A nonmetal approach to α-heterofunctionalized carbonyl derivatives by formal reductive X-H insertion

Full text of DOI:10.1002/anie.201205604

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DOI: 10.1002/anie.201205604
Carbenoids
A Nonmetal Approach to a-Heterofunctionalized Carbonyl
À
Derivatives by Formal Reductive X H Insertion**
Eric J. Miller, Wei Zhao, Jonathan D. Herr, and Alexander T. Radosevich*
Synthetic methods leading to the formation of a-heterofunc-
tionalized carbonyl derivatives are valuable for the prepara-
tion of important molecular targets.[1] Among the varied
synthetic approaches to these compounds,[2] the direct func-
À
tionalization of an X H bond by insertion of a carbene
equivalent has proven expedient and versatile.[3–5] In practice,
the required carbene synthons may be accessed by metal-
catalyzed decomposition of a-diazo compounds.[6] Despite the
utility of this approach, its appeal is tempered by the fact that
only a modest number of diazo compounds are commercially
available, a circumstance that is due in large part to hazards
associated with preparation, isolation, and storage of these
compounds.[7] Consequently, alternative strategies for the
À
direct X H functionalization transformation that retain the
power and simplicity of the diazo decomposition approach,
Scheme 1. Synthetic routes to access carbene synthons.
but broaden access to starting materials, would be desirable.
In considering alternative carbene synthetic equivalents,[8]
we recognized that a-diazo carbonyl compounds are routinely
prepared from the corresponding a-keto carbonyl deriva-
tive.[9] Consequently, we considered the possibility that this
class of readily accessible and bench-stable compounds might
be utilized directly en route to carbene-like reactivity, thereby
obviating the intermediacy of unstable diazo compounds. We
envisioned that exposure of a-keto ester 3 to a suitable
oxygen-atom acceptor would furnish a dipolar structure of the
type 4, which by analogy to a-diazo ester resonance contrib-
utor 2 might serve as a synthetic equivalent of a carbenoid.[10]
In a practical sense, intermediates of the type 4 may be
accessed by the well-known Kukhtin–Ramirez redox con-
densation of 1,2-dicarbonyl compounds with trivalent phos-
phorus derivatives (E = PR3; Scheme 1).[11] Indeed, the inter-
mediacy of these adducts in various epoxide- and cyclo-
propane-forming procedures[12,13] lends support for their
An investigation was initiated using the direct reductive
coupling of methyl benzoylformate (5) and p-cresol (6)
mediated by oxygen-atom acceptors as a demonstration
reaction [Eq. (1)]. In accord with the hypothesis outlined
above, we have found the addition of tris(dimethylamino)-
formal carbene equivalency, and isolated evidence suggests
phosphorus to a solution of 5 and 6 results in direct reductive
[14]
À
À
a further potential for X H functionalization reactivity.
O H functionalization, leading to the formation of the a-
Herein, we realize this potential in an operationally simple,
phenoxy ester 7 in good yield.[15] Neither phosphines (PPh3)
metal-free method for the preparation of a-heterofunction-
nor phosphites (P(OMe)3) are similarly reactive under
alized carbonyl derivatives by direct reductive X H function-
otherwise identical conditions,[16] an observation that may
À
[17]
=
alization employing readily available and bench-stable cou-
pling components.
be attributed to inferior P O bond enthalpies.
In terms of scope, the coupling method tolerates a range
of electronically and sterically diverse a-keto ester substrates
(Table 1). Both electron-rich (9) and electron-deficient (10)
benzoylformate derivatives serve as viable substrates for
coupling, and the series of p-halogenated O-aryl mandelate
derivatives (11–13) may be prepared. Aryl substitution of the
ketone is not strictly required for efficient reaction; alkyl-
substituted keto ester substrates yield the expected corre-
sponding a-phenoxy ester product in good yield. For example,
methyl (14), primary alkyl (15), and secondary alkyl sub-
stituents (16) are all well-tolerated.
