Nucleophilic acylation of o-quinone methides: An umpolung strategy for the synthesis of α-aryl ketones and benzofurans

Article abstract of DOI:10.1021/ja068189n

The synthesis of α-aryl ketones is accomplished by the direct nucleophilic acylation of o-quinone methide electrophiles. In this process, two reactive intermediates, carbonyl anions and o-quinone methides, are generated in one flask upon treatment of the corresponding thiazolium carbinols and silyl protected phenols with a soluble fluoride source. These intermediates then undergo productive addition reactions to afford the desired α-aryl ketone adducts. This new strategy has been applied to a short synthesis of the natural product demethylmoracin I. Copyright

Full text of DOI:10.1021/ja068189n

Published on Web 03/23/2007
Nucleophilic Acylation of o-Quinone Methides: An Umpolung Strategy for the
Synthesis of r-Aryl Ketones and Benzofurans
Anita E. Mattson and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received November 15, 2006; E-mail: scheidt@northwestern.edu
Table 1. Optimization of Carbonyl Anion Additionsa
The inversion of normal reactivity patterns, or umpolung, enables
the development of unconventional bond-forming strategies for the
synthesis of biologically active target molecules.1 The generation
of acyl anion equivalents by the polarity reversal of carbonyl
functional groups is one valuable umpolung tactic. Given our
interest in unconventional bond-forming strategies,2 we decided to
concentrate on developing an acyl anion approach to synthesize
R-aryl ketones. The preparation of R-aryl ketones is a challenging
goal, and the majority of recent progress has focused on the
development of transition-metal-catalyzed couplings of enolates and
aryl halides.3 Herein, we report the direct synthesis of R-aryl ketones
(3) by the fluoride promoted addition of protected thiazolium
carbinols (1) to quinone methides that are generated in situ from
silyl protected phenols (2, eq 1).
entry
temp (
°
C)
X
concentration
yieldb
1
2
3
4
5
-50 to 23
-78 to 23
-78 to 23
-78 to 23
-78 to 23
Br (2a)
Br (2a)
Br (2a)
Br (2a)
Cl (2b)
0.1 M
0.1 M
0.3 M
0.05 M
0.1 M
43%
72%
23%
45%
53%
a See Supporting Information for details. b Isolated yield.
5), albeit in reduced yield (53%).11 To lend support to the
intervention of an o-quinone methide, a competition experiment
was conducted with 1 equiv each of 1a, 2a, and 2-methoxy-
benzylbromide in the presence of 2 equiv of Me4N‚F. Using the
reaction conditions from Table 1, only aryl ketone 3 is observed
with none of the methyl ether product that would arise from direct
alkylation of the carbonyl anion.10
With the optimal parameters established for this umpolung
reaction, we turned our attention to investigating the scope of the
process (Table 2, eq 3). A brief survey of protected thiazolium
carbinols reveals the reaction accommodates additional aromatic
substituents (entries 1-3). When carbinols derived from alkyl and
R,â-unsaturated aldehydes are employed as the acyl anion precursor,
the desired R-aryl ketones are formed in moderate yields (not shown
40-53%). While these observations are encouraging, further
investigations of this new strategy are necessary to accommodate
these particular substrates.
An examination of the o-quinone methide component of the
reaction indicates that variously substituted protected phenols are
competent electrophile progenitors. In addition to the unsubstituted
methides (e.g., derived from 2), alkyl and aryl substitution at R1
provides good yields of the corresponding acylated products (60%
and 68%, entry 5). Substitution on the phenyl ring is also well
tolerated. The quinone methide precursor derived from o-vanillin
was able to produce the desired R-aryl ketone in 68% yield (entry
6). A high yield of product was also observed when the quinone
methide precursor 2f was subjected to the reaction conditions (75%,
entry 7). For certain structures, the benzylic bromide reactants are
unstable and could not be easily isolated. For these cases, the
corresponding benzylic chlorides can be successfully employed in
the reaction (entries 5 and 7).
We recently disclosed that fluoride promotes the nucleophilic
acylation of nitroalkenes when stable O-silyl thiazolium carbinols
(1) are employed as carbonyl anion precursor.4 Interestingly, Rokita
has reported that O-silylated phenols (such as 2) produce o-quinone
methides when exposed to fluoride.5,6 We envisioned that combining
