Tandem carbocupration/oxygenation of terminal alkynes

Article abstract of DOI:10.1021/ol052413g

(Chemical Equation Presented) A direct and general synthesis of α-branched aldehydes and their enol derivatives is described. Carbocupration of terminal alkynes and subsequent oxygenation with lithium tert-butyl peroxide generates a metallo-enolate. Trapping with various electrophiles provides α-branched aldehydes or stereo-defined trisubstituted enol esters or silyl ethers. The tandem carbocupration/ oxygenation tolerates alkyl and silyl ethers, esters, and tertiary amines. The reaction is effective with organocopper complexes derived from primary, secondary, and tertiary Grignard reagents and from n-butyllithium.

Full text of DOI:10.1021/ol052413g

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5681-5683
Tandem Carbocupration/Oxygenation of
Terminal Alkynes
Donghui Zhang and Joseph M. Ready*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
joseph.ready@utsouthwestern.edu
Received October 5, 2005
ABSTRACT
A direct and general synthesis of
r-branched aldehydes and their enol derivatives is described. Carbocupration of terminal alkynes and
subsequent oxygenation with lithium tert-butyl peroxide generates a metallo-enolate. Trapping with various electrophiles provides
r
-branched
aldehydes or stereo-defined trisubstituted enol esters or silyl ethers. The tandem carbocupration/oxygenation tolerates alkyl and silyl ethers,
esters, and tertiary amines. The reaction is effective with organocopper complexes derived from primary, secondary, and tertiary Grignard
reagents and from n-butyllithium.
R-Branched aldehydes represent valuable synthetic interme-
diates but remain difficult to access. Alkylation of aldehyde
enolates generally fails, so recourse has been taken to indirect
methods. In a common tactic, reaction of metalated hydra-
zones or imines with alkyl halides leads to R-branched
hydrazones or imines.1 Hydrolysis provides the substituted
aldehyde. Alternatively, alkylation of carboxylic acid deriva-
tives and subsequent partial reduction can yield R-branched
aldehyde products. In addition to requiring multiple synthetic
operations, these indirect methods also suffer from limited
reaction scope. Specifically, enolate or metalloenamine
alkylation proceeds efficiently only with unhindered and/or
electronically activated electrophiles.
Carbometalation of terminal alkynes (1) generates stereo-
defined vinylmetal intermediates (2) that can react with
various electrophiles.4 In principle, trapping with an elec-
trophilic oxygen donor (Scheme 1, path a) could provide an
Scheme 1
Hydroformylation of terminal olefins provides an alterna-
tive to aldehyde enolate alkylation, but general strategies to
control regioselectivity have proved elusive.2 We report here
a general and direct approach based on the addition of a
carbon-based nucleophile and oxygen-based electrophile to
monosubstituted acetylenes, the tandem carbocupration/
oxygenation of terminal alkynes (eq 1).3
R-branched aldehyde (3) or its enol derivative. Among
various carbometalation protocols, those based on organo-
copper reagents display the broadest generality.5 For this
(3) An elegant methylalumination/oxidation of terminal olefins has been
reported: (a) Shaughnessy, K. H.; Waymouth, R. M. J. Am. Chem. Soc.
1995, 117, 5873-5874. (b) Kondakov, D. Y.; Negishi, E.-i. J. Am. Chem.
Soc. 1995, 117, 10771-10772. (c) Tandem allyl zincation/thiolation:
Creton, I.; Marek, I.; Normant, J. F. Synthesis 1996, 1499-1508.
(4) Marek, I.; Normant, J. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P., Eds.; Wiley-VCH: Great Britain, 1998; pp 271-
283.
(1) (a) Wittig, G.; Frommeld, H. D.; Suchanek, P. Angew. Chem., Int.
Ed. Engl. 1963, 2, 683-684. (b) Stork, G.; Dowd, S. R. J. Am. Chem. Soc.
1963, 85, 2178-2180. (c) Enders, D.; Eichenauer, H. Tetrahdron Lett. 1977,
191-194. (d) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450-
451. (e) review: Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517-
536.
(2) Review: Clarke, M. L. Curr. Org. Chem. 2005, 9, 701-710.
10.1021/ol052413g CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/18/2005