[*] E. J. Miller, W. Zhao, J. D. Herr, Prof. Dr. A. T. Radosevich
Department of Chemistry, Pennsylvania State University
University Park, PA 16802 (USA)
E-mail: radosevich@psu.edu
[**] We thank the Pennsylvania State University for financial support of
this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205604.
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Table 1: Scope of a-keto ester substrates for reductive O H functiona-
indeed, carboxylic acids undergo smooth coupling to give a-
acetoxylated esters (23, 24) in good yields. The method can
also be extended to aliphatic alcohols, although the reaction
with these nucleophiles appears somewhat less general. For
instance, propargyl alcohol and trifluoroethanol both undergo
functionalization under standard conditions to give the
anticipated products 25 and 26, respectively. However, only
trace amounts compound 27 can be observed when ethanol is
employed as a coupling partner.[18,19] This observed reactivity
for aliphatic alcohols correlates with pKa,[20] suggesting
lization.[a]
À
a degree of O H bond heterolysis in the coupling event
(see below).
The coupling method can be successfully applied to the
À
direct X H functionalization of other heteroatomic nucleo-
philes (Table 3). Sulfonyl-protected amine derivatives
[a]
À
Table 3: Scope of nucleophiles for reductive N H functionalization.
[a] Yields of isolated product.
With respect to the protic oxygen coupling partner, the
method also proves to be quite versatile (Table 2). The suite
of cresol regioisomers all react smoothly to provide the
corresponding a-aryloxy esters in uniformly high yields (17–
19). Modulation of the electronic character of the phenol
derivative has only a modest influence on the reaction
outcome; the reactivity of electron-rich phenols (4-methoxy-
phenol) is exemplary (20), whereas yields are modestly
diminished by electron-withdrawing substitution (22). The
À
method is not limited to phenolic O H functionalization;
[a] Yields of isolated product.
[a]
À
Table 2: Scope of nucleophiles for reductive O H functionalization.
undergo smooth coupling to give protected phenylglycine
(28) and alanine (29) derivatives in good yield. This method
thus permits the direct synthesis of diverse N-substituted a-
amino ester products by reaction of N-aryl (30) and N-alkyl
(31–33) sulfonamides. Protic N-heterocyclic compounds can
also be employed in the coupling; for example, phthalimide
(34), imidazole (35), and pyrazole (36) all lead to the coupling
products.
À
Mechanistically, we believe the reductive X H function-
alization transformation is initiated by Kukhtin–Ramirez
condensation of tris(dimethylamino)phosphorus with the a-
keto ester substrate (Scheme 2).[11] Addition of the amino-
phosphine reagent to the carbonyl oxygen of the keto ester
substrate could give a 1,3-dipolar intermediate (37), which
would experience stabilization as oxyphosphonium enolate
resonance structure 37’ or dioxaphospholene valence isomer
38; features governing partitioning of the type 37–38 have
been investigated.[21] Subsequent X H functionalization
À
could then evolve along two distinct mechanistic pathways.
Loss of tris(dimethylamino)phosphine oxide could reveal
[a] Yields of isolated product.
2
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formed (pathway A) under our conditions; instead, carbenoid
reactivity evinced by a stepwise, polar mechanism (pathway
B) would appear to be most consistent with the observed
outcome. This mechanism, in which proton transfer precedes
À
a-C X bond formation, distinguishes our metal-free method
À
from X H bond functionalization by metal carbenoids, where
[27]
À
proton transfer follows a-C X bond formation.
