Copper-catalyzed synthesis of 2,4-disubstituted allenoates from α-diazoesters

Article abstract of DOI:10.1021/ol2006242

Chemical equations presented. A Cu-catalyzed method for coupling α-substituted-α-diazoesters with terminal alkynes to give substituted allenoates is described. Key to the development of a selective method was the recognition that an adventitous base catalyzes the isomerization to form the allenoate product. A plausible mechanism is proposed, based in part on evidence against a mechanism that involves a Cu(I)-acetylide as a low-valent intermediate.

Full text of DOI:10.1021/ol2006242

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2388–2391
Copper-Catalyzed Synthesis of 2,
4-Disubstituted Allenoates from
r-Diazoesters
Matthew Hassink, Xiaozhong Liu, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716, United States
jmfox@udel.edu
Received March 10, 2011
ABSTRACT
A Cu-catalyzed method for coupling R-substituted-R-diazoesters with terminal alkynes to give substituted allenoates is described. Key to the
development of a selective method was the recognition that an adventitous base catalyzes the isomerization to form the allenoate product. A
plausible mechanism is proposed, based in part on evidence against a mechanism that involves a Cu(I)-acetylide as a low-valent intermediate.
Allenoates are building blocks for complex molecule
synthesis that have found use in a broad array of reacti-
vities,1 including nucleophilic addition reactions,2 electrophi-
lic addition reactions,3 MoritaꢀBaylisꢀHillman reactions,4
rearrangements,5 and cycloaddition and formal cycloaddi-
tion reactions.6 Of the varied ways to create allenoates,7
(6) [3 þ 2] cycloadditions: (a) Mercier, E.; Fonovic, C.; Henry, C.;
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2009, 131, 6318. [4 þ 2] cycloadditions: (d) Tran, Y. S.; Kwon, O. J.
Am. Chem. Soc. 2007, 129, 12632. (e) Zhu, X.; Lan, J.; Kwon, O. J. Am.
Chem. Soc. 2003, 125, 4716. For a review, see: Ma, S. Acc. Chem. Res.
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r
10.1021/ol2006242
Published on Web 04/12/2011
2011 American Chemical Society

