Deacylative oxidation strategy for the preparation of α- functionalized carbonyls

Article abstract of DOI:10.1021/ol040039z

(Matrix Presented) α-Alkoxylation and amination of carbonyl derivatives is made possible through a unique deacylative coupling reaction that proceeds via in situ Rh-carbene formation and subsequent heteroatom-H (X-H) insertion. Reactions perform optimally

Full text of DOI:10.1021/ol040039z

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2619-2621
Deacylative Oxidation Strategy for the
Preparation of r-Functionalized
Carbonyls
Benjamin H. Brodsky and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jdubois@stanford.edu
Received May 25, 2004
ABSTRACT
r-Alkoxylation and amination of carbonyl derivatives is made possible through a unique deacylative coupling reaction that proceeds via in
situ Rh-carbene formation and subsequent heteroatom-H (X−H) insertion. Reactions perform optimally with five- and six-membered ring lactone
and lactam derivatives using both alcohol and carbamate substrates as coupling partners. Substituted ethylbenzoyl acetate starting materials
have also proven to be effective for this oxidative process, affording r-functionalized esters under particularly mild and operationally facile
conditions.
Metal-mediated carbene insertion reactions continue to
evolve as powerful tools for synthesis. Such processes can
be used to fashion new C-C and C-X (X ) N, O) bonds
from readily available precursors under conditions that are
favorable for the assembly of complex molecules. In certain
instances, the preparation of R-hydroxy and R-amino acid
derivatives has been achieved through metal-carbene X-H
insertion.1 Efforts to develop new protocols for the synthesis
of such compounds have led us to explore 1,3-dicarbonyl
derivatives as viable starting materials for tandem carbene
generation and R-heteroatom functionalization (Figure 1).
The successful implementation of such a strategy rests on a
number of important mechanistic considerations and requires
the careful coordination of many disparate chemical events.
Importantly, such methodology obviates the preparation and
isolation of potentially unstable R-diazo carbonyls.2-4 More-
over, both R-oxygen and nitrogen-derived products are made
Figure 1. Oxidative reaction affords R-substituted carbonyl
derivatives.
available from a common starting material. In all, the process
developed herein offers a simple and effective approach for
exploiting the unique reactivity of carbenoid intermediates
to assemble structural units found ubiquitously in natural and
synthetic products.
Notable advances by Doyle, Danheiser, and Taber have
demonstrated the usefulness of â-dicarbonyls (e.g., 1, Figure
2) as starting materials for R-diazoketone and -ester synthe-
sis.5,6 Analysis of the mechanism for such reactions suggested
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley and Sons, Ltd.: New York, 1997; and references therein; (b)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-2904.
(2) For recent applications of hydrazones as carbene precursors, see: (a)
Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3, 2785-
2788. (b) May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426-
12427. (c) Zhang, J.-L.; Chan, P. W. H.; Che, C.-M. Tetrahedron Lett.
2003, 44, 8733-8737. (d) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res.
2004, 37, ASAP.
(3) For use of iodonium ylides as carbene precursors, see: (a) Mu¨ller,
P.; Fernandez, D. HelV. Chim. Acta 1995, 78, 947-958. (b) Wurz, R. P.;
Charette, A. B. Org. Lett. 2002, 4, 4531-4533. (c) Mu¨ller, P.; Ghanem, A.
Synlett 2003, 1830-1833. (d) Wurz, R. P.; Charette, A. B. J. Org. Chem.
2004, 69, 1262-1269. (e) Mu¨ller, P. Acc. Chem. Res. 2004, 37, 243-251.
(4) In situ diazotization of glycine ethyl ester with NaNO2 has been
described; see: Barrett, A. G. M.; Braddock, D. C.; Lenoir, I.; Tone, H. J.
Org. Chem. 2001, 66, 8260-8263.
10.1021/ol040039z CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/18/2004