The
complementarity in electronic character implied by this
mechanistic distinction (species 37–38 are nucleophilic,
whereas metal carbenoids are electrophilic[28]), suggests the
potential for differential application of these two classes of
À
reactive intermediates (Scheme 3). Specifically, N H func-
À
Scheme 2. Possible mechanisms for X H functionalization.
a free carbene intermediate (39) in solution (Scheme 2,
pathway A),[21] the capture of which by X H bond insertion
À
would lead to product 41. Alternatively, adducts 37–38 may be
À
intercepted by proton transfer from the pronucleophile (X
H) to give alkoxyphosphonium intermediate 40 (pathway B),
which could then undergo nucleophilic displacement to
furnish product.[22–24]
In principle, the foregoing mechanistic possibilities may
be differentiated by stereochemical experiments employing
homochiral phosphorus reagents. In this analysis, use of
a homochiral phosphorus reagent would desymmetrize key
intermediates 37–38. In the event a stepwise polar mechanism
were operative, facially selective protonation to give stereo-
defined alkoxyphosphonium 40 could be envisioned, and
subsequent stereospecific displacement of the phosphoric
triamide leaving group would yield stereodefined product 41.
By contrast, if a free carbene were generated in accord with
À
Scheme 3. Intermolecular N H functionalization versus intramolecular
cyclopropanation.
tionalization prevails when a solution of allyl benzoylformate
(44) and N-phenyl sulfonamide 46 are exposed to tris(dime-
thylamino)phosphorus under our optimized conditions; prod-
uct 47 is selectively produced in 82% yield, and cyclopropane
48 is not observed. By contrast, only 48 is produced from the
addition of rhodium acetate to a methylene chloride solution
of diazo substrate 45 and sulfonamide 46, indicating that
intramolecular olefin trapping effectively competes with
À
pathway A, a stereoselective X H functionalization would
not be expected.
As depicted in Equation (2), we have found that reductive
coupling of methyl benzoylformate and benzoic acid deriv-
À
intermolecular N H insertion for the electrophilic metal
carbenoid.
In conclusion, we have described a mild and direct method
the coupling of a-keto esters and protic oxygen and nitrogen
pronucleophiles for the synthesis of valuable a-heterofunc-
tionalized carbonyl derivatives. The reaction effects a direct
À
reductive X H functionalization by employing nonmetal
reagents and substrates that are readily available and bench-
stable. Consequently, neither prefunctionalization of the
coupling partners nor the intermediacy of highly reactive
diazo compounds is required. Additional applications of the
reactive system composed of a-dicarbonyl compounds and
oxygen-atom acceptors for the controlled access to nucleo-
philic carbene synthons are currently under investigation.
atives employing homochiral diazaphospholidine (R,R)-42[25]
is indeed stereoselective. The reductive coupling gives O-acyl
mandelate derivative (S)-43 with good yield and excellent
stereoselectivity.[26]
In light of the observed stereoselectivity, we regard as
remote the possibility that genuine carbene intermediates are
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[8] a) Closs and Moss described “intermediates which exhibit
reactions qualitatively similar to those of carbenes without
necessarily being free divalent carbon species” as carbenoids.
G. L. Closs, R. A. Moss, J. Am. Chem. Soc. 1964, 86, 4042;
b) IUPAC describes carbenoids as “complexed carbene-like
entities that display the reactivity characteristics of carbenes”.
G. P. Moss, P. A. S. Smith, D. Tavernier, Pure Appl. Chem. 1995,
67, 1307; for example, see iodonium ylides: c) P. Mꢀller, Acc.
Chem. Res. 2004, 37, 243; a-halo organometallics: d) G. Kçbrich,
A. Akhtar, F. Ansari, W. E. Breckoff, H. Bꢀttner, W. Drischel,
R. H. Fischer, K. Flory, H. Frçhlich, W. Goyert, H. Heinemann,
I. Hornke, H. R. Merkle, H. Trapp, W. Zꢀndorf, Angew. Chem.
1967, 79, 15; Angew. Chem. Int. Ed. Engl. 1967, 6, 41; sulfonium
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zone salts: h) J. R. Fulton, V. K. Aggarwal, J. de Vicente, Eur. J.