among the most versatile are methods that involve the bi-
molecular construction of the allene framework. Previously,
such methods had generally been based on Wittig8 or
HornerꢀWadsworthꢀEmmons reactions9 of ketenes or ke-
tene equivalents. Herein, we describe a complementary
method for the preparation of allenoates in which the allene
framework is constructed through the coupling of terminal
alkynes with functionalized diazo compounds.
R-substituted diazoesters. Furthermore, while 3-alkyno-
ates can be isomerized to allenoates upon treatment with
base,7b a one-pot method for accessing 2,3-allenoates from
alkynes with diazo compounds had not been described.
Herein, we describe a method that couples alkynes with
R-aryl-R-diazoesters or R-alkyl-R-diazoesters to provide
allenoates directly in good yields (Scheme 1b).
Copper complexes are known to catalyze the reaction
between alkyneswithalkyl diazoacetatesorN,N-dimethyl-
R-diazoacetamide togive3-alkynoatesand 3-alkynamides,
respectively.10 The first example of such a coupling was
originally described by Jones and Deutschman,10a and
improved catalytic systems have been described in subse-
quent years.10 Most recently, Suarez and Fu described the
CuI/MeCN-catalyzed coupling between alkynes withethyl
diazoacetate or N,N-dimethyl-R-diazoacetamide with high
yield and efficiency to give 3-alkynoate and 3-alkynamide
products, respectively (Scheme 1a).11 In several cases, 2,3-
allenoates were formed as minor products (3ꢀ5% yield) in
the reactions of ethyl diazoacetate with terminal alkynes.
Table 1. Selected Screening Results
Scheme 1. Cu-Catalyzed Coupling Reactions of Alkynes with
Diazo Compounds
a NMR conversion or yield. b GC conversion or yield. c Inferior
yields of 3a þ 4a were obtained for analogous reactions run in toluene
(<1%), MeCN (32%), THF (7%), ether (1%), or hexane (29%).
Inferior yields were also obtained with bipyridine (13%), phenanthro-
line (10%), or 4,7-dihydroxyphenanthroline (13%).
To uncover an effective catalytic system for coupling
R-substituted diazoesters with alkynes, the reaction be-
tween 5-chloro-1-pentyne (1a) and methyl R-phenyldia-
zoacetate (2) was studied. Selected screening results are
displayed in Table 1. Most Cu(I)-catalyst systems, includ-
ing CuI/CH3CN (entry 1), did not catalyze formation of
allenoate 3a or alkynoate 4a. However, CuBr supported by
bipyridyl or phenanthroline ligands did produce these
coupling products. Of the ligands and solvents studied,
3,6-di(2-pyridyl)-s-tetrazine (5) and 1,2-dichloroethane
(DCE) were most effective. A number of Cu-sources were
also studied, and the highest conversion and yield was
obtained with Cu(II)(trifluoroacetylacetonate)2. With Cu-
(II) (trifluoroacetylacetonate)2/5 in DCE, a 70% NMR
yield of 3a and 4a was measured. This reaction proceeds
smoothly at 45 °C: reactions at lower temperatures did not
proceed to completion, and higher temperatures provided
no advantage. A 2-fold excess of 2 was required; conversion
of the alkyne was incomplete when only 1 equiv of the
diazoester was employed.
Prior descriptions of coupling reactions between alkynes
and diazo compounds have been limited to the reactivity
of diazoacetates or diazoacetimides. No catalysts have
been described that function in the coupling reactions of
(8) (a) Lang, R. W.; Hansen, H. Org. Synth. 1984, 62, 202. (b) Li, C.;
Sun, X.; Jing, Q.; Tang, Y. Chem. Commun. 2006, 2980. (c) Li, C.; Zhu,
B.; Ye, L.; Jing, Q.; Sun, X.; Tang, Y.; Shen, Q. Tetrahedron 2007, 63,
8046. (d) Lang, R. W.; Hansen, H. Helv. Chim. Acta 1980, 63, 438. (e)
Himbert, G.; Fink, D. Tetrahedron Lett. 1985, 26, 4363. (f) Silveira,
C. C.; Boeck, P.; Braga, A. L. Tetrahedron Lett. 2000, 41, 1867. (g)
€
€ €
Tomoskozi, I.; Bestmann, H. J. Tetrahedron Lett. 1964, 5, 1293.
(9) (a) Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett. 1996, 37,
ꢀ
3735. (b) Musierowicz, S.; Wroblewski, A. E. Tetrahedron 1980, 36,
1375. (c) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
ꢀ
1733. (d) Musierowicz, S.; Wroblewski, A.; Krawczyk, H. Tetrahedron
Lett. 1975, 16, 437.
(10) (a) Jones, V. K.; Deutschman, A. J. Org. Chem. 1965, 30, 3978.
(b) Arnaud, P.; Vincens, M.; Vidal, M. Bull Soc. Chim. Fr. 1972, 2, 657.
(c) Nefedov, O. M.; Dolgii, I. E.; Shapiro, E. A. Bull. Acad. Sci. USSR
Div. Chem. Sci. (Engl. Transl.) 1980, 29, 1493. (d) Nefedov, O. M.;
Dolgii, I. E.; Shapiro, E. A. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl.
Transl.) 1974, 23, 929.
(11) Suarez, A.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 3580.
Org. Lett., Vol. 13, No. 9, 2011
2389

