Nhc-catalyzed reactions of aryloxyacetaldehydes: A domino elimination/conjugate addition/acylation process for the synthesis of substituted coumarins

Article abstract of DOI:10.1021/ol802448c

N-Heterocyclic carbenes (NHCs) catalyze a domino Michael addition/acylation reaction to form 3,4-dihydrocoumarins. The reaction proceeds through addition of the NHC to an aryloxyaldehyde followed by elimination of a phenoxide leaving group, generating an

Full text of DOI:10.1021/ol802448c

ORGANIC
LETTERS
2009
Vol. 11, No. 1
105-108
NHC-Catalyzed Reactions of
Aryloxyacetaldehydes: A Domino
Elimination/Conjugate Addition/Acylation
Process for the Synthesis of Substituted
Coumarins
Eric M. Phillips, Manabu Wadamoto, Howard S. Roth, Andrew W. Ott, and
Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received October 23, 2008
ABSTRACT
N-Heterocyclic carbenes (NHCs) catalyze a domino Michael addition/acylation reaction to form 3,4-dihydrocoumarins. The reaction proceeds
through addition of the NHC to an aryloxyaldehyde followed by elimination of a phenoxide leaving group, generating an enol intermediate.
This transient nucleophile generated in situ performs a 1,4-addition onto a conjugate acceptor, and the carbene catalyst is regenerated upon
acylation of the phenoxide anion resulting in formation of 3,4-dihydrocoumarins.
Enolates are essential intermediates in chemistry and biology
due to their high utility in carbon-carbon bond-forming
reactions.1 The catalytic, in situ generation of enolates or
enols has become increasingly important due to their
efficiency in synthesis and emerging environmental concerns.
Consequently, significant effort in this area has been directed
toward metal-catalyzed processes2 that allow for the addition
of the corresponding metalloenolate to various electrophiles.3
More recently, attention has turned toward the formation of
enolates using only organic molecules as catalysts.4 Numer-
ous groups5-8 have employed secondary amines to catalyze
enantioselective aldol, Michael, and Mannich reactions
(3) Sodeoka, M.; Hamashima, Y. Bull. Chem. Soc. 2005, 78, 941–956.
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10.1021/ol802448c CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