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Experimental Section
Representative procedure: In a dried 25 mL round bottom flask,
methyl benzoylformate (164 mg, 1.0 mmol) and p-cresol (113 mg,
1.05 mmol) were dissolved in dry tetrahydrofuran (10 mL, 0.1m) and
the solution was cooled to À788C. Tris(dimethylamino)phosphine
(0.20 mL, 1.05 mmol) was added dropwise by a syringe. Upon
complete addition of the aminophosphine, the cooling bath was
removed and the solution was allowed to warm to ambient temper-
ature over the course of 1 h. Once the starting material was consumed
(monitored by TLC), the reaction mixture was concentrated to
a residue and redissolved in 50 mL of ethyl acetate. The organic layer
was washed sequentially with 10% NaOH and brine, then dried
(Na2SO4) and concentrated. The product was isolated in 88% yield
(225 mg) after purification by column chromatography (silica gel, 1:10
EtOAc/hexanes as eluent).
Received: July 14, 2012
Published online: && &&, &&&&
Keywords: carbenoids · insertion · ketones · phosphorus ·
.
synthetic methods
[9] G. Maas, Angew. Chem. 2009, 121, 8332; Angew. Chem. Int. Ed.
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[15] Formation of hexamethylphosphoramide as a by-product is
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[2] For alternative syntheses of a-heterofunctionalized carbonyl
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À
Under these conditions, the reductive X H functionalization
apparently outcompetes amide-to-alkoxide ligand exchange at
phosphorus(III). E. E. Nifantiev, M. K. Grachev, S. Y. Burmis-
trov, Chem. Rev. 2000, 100, 3755.
À
[3] For examples of racemic carbenoid X H insertions, see: a) P.
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Feldman, H. Rapoport, J. Org. Chem. 1985, 50, 5223.
[16] See Supporting Information for full experimental details.
=
[17] The following P O bond dissociation enthalpies have been
À
[4] For enantioselective O H insertions, see: a) T. C. Maier, G. C.
=
=
=
reported: (Et2N)3P O 156, (EtO)3P O 151, Ph3P O 127 kcal
molÀ1. S. B. Hartley, W. S. Holmes, J. K. Jacques, M. F. Mole, J. C.
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[18] Epoxide products arising from reductive dimerization of sub-
strate (see Ref. [12]) are formed instead under these conditions.
À
[5] For enantioselective N H insertion, see: a) S. Bachmann, D.
À
[19] When ethanol is employed as bulk solvent, O H functionaliza-
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tion is observed but is attended by concomitant transesterifica-
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[20] The following pKa values have been determined in H2O at 258C:
pKa(trifluoroethanol) 12.4, pKa(propargyl alcohol) 13.6, pKa-
4
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(ethanol) 15.9. See: P. Ballinger, F. A. Long, J. Am. Chem. Soc.
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[25] Chiral diazaphospholidine 42 is prepared in one step on a gram
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[26] Stereoselectivity is observed for phenol and sulphonamide
nucleophiles, although the optical yields are diminished.
[27] A polar mechanism is also believed to operate in metal
[23] For
a phosphine-mediated reduction of electron-deficient
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À
carbenoid X H insertion reactions: a) W. Kirmse, in Advances
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[24] For related displacements of phosphine oxide from alkoxyphos-
phonium intermediates, see the Mitsunobu reaction: a) K. C.
Kumara Swamy, N. N. Bhuvan Kumar, E. Balaraman, K. V. P.
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Communications
Carbenoids
E. J. Miller, W. Zhao, J. D. Herr,
A. T. Radosevich*
&&&& — &&&&
A Nonmetal Approach to a-
Heterofunctionalized Carbonyl
Derivatives by Formal Reductive X H
Insertion
Keeping it organic: A direct synthesis of
a-alkoxy and a-amino ester derivatives by
direct reductive coupling of widely avail-
able, stable a-keto esters and protic
pronucleophiles is described (see
scheme; X=OR, NR2). The method
serves as a convenient nonmetal alter-
À
À
native to X H insertion by diazo decom-
position.
6
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