Using 5/Cu(II)(trifluoroacetylacetonate)2, wewereableto
obtain allenoate 3a with high selectivity over 4a. However,
the ratios of 3a/4a were inconsistent, and the selectivity was
dependent on the equivalency of diazoester 2 (the selectivity
increased dramatically when more than 2 equiv of
diazoester 2 was used). These confusing observations
prompted us to understand the factors that influence
the ratio of 3a and 4a.
Scheme 3. Time-Dependent Product Distributiona
Scheme 2. Byproduct Azine 6 Improves the Ratio of 3a/4a
a Yields were determined by GC analysis (vs internal standard).
Finally, evidence that alkynoate products rearrange to
allenoate products was obtained by including alkynoate 4b
in the Cu-catalyzed reaction between phenylacetylene (1c)
and 2 (Scheme 4). Compound 4b was isomerized (>95%)
to 3b with >85% mass recovery in a reaction that coupled
1c and 2.
a 2 equiv of 2 was used. b 4 equiv of 2 were used.
Scheme 4. Alkynoate 4ba Isomerizes under Coupling Condi-
tions
Our efforts began with characterizing isolable bypro-
ducts from the Cu-catalyzed reactions of 1a and 2. One
of the compounds that was isolated was the azine 6
(Scheme 2).12 To probe the function of the azine 6, several
control experiments were run. An attempt to catalyze
reaction between 1a and 2 with 6 (5 mol %)/CuBr (5 mol
%) didnot leadtoeitherofthe products3aor 4a. However,
under conditions that typically lead to poor selectivity
(CuBr/ligand combinations), the addition of azine 6
greatly improved the selectivity for 3a. As shown in
Scheme 2, the inclusion of azine 6 dramatically improved
the selectivity for allenoate formation.
The observations of Scheme 2, and the inability of 6 to
serve as a ligand for the coupling of 1a and 2, led us to
hypothesize that the azine was functioning as a base that
isomerizes an initially formed alkynoate to the allenoate
product. Accordingly, we screened a series of simpler bases
and determined that inclusion of K2CO3 improves the
selectivity for allenoate products. Further evidence that
alkynoate formation precedes allenoate formation was
provided by monitoring the Cu(II) (trifluoroacetylaceto-
nate)2/5 catalyzed reaction between 1-octyne (1b) and
diazoester 2 (Scheme 3). The yields of products 3b and 4b
were monitored as a function of time. After 15 min, only
alkynoate 4b (6%) is observed. After 1.5 h, 4b is maximized
(15%), but then decreases to 2% after 15 h. Concomitantly,
the yield of 3b increases from 8% after 1.5 h to 60% after 15 h.
a Compound 4b was added to the reaction as an inseparable 1:1
mixture with 3b. b The yield of 3c was determined by 1H NMR spectro-
scopy, as this compound is unstable to chromatography.
The optimized reaction conditions were applied to a
variety of substrates (Scheme 5). The reactions of R-aryl
diazoacetates with nine aliphatic alkynes were studied and
found to proceed with an average of 62% yield (44ꢀ71%).
The protocol is straightforward, and syringe-pump addi-
tion of the diazoester was unnecessary. Halogen, ether,
silyl, and alkene functional groups were tolerated. R-Aryl
diazoacetates with aromatic substituents (p-F, o-Me,
p-OMe) could also be utilized to give products 3hꢀj.
Under a modified protocol, both ethyl diazopropionate
and ethyl diazobutanoate were effective in this coupling
reaction (Scheme 5). Because these diazo compounds were
more susceptible to azine formation, a larger excess of
diazoester (6 equiv) and a syringe-pump addition protocol
were necessary. With these modifications, products 3kꢀm
were obtained in 65ꢀ80% yield.
With propargyl sulfides a different mode of reactivity
was observed. Putative ylide formation followed by a 2,
3-sigmatropic rearrangement to give R-allenyl-R-thiophe-
nyl esters (DoyleꢀKirmse reaction13) was observed (see the
Supporting Information). Notably, R-alkyldiazo compounds
(12) Azine dimer 6, was independently synthesized by treating 2 with
N-hydroxyphthalimide in the presence of rhodium(II) acetate dimer.
Dimethyl 2,3-diphenylfumarate was also formed in this reaction.
2390
Org. Lett., Vol. 13, No. 9, 2011

fumarate dimers.12 This observation provides support for
a mechanism that does not involve initial formation of a
copper acetylide.
Scheme 5. Substrate Scope for Allenoate Formation
A plausible mechanism (Scheme 6b) involves the reac-
tion of a low-valent Cu-chelate (A) with an R-diazoester to
give carbenoid B. The reaction of B with the terminal
acetylene may proceed via an intermediate C, which can
undergo reductive elimination to regenerate A and the
alkynoate, which isomerizes to the allenoate product.
Inconclusion, aCu-catalyzedmethodforcouplingdiazo
Scheme 6. (a) Cu-Acetylide 7 Does Not Couple with 2. (b)
Possible Catalytic Cycle
Yields represent the average of isolated yields from two separate
runs, unless noted otherwise. a 3:1 mixture with isomeric alkynoate
4g. b Temperature was 65 °C. c The yield was determined by 1H NMR
spectroscopy, as 3j decomposed partially upon chromatography. d An
additional 4 equiv of diazoester was added via syringe pump. Afterward,
the mixture was stirred with DBU (2 equiv) before workup.
compounds with terminal alkynes to give substituted
allenoates has been developed. Key to the development
of a selective method was the recognition that an adven-
titous base catalyzes the isomerization to form the alleno-
ate product. A plausible mechanism is proposed on the
basis of evidence against a mechanism that involves a
Cu(I)-acetylide as a low valent intermediate.
with β-hydrogens function efficiently in the transforma-
tion catalyzed by Cu(II) (trifluoroacetylacetonate)2/5.14
Previously, there had been few reports of using R-alkyldia-
zo compounds with β-hydrogens in the DoyleꢀKirmse
reaction,13c,f as such compounds can undergo an undesir-
able, intramolecular elimination to produce R,β-unsatu-
rated esters.
To provide further insight into the mechanism, we also
tested whether the preformed copper acetylide 7 would
couple with 2 in the presence of ligand 5 (Scheme 6a).
However, neither the allenoate nor alkynoate products
were detected. The alkyne was converted to hexadeca-7,9-
diyne, and diazoester 2 was converted into azine 6 and
Acknowledgment. We thank the NIGMS (NIH R01
GM068650) for financial support. NMR spectra were
from instruments supported by NSF CRIF:MU, CHE
0840401.
Supporting Information Available. Full experimental
details and 1H and 13C NMR spectra are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 13, No. 9, 2011
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