through the generation of a reactive enamine intermediate.9
We report here that N-heterocyclic carbenes (NHCs) catalyze
the formation of enolates/enols through an elimination
process of R-aryloxy aldehydes. The capture of these
nucleophiles leads to substituted coumarins by a domino
Michael addition/acylation process (eq 1 in Scheme 1).
Scheme 2. Proposed Reaction Pathway
Scheme 1. General Concept
group (e.g., chloride or sulfonate) would potentially initiate
the reaction faster (I to II and III) but would fail to turn
over the catalyst due to weak nucleophilicity (IV to 2).
Enone 1a was chosen to explore this carbene-catalyzed
enolate formation strategy and leads to the formation of 3,4-
dihydrocoumarin products.14 Substituted coumarins and
related compounds are biologically active,15 and access to
this particular substitution pattern by Michael additions
to the parent coumarin remains challenging.16 For example,
to the best of our knowledge, there are no general and high-
yielding reports of conjugate additions of enolates to cou-
marins. While combining enone 1a with imidazolium or
benzimidazolium salts in the presence of base produced a
minor amount of the desired product (entries 1 and 2, Table
1), a large increase in yield was observed when triazolium
precatalyst C17 was used with DBU (entry 5). Further
optimization revealed that acetonitrile was the best solvent
(60% yield, entry 6). In this particular case, the moderate
yield was due to decomposition from prolonged exposure
to silica gel. Indeed, quick filtration through SiO2 provided
an improved 83% yield of pure desired product 2a
(entry 7).
In our recent carbene catalysis studies to access enols by
the protonation of homoenolates,10 we became interested in
whether new carbon-carbon bond-forming reactions were
possible using reactive acetate-type enol-NHC intermediates
from R-aryloxyacetaldehydes. This concept is distinctive
since the phenol in the R-position serves an important dual
purpose: first to facilitate generation of the enol equivalent
and second to liberate the carbene catalyst through an
acylation event.11 We hypothesized that this process could
be evaluated with an aldehyde containing a tethered conju-
gate acceptor in the ortho-position.12 The likely pathway
involves initial addition of the NHC to aldehyde 1 (Scheme
2).13 A formal 1,2-shift of the aldehyde proton results in
elimination of phenoxide/phenol derivative III and concomi-
tant formation of enol equivalent II. A Michael addition
could then occur which, when followed by intramolecular
O-acylation, promotes regeneration of the carbene catalyst.
A delicate balance of leaving group ability and nucleophi-
licity of the R-position substituent is crucial. A catalytic
process is untenable if these factors are not optimal in this
new type of “rebound” process. For example, a strong leaving
With azolium salt C identified as the most efficient
precatalyst to promote this well-orchestrated domino process,
we investigated the scope of the reaction. Electron-withdraw-
ing (Table 2, entry 3) and electron-donating aryl ketones
(entries 4 and 5), as well as naphthyl ketones (entry 6), are
accommodated by the reaction conditions. Electron-with-
(9) List, B. Acc. Chem. Res. 2004, 37, 548–557.
(10) (a) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 3107–3110. (b) Wadamoto, M.; Phillips, E. M.;
Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098-10099.
For excellent reviews on carbene catalysis, see: (c) Enders, D.; Niemeier,
O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (d) Marion, N.; Diez-
Gonzalez, S.; Nolan, I. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000.
(11) For a review on domino reactions, see: (a) Tietze, L. F. Chem.
ReV. 1996, 96, 115-136. For NHC reactions using unstable a-chloroalde-
hydes in which the leaving group (chloride) is not involved in catalysts
turnover, see: (b) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
16406–16407. (c) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 15088–15089.
(14) (a) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E.
Curr. Med. Chem. 2005, 12, 887–916. (b) Murray, R. D. H. Nat. Prod.
Rep. 1995, 12, 477–505.
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Arichi, S. Chem. Pharm. Bull. 1983, 31, 1625–1631. (b) Demir, A. S.; Gross,
R. S.; Dunlap, N. K.; Bashirhashemi, A.; Watt, D. S. Tetrahedron Lett.
1986, 27, 5567–5570. (c) Posakony, J.; Hirao, M.; Stevens, S.; Simon, J. A.;
Bedalov, A. J. Med. Chem. 2004, 47, 2635–2644.
(12) (a) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
Nature 2008, 452, 453–455. (b) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa,
H. Angew. Chem., Int. Ed. 2008, 47, 4722–4724.
(16) (a) Connor, R.; McClellan, W. R. J. Org. Chem. 1939, 3, 570–
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106
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Optimization of Conditions
Table 2. Substrate Scope
a All reactions performed on 0.2 mmol scale. b Isolated yields.
drawing and -donating groups (entries 7-12) can also be
placed on the aromatic ring in a variety of patterns. The 3,4-
dihydrocoumarin derived from substrate 7 (entry 11) is
formed in good yield, although the diastereoselectivity with
achiral NHCs is marginal. Additionally, catalyst loading can
be decreased to 5 mol % without diminishing the yield (entry
2). Currently, substitution at the R-position of the aldehyde
is not accommodated under the reaction conditions. The use
of saturated substrates, which replace the phenoxide leaving
group with an alkoxide, results in no reaction. From these
data, it seems that normal alcohols are not sufficiently
stabilized to undergo the first step of the catalytic cycle, i.e.,
elimination from the initial carbene·aldehyde adduct I. An
extensive survey of known chiral azolium salts as catalysts
in this reaction provides products in moderate yields but low
levels of enantioselectivity (<10% ee). Importantly, the
discovery of this new process provides a strong impetus to
develop new chiral catalysts to provide optically active
substituted coumarins.
b
a Isolated yields. 5 mol % of C and DBU. dr 1.3:1 as observed by
c
1
500 MHz H NMR spectroscopy.
bution of the labeled oxygen and methyl group on the aryl
ring lends additional support to a pathway involving a
bimolecular Michael addition in which the R-aryloxy ac-
etaldehyde fragments to form a reactive enol.
In conclusion, we have developed a new carbene-catalyzed
domino process to generate substituted coumarins. A reactive
enol is generated catalytically through the addition of an
N-heterocyclic carbene to an R-aryloxy aldehyde followed
by elimination of a phenoxide ion. The resulting enol
Our investigations of the proposed pathway have focused
on probing alternative pathways to the one depicted in
Scheme 1. The possibility of the acylation of the phenol by
II occurring prior to the Michael addition was strongly
discounted by subjecting 9 to reaction conditions. No reaction
was observed, thereby supporting that intermediate II, a
catalytic enolate equivalent, undergoes C-C bond formation
prior to C-O bond formation (Scheme 3).
Scheme 3. Reaction Pathway Investigation
A cross-over experiment was performed (Scheme 4) to
determine the fate of the enol (II) that is potentiallly formed
in situ. When compounds 1g and 18O-labeled 1j were
subjected to the optimized reaction conditions in a single
flask, a mixture of compounds 2a, 2g, 10, and 11 was
obtained (as observed by HRMS).18 The randomized distri-
(18) See Supporting Information for details.
Org. Lett., Vol. 11, No. 1, 2009
107

investigations employing both the subjection of potential
intermediates to the reaction conditions and cross-over
experiments using isotopically labeled substrates support a
sequential elimination/C-C formation/C-O acylation path-
way. There are many promising potential uses of enols
derived from a carbene-catalyzed elimination process, and
our continued investigations in this area will be reported in
due course.
Scheme 4. Cross-Over Experiment
Acknowledgment. Financial support for this work has
been provided by the NIH (NIGMS, GM73072). We thank
GlaxoSmithKline, AstraZeneca, and Boerhinger-Ingelheim
for generous research support and Wacker Chemical Corp.
and FMCLithium for reagent support. KAS is a Sloan
Foundation Fellow. Funding for the NU Integrated Molecular
Structure Education and Research Center (IMSERC) has
been furnished in part by the NSF (CHE-9871268). EMP is
a recipient of a 2008-2009 ACS Division of Organic
Chemistry fellowship sponsored by Organic Reactions. We
thank Prof. Regan Thomson (NU) for helpful discussions.
intercepts a conjugate acceptor, thereby forming a 3,4-
dihydrocoumarin after acylation of the phenoxide/phenol by
the acyl azolium intermediate. This new concept of leaving
group “rebound” has been developed in the context of
carbene catalysis to access enolate reactivity in situ and yield
an efficient synthesis of important oxygenated heterocycles.
One can envision incorporating additional groups beyond
phenols with this rebound capacity that will undoubtedly
broaden the scope and utility of this process. Our mechanistic
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
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