compounds with the general structures of 1 and 2 with an
appropriate fluoride source would simultaneously generate the
corresponding carbonyl anion and o-quinone methide species in
the same reaction flask. The subsequent combination of the
nucleophilic carbonyl anion and electrophilic o-quinone methide
should provide the desired R-aryl ketones (3) in a single operation.7
The main challenge with this approach is the simultaneous
generation of two highly reactive intermediates.
Our investigations of this new coupling strategy focused on the
addition of protected thiazolium carbinol 1a to o-quinone methide
precursor 2 in the presence of tetramethylammonium fluoride (Table
1, eq 2).8 The exposure of 1a and 2a to this fluoride source at -50
°C afforded an encouraging 43% yield of the desired R-aryl ketone
3 (entry 1). Optimization of the reaction conditions revealed that
the best yields of 3 are obtained with lower temperatures (-78 °C,
23 h) followed by slowly warming to 23 °C (entry 2).9,10 Another
important factor affecting the yield of the reaction is concentra-
tion: the optimal value of 0.1 M affords 72% of 3 (entries 2-4).
Although bromide leaving groups on the o-quinone methide
precursor gives the highest yields, the corresponding benzylic
chloride (2b) is also a suitable reaction partner (entry 2 vs entry
This fluoride-induced umpolung strategy can be extended beyond
o-quinone methides. For example, R-indoyl ketone compounds such
as 12 can be accessed in good yield (70%) from the combination
of a silyl protected gramine derivative 11 and thiazolium carbinol
1a in the presence of 2.5 equiv of Me4N‚F (Scheme 1).12
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J. AM. CHEM. SOC. 2007, 129, 4508-4509
10.1021/ja068189n CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. R-Aryl Ketones Prepared from Thiazolium Carbinols (1)
and Silylated Phenols (2)a
Scheme 1
Scheme 2. Synthesis of Demethylmoracin Ia
a Conditions: (a) Me4N‚F, CH2Cl2, -78 to 23 °C, 62%; (b) Amberlyst
15, 4 Å Sieves, CH2Cl2 79%; (c) prenyl tributyltin, PdCl2(dppf), DMF,
100 °C, 76%; (d) nBuLi, PHPh2, THF, 61%.
Abbott Laboratories, Amgen, Boehringer-Ingelheim, 3M, and
Wacker Chemical Corp. A.E.M. acknowledges an ACS Division
of Organic Chemistry Fellowship sponsored by Eli Lilly. We thank
a reviewer for suggesting the competition experiment employing
1a, 2a, and 2-methoxy-benzylbromide with Me4N‚F.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a See Supporting Information for reaction details. b Tz ) 2-substituted
3,4,5-trimethylthiazol-3-ium iodide.
(5) For a review on o-quinone methides, see: Van de Water, R. W.; Pettus,
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This new bond-forming process facilitates a total synthesis of
the naturally occurring aromatase inhibitor, demethylmoracin I.13
In the key step, highly substituted R-aryl ketone 14 is prepared in
62% yield from thiazolium carbinol 139 and 2f with Me4N‚F. The
acid-catalyzed cyclization to the corresponding benzofuran 15 is
accomplished in 79% yield. The prenyl group is installed using a
Stille cross coupling reaction and global demethylation with lithium
diphenylphosphanide14 in refluxing THF affords demethylmoracin
I. (Scheme 2).
In summary, the synthesis of R-aryl ketones via the direct
nucleophilic acylation of o-quinone methides has been reported.
In this umpolung process, a reactive carbonyl anion and o-quinone
methide are generated in the same flask by the addition of fluoride
ion and then undergo productive bond formation to yield the desired
adducts. Investigations into the utility and applications of thiazolium
carbinols as unique acyl anion precursors are ongoing in our
laboratory.
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(9) The yield of 3 is lower (45%) when incubating the reaction at -78 °C
for 1 h (vs. 23 h) followed by warming to 23 °C.
(10) See Supporting Information for details.
(11) The combination of 1a and Me4NF with benzyl bromide affords only low
yields of benzyl ketone under the best conditions from Table 1.
(12) For examples of fluoride-induced elimination-addition reactions of N-
triisopropylsilyl gramine methyliodide, see: Iwao, M.; Motoi, O. Tetra-
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Acknowledgment. This work has been generously supported
by Northwestern University, the NIH (Grant RO1 GM73072),
JA068189N
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