reason, we sought a method to effect oxygenation of vinyl
copper species (2, M ) Cu). However, a significant obstacle
to implementing this strategy was related to the known
chemistry of organocopper compounds: the oxidative dimer-
ization of phenyl copper has been known since the early
twentieth century,6 and more than 30 years ago Nomant
described a carbocupration/oxidation sequence leading to
symmetrical dienes (4, Scheme 1, path b).7
Table 1. Tandem Carbocupration/Oxygenation of Terminal
Alkynes
Initial efforts to effect oxygenation of vinyl copper
intermediates confirmed the large body of evidence indicating
that dimerization constituted the predominant reaction path-
way. In particular, oxygen transfer agents such as dimethyl
dioxirane and nitrosobenzene provided diene (4) to the
exclusion of aldehyde derivatives. Other oxidants, including
N-methyl morpholine N-oxide and metal salts of m-CPBA,
were unreactive, and terminal olefin (5) was recovered from
the reactions.
Experiments with LiOOtBu (6) proved more rewarding.
Boche and co-workers oxidized phenyl cuprates to phenol
with this reagent.8 We have discovered that LiOOtBu in
conjunction with carbocupration enables the preparation of
R-branched aldehydes and their derivatives from organome-
tallic reagents and terminal alkynes. For example, carbo-
cupration of 1-dodecyne (1a) with ethylcopper was followed
by oxidation with LiOOtBu. After addition of acetic anhy-
dride to the reaction mixture, we isolated the trisubstituted
enol acetate (7) in moderate yield. Increases in yield and
reproducibility accompanied the addition of N,N,N′,N′-
tetramethylethylenediamine (TMEDA) to the vinyl copper
intermediate prior to oxidation (Table 1, entry 1). Other
amine ligands showed no discernible effect, while phosphorus-
based ligands totally suppressed oxygenation.
To expand the scope of the carbo-oxygenation, three
carbocupration protocols were developed or appropriated to
accommodate primary, secondary, and tertiary Gringard and
primary alkyllithium reagents (Table 1). In all cases, the vinyl
copper intermediate (2, M ) Cu) was oxidized with LiOOt-
Bu at -78 °C; addition of Ac2O to the crude reaction mixture
led to trisubstituted enol acetates, 7. Carbometalation with
primary Grignard reagents is optimal using CuBr‚Me2S and
a 1:1.5 Cu/Mg ratio (conditions A), as has been previously
reported.9 In contrast, terminal alkynes were inert to orga-
nocopper reagents derived from secondary and tertiary
alkylmagnesium halides. Diorganocuprates displayed im-
proved reactivity, but these reactions were initially plagued
by incomplete consumption of the alkyne and formation of
multiple products. The low yields stemmed not from
recalcitrance of the alkyne; rather, the cuprate intermediates
decomposed under the reaction conditions.10 For instance,
a Condition A: carbocupration carried out in Et2O/Me2S (1:0.3) with
RMgx/CuBr‚Me2S ) 1.5:1; TMEDA (1 equiv relative to Cu) added after
carbocupration. Conditions B: carbocupration carried out in THF with 2:1:1
RMgX/CuBr/TMEDA. Conditions C: carbocupration carried out in Et2O/
Me2S (1:0.8) with 1:1 RLi/CuBr‚Me2S; TMEDA and MgBr2 (each 1 equiv
relative to Cu) added after carbocupration. For all reactions, LiOOtBu added
as solution in THF at -78 °C. See Supporting Information for complete
experimental details. b Isolated yield. c Carbocupration carried out in Et2O.
reactions involving (c-hexyl)2CuMgBr and 1-dodecyne pro-
duced significant quantities of bicyclohexyl and 1,2-di-cyclo-
hexyl-1-dodecene. As TMEDA appeared to minimize dimer-
ization during oxidation, we speculated that it might also
increase the stability of cyclohexyl cuprates. Indeed, the use
of CuBr‚TMEDA enabled the carbo-oxygenation to be
performed with secondary and tertiary alkyl Grignard
reagents (conditions B).
In contrast to a previous report11 we observe efficient
carbocupration with organocopper reagents derived from
n-butyllithium. Unfortunately, TMEDA did not suppress
diene formation during oxidation. However, the amelioratory
effects of TMEDA were restored by admixture with MgBr2
(1 equiv relative to Cu, conditions C).
(5) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(6) Krizewsky, J.; Turner, E. E. J. Chem. Soc. 1919, 115, 559-561.
(7) Normant, J. F.; Cahiez, G.; Chuit, C.; Villieras, J. J. Organomet.
Chem. 1974, 77, 269-279.
The carbo-oxygenation reaction tolerates common func-
tionality including esters, silyl ethers, benzyl ethers and
tertiary amines. In every case studied to date, the enol acetate
has been isolated as a single regio- and stereoisomer.12,13 In
(8) Moller, M.; Husemann, M.; Boche, G. J. Organomet. Chem. 2001,
624, 47-52.
(9) (a) Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem. 1979,
3888-3901. (b) Ashby, E. C.; Smith, R. S.; Goel, A. B. J. Org. Chem.
1981, 46, 5133-5139.
(10) (a) Whitesides, G. M.; Casey, C. P. J. Am. Chem. Soc. 1966, 88,
4541-4542. (b) Whitesides, G. M.; Stedronsky, E. R.; Casey, C. P.; Filippo,
J. S., Jr. J. Am. Chem. Soc. 1970, 92, 1426-1427.
(11) Westmijze, H.; Kleijn, H.; Vermeer, P. Tetrahedron Lett. 1977,
2023-2026.
5682
Org. Lett., Vol. 7, No. 25, 2005