Deacylative oxidation has proven to be general for five-
and six-membered rings lactones and lactams (Table 1).
Table 1. Detrifluoroacetylative X-H Insertion with Catalytic
Rh2(oct)4
Figure 2. Tandem deacylative diazotization and X-H insertion.
that enolate diazotization and subsequent retro-Claisen could
be performed in the absence of added H2O and/or amine
base, as had been employed in previous reports. Such
speculation posits diazocarbonyl 4 formation to occur through
intramolecular acyl transfer (2f3), extruding the sulfonamide
salt as the sole byproduct (Figure 2). By avoiding water and
amine reagents, the intermediate Rh-carbenoid would be free
to react with a given nucleophile, RXH (4f5). Accordingly,
we envisioned a protocol in which successive diazo transfer,
metallocarbene generation, and carbene insertion would
proceed in a single operation.
For initial studies, trifluoroketone 1 (Figure 2) was chosen
as a model substrate and tested in combination with inorganic
bases, sulfonyl azide oxidants, and Rh catalysts. The nature
of and interactions between the diverse number of reaction
components are critical to the success of this coupling
process. Unlike amine bases commonly employed in diazo
transfer reactions (Et3N, DBU), the insolublity of Cs2CO3
in CH2Cl2 establishes a phase partition between the solid
base and the solution containing dissolved catalyst. We
hypothesized that such conditions would minimize axial
coordination of carbonate ion and/or the Cs+ enolate to the
Rh dimer, thus freeing the catalyst to decompose the R-diazo
carbonyl substrate rapidly as it was generated.7 Viable
oxidants were considered on the basis of their activity with
the weakly nucleophilic enolate derived from 1. Readily
prepared o-nitrobenzenesulfonyl azide (o-NBSA) was found
to outperform considerably other sulfonyl azide reagents and
does not decompose in the presence of the Rh-catalyst.8 The
optimized reaction thus employs trifluoroketone 1, 2 mol %
Rh2(oct)4, 1 equiv of o-NBSA, Cs2CO3, and BnOH to afford
68% of the corresponding R-benzyloxy lactone 5 (RX )
OBn).9
a Standard reaction conditions employed 1 equiv of o-NBSA, 1 equiv
of Cs2CO3, and 4 equiv of RXH. b Isolated yield of product over two steps.
Chiral products are formed with diastereomeric ratios ranging from 1 to
3:1; see Supporting Information for details. c Optimum results were obtained
with LiNiPr2 in place of LiN(SiMe3)2. d Optimum results were obtained with
LiN(cHx)iPr in place of LiN(SiMe3)2.
Preparation of the requisite trifluoroketone is facilitated using
LiN(SiMe3)2 and commercial trifluoroethyl trifluoroacetate
(TFEA). Enolate acylation is efficient under these conditions,
and purification of the product is unnecessary prior to
conducting the subsequent step. The method extends to
medium-sized ring systems as well as aliphatic esters (entries
9, 13); reaction efficiencies are slightly more variable,
however, for such substrates. To highlight the versatility of
this process, a number of structurally diverse alcohols were
screened as nucleophilic partners for the coupling reaction.
Primary and secondary alcohols, including benzylic and
allylic derivatives, all perform effectively. With allyl alcohol
(5) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse, R. A. J.
Org. Chem. 1985, 50, 1663-1666.
(6) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J.
Org. Chem. 1990, 55, 1959-1964. (b) Danheiser, R. L.; Miller, R. F.;
Brisbois, R. G. Org. Synth. 1996, 73, 134-143. (c) Detrifluoroacetylative
diazo transfer to form R-diazo-γ-lactones has been described. See: Brown,
R. C. D.; Bataille, C. J. R.; Bruton, G.; Hinks, J. D.; Swain, N. A. J. Org.
Chem. 2001, 66, 6719-6728.
(7) Axial coordination of dirhodium catalysts by Lewis basic ligands is
known to inhibit catalytic activity; see: Nagashima, T.; Davies, H. M. L.
Org. Lett. 2002, 4, 1989-1992.
(8) For a discussion of the unique electronic properties of o-NBSA, see:
Besenyei, G.; Pa´rka´nyi, L.; Foch, I.; Sima´ndi, L. I.; Ka´lma´n, A. J. Chem.
Soc., Perkin Trans. 2 2000, 1798-1802.
(9) In the absence of BnOH, several decomposition products are observed,
none of which appear to correspond, however, to the R,â-unsaturated lactone
or dimerized material.
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Org. Lett., Vol. 6, No. 15, 2004

