditions (DIBAL, -40 °C) for the
rearrangement of the intermediate (Z)-enol ethers furnished the
corresponding unsaturated alcohol as the major product (Table 2,
entries 3-5). Notably, R,â-unsaturated hydrazones 34 and 36
undergo a Bamford-Stevens/Claisen/Cope rearrangement cascade
(entries 6 and 7) with excellent stereoselectivity observed for each
example.14
In summary, we have developed a tandem rhodium-catalyzed
Bamford-Stevens/Claisen rearrangement sequence. The method
relies on the in situ generation and presumed catalytic interception
of non-carbonyl-stabilized diazoalkanes to form (Z)-enol ethers with
nearly complete stereoselectivity, thereby establishing a general
route to the (Z)-isomer of simple acyclic Claisen enol ethers.
Additionally, this work further establishes the utility and feasibility
of generating rhodium carbenoids from ketones. We are currently
investigating the scope and generality of such in situ generated non-
carbonyl-stabilized rhodium carbenoids for other reactions including
those involving asymmetric catalysis and chemically triggered
Eschenmoser hydrazone equivalents.
Acknowledgment. The authors wish to thank the NSF (CHE-
0135056), the Dreyfus Foundation, Merck Research Laboratories,
and Abbott Laboratories for financial support.
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
a Rh2(OAc)4 (1 mol %), ClCH2CH2Cl, 130 °C, 2-4 h. b R ) NCH2CHPh.
c Diastereomer ratios determined by 1H NMR of the crude reaction mixture.
d Subsequent treatment with Me2AlCl at -40 °C. e Rh2(OAc)4, NMP, 200
°C, 1 h.
References
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Ziegler, F. E. Chem. ReV. 1988, 88, 1423.
Table 2. Cascade Reactionsa
(2) Santelli, M.; Pons, J.-M. Lewis Acids and SelectiVity in Organic Synthesis;
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(3) For alternative approaches, see: (a) Aggarwal, V. K.; Vicente, J.; Bonnert,
R. V. Org. Lett. 2001, 3, 2785. (b) Doyle, M. P.; High, K. G.; Su-Min,
O.; Osborn, A. K. Tetrahedron Lett. 1989, 30, 3049.
(4) (a) Felix, D.; Mu¨ller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser,
A. HelV. Chim. Acta 1972, 55, 1276. For a recent review, see: (b) Kirmse,
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Cyclopropanes to Ylides; Wiley & Sons: New York, 1998.
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For examples, see: (a) Padwa, A.; Austin, D. J.; Gareau, Y.; Kassir, J.
M.; Xu, S. L. J. Am. Chem. Soc. 1993, 115, 2637. (b) Sarkar, T. K.; Ghorai,
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(9) All hydrazones were prepared from the corresponding ketones. See the
Supporting Information.
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1996, 61, 2908. (b) Pirrung, M. C.; Hwu, J. R. Tetrahedron Lett. 1983,
24, 565. (c) See refs 3b and 8b.
(11) For an alternative rhodium carbenoid-initiated Claisen rearrangement,
see: Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A.
A.; Dietrich, H.-J. J. Am. Chem. Soc. 1999, 121, 1748.
(12) (a) Lutz, R. P. Chem. ReV. 1984, 84, 205. (b) Nonoshita, K.; Banno, H.;
Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (c) Takai,
K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1984, 57,
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(13) For a similar ene reaction, see: Corey, E. J.; Roberts, B. E.; Dixon, B. R.
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(14) For the Tandem Claisen Cope reaction, see: Ziegler, F. E.; Piwinski, J.
J. J. Am. Chem. Soc. 1982, 104, 7181.
a Rh2(OAc)4 (1 mol %), ClCH2CH2Cl, 130 °C, 2-8 h. b R ) NCH2CHPh.
c Diastereomer ratios determined by 1H NMR of the crude reaction mixture.
d Subsequent treatment with Me2AlCl at -40 °C. e Subsequent treatment
with DIBAL at -40 °C.
In addition to the Bamford-Stevens/Claisen sequence, we have
investigated a number of cascade reactions, wherein a third chemical
step occurs after the initial tandem process. For instance, Lewis
acid promotion of neryl and geranyl ethers 27 and 29 induces a
cascade terminating in a carbonyl-ene reaction to produce the
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