many instances, NOEs were observed between the olefinic
proton and the formerly propargylic protons, indicating cis
addition to the triple bond. In other cases, stereochemical
assignment was made by analogy.15
Scheme 3
Oxidation likely generates a metallo-enolate (8), and this
intermediate can be trapped with electrophiles other than
acetic anhydride. For example, quenching the reaction with
benzoic anhydride or chlorotrimethylsilane yields the cor-
responding enol derivatives 9 and 10 (Scheme 2). Alterna-
Oxidation of the vinyl copper intermediate could occur
by direct addition to lithium tert-butyl peroxide. Alterna-
tively, peroxide coordination to copper could precede an alkyl
migration from Cu to O. Such a process would resemble
the oxidation of alkyl boron and silicon compounds. The
stereospecificity of the oxygenation undermines mechanistic
proposals involving free radicals. Future efforts will aim to
clarify the reaction mechanism with the anticipation that this
understanding will aid efforts to expand the utility of the
carbocupration/oxygenation method. Irrespective of mech-
anism, this transformation currently enables the direct
synthesis of R-branched aldehydes and stereodefined enol
derivatives. The latter hold promise as valuable reagents for
asymmetric reductions, oxidations, and umpolung reactions.17
Scheme 2
tively, R-haloaldehydes (11, 12) can be isolated following
addition of Br2 or BuOCl to the reaction mixture.
t
Surprisingly, attempts to quench the enolate 8 with proton
sources led not to the expected aldehyde 14 but to ketone
13 (Scheme 3). Ultimately, we determined that addition of
ethylenediamine prior to the addition of water allowed the
isolation of the R-branched aldehyde in good yield. Other
Lewis bases (Et3N, Bu3P) were similarly effective, although
simple reductive aqueous workup (e.g., Na2S2O3(aq)) led to
lower yields of 14. Ketone 13 is likely the product of a
Baeyer-Villiger oxidation of aldehydes 11 and/or 15
promoted by excess tert-butyl peroxide. Aldehydes 11 and
15 may arise in situ from R-oxidation of 8 or 14.14 Consistent
with this interpretation, aldehydes 11 and 15 both convert
to ketone 13 under the reaction conditions.15,16
Acknowledgment. We acknowledge financial support
from the NIGMS (GM074822) and UT Southwestern (J.M.R.
is a Southwestern Medical Foundation Scholar in Biomedical
Research). This investigation was conducted in a facility
constructed with support from the Research Facilities
Improvement Program Grant Number C06 RR-15437.
Supporting Information Available: Experimental pro-
cedures for carbo-oxygenation reactions. Spectral data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL052413G
(16) (a) Joshi, A. P.; Nayak, U. R.; Dev, S. Tetrahedron 1976, 32, 1423-
1425. (b) Syper, L. Tetrahedron 1987, 43, 2853-2871.
(12) Carbocupration of 1-decyne with (tBu)2CuMgBr proceeds with 4.7:1
regioselectivity favoring the 2,2-disubstituted product. However, no products
derived from oxidation of the minor regioisomer were detected in the crude
carbo-oxygenation reaction mixture. All other carbocuprations occurred with
>50:1 selectivity.
(17) Representitive Procedure. EtMgBr (0.48 mmol) was added drop-
wise to a suspension of CuBr‚Me2S (68 mg, 0.33 mmol) in ether (1 mL)
and Me2S (0.3 mL) at -45 °C. The resulting yellow mixture was stirred at
this temperature for 1 h, and then dodecyne (0.3 mmol) was added by
syringe. The reaction flask was rinsed with ether (0.5 mL). After stirring at
-25 °C for 2.5 h, the resulting dark green solution was cooled to -78 °C,
and TMEDA (0.05 mL, 0.33 mmol) was added by syringe. After 1 h freshly
prepared15 t-BuOOLi (1.0 mmol in 2.0 mL THF) was added slowly along
the wall of the reaction flask. Stirring was continued for 3 h at -78 °C
after which Ac2O (0.3 mL, 3.0 mmol) was added. The reaction mixture
was stirred at -78 °C for 5 min and then allowed to warm to room
temperature over 20 min. The suspension was diluted with ether and washed
with saturated aqueous NaHCO3. The aqueous phase was extracted with
ether. The combined organic phases were dried over Na2SO4, concentrated,
and purified by flash chromatography.
(13) Identifiable side products include trisubstituted olefin I (ca. 5%),
vinyl bromide II (ca. 5%), and dimer 4 (ca. 10%). See also ref 14.
(14) Bromoaldehyde 11 was observed as a minor product (< 5%) in
reactions leading to 9, 10, and 12, as well as in the reaction described in
Table 1, entry 1. tert-Butyl hypobromite is likely formed from oxidation
of Br- present in the reaction mixture.
(15) See Supporting Information for details.
Org. Lett., Vol. 7, No. 25, 2005
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