as the trapping agent, olefin cyclopropanation and allylic
C-H insertion were not observed.10 Somewhat diminished
product yields were obtained when t-BuOH and, inexplicably,
MeOH were employed (entries 4, 10). In addition to alkanol
nucleophiles, 1° carbamate esters can also act as suitable
partners in the X-H insertion step (entry 8).11 Thus, access
to either R-alkoxy or R-amino adducts is achieved from a
common precursor.
makes possible use of the less reactive toluenesulfonyl azide.
R-Functionalized ester products are isolated in moderate
yields by employing this reagent combination. Importantly,
ethylbenzoyl acetate 6 (R1 ) H) may be easily converted
into substituted derivatives and thus offers particularly
convenient access to numerous R-alkoxy and amine products.
As an example, alkylation of 6 with N-CBz-3-bromopropy-
lamine (NaH, KI, DMF, 50 °C) and subsequent deacylative
oxidation affords proline ester 11.14,15 The synthesis of more
advanced heterocyclic structures should follow through a
similar route.
In an effort to advance further strategies for deacylative
oxidation, we have investigated alternative 1,3-dicarbonyl
starting materials (Figure 3). Inspired by the work of Taber,12
A two-step method for the preparation of R-functionalized
carboxylic acid derivatives has been developed. This process
capitalizes on the unique activity of Rh-carbene intermediates
to insert into heteroatom-H bonds. A tandem sequence of
events leading to product formation is made possible with
the ability to modulate the production of reactive diazo and
carbenoid species. As such, new opportunities to exploit Rh-
carbene reactions for complex molecule synthesis are af-
forded that circumvent the assembly of potentially unstable
diazo compounds. The effectiveness of â-dicarbonyls as
carbene precursors should thus expand the general utility of
carbenoid chemistry for C-C and C-X bond formation.
Figure 3. Debenzoylative R-functionalization of acyclic esters.
Acknowledgment. Support for this research has been
generously provided by Abbott Laboratories, Amgen, Boeh-
ringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Glaxo-
SmithKline, Merck, and Pfizer. B.H.B. would like to thank
Eli Lilly for a graduate research fellowship.
a small set of benzoylated esters was evaluated. Reactions
of these compounds proceed efficiently with TsN3 as the
diazo transfer agent and Rh2(HNCOCF3)4 as the catalyst
(5 mol %).13 The increased reactivity of the Cs+ enolate
Supporting Information Available: Experimental details
and analytical data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Charette, A. B.; Wurz, R. P.; Ollevier, T. HelV. Chim. Acta 2002,
85, 4468-4484.
(11) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody,
C. J.; Pearson, N. D.; Sanghera, J. B. J. Chem. Soc., Perkin Trans. 1 1996,
2879-2884.
OL040039Z
(14) Wei, W.-H.; Tomohiro, T.; Kodaka, M.; Okuno, H. J. Org. Chem.
2000, 65, 8979-8987.
(15) For select examples of intramolecular N-H insertion reactions
leading to substituted prolines, see: (a) Moyer, M. P.; Feldman, P. L.;
Rapoport, H. J. Org. Chem. 1985, 50, 5223-5230. (b) Davis, F. A.; Fang,
T.; Goswami, R. Org. Lett. 2002, 4, 1599-1602. (c) Davis, F. A.; Yang,
B.; Deng, J. J. Org. Chem. 2003, 68, 5147-5152.
(12) Taber, D. F.; You, K.; Song, Y. J. Org. Chem. 1995, 60, 1093-
1094.
(13) (a) Rh2(HNCOCF3)4 has been employed previously for X-H
insertion reaction. See: Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R.
H. B. Tetrahedron 1994, 50, 3195-3212. (b) A detailed preparation of
Rh2(HNCOCF3)4 is available in Supporting Information.
Org. Lett., Vol. 6, No. 15, 2004
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