Direct nucleophilic acylation of nitroalkenes promoted by a fluoride anion/thiourea combination

Article abstract of DOI:10.1021/ja056565i

The direct nucleophilic acylation of nitroalkenes is reported utilizing a fluoride-initiated rearrangement of protected thiazolium carbinols. The key combination of fluoride anion and thiourea accesses carbonyl anion reactivity without the use of amine or

Full text of DOI:10.1021/ja056565i

Published on Web 03/28/2006
Direct Nucleophilic Acylation of Nitroalkenes Promoted by a Fluoride Anion/
Thiourea Combination
Anita E. Mattson, Andrea M. Zuhl, Troy E. Reynolds, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received September 24, 2005; E-mail: scheidt@northwestern.edu
The ability to invert the reactivity of functional groups, or
Umpolung, provides access to unconventional strategies for the
synthesis of important target molecules.1 A powerful tactic that
accomplishes this goal converts a normally electrophilic carbonyl
unit into a nucleophilic species with a subsequent bond-forming
event. There are many established indirect stoichiometric methods
to access this unusual reactivity, including metalated dithianes2 and
protected cyanohydrins.3 These conventional approaches typically
require strongly basic conditions and processing of the resulting
products to unmask the carbonyl moiety. As part of our studies
involving accessing new Umpolung bond-forming processes,4 we
wished to engage nitroalkenes as potential electrophiles with
carbonyl anions. In general, conjugate additions to nitroalkenes
afford highly useful compounds with diverse functionality for
organic synthesis.5 In this communication, we describe the first
direct nucleophilic acylation of nitroalkenes (2) to produce â-nitro
ketones (3) by the combination of a fluoride source with silylated
thiazolium carbinols 1 (eq 1).
alkoxide 4 via addition of a deprotonated thiazolium salt to an
aldehyde is untenable due to competing pathways, such as dimer-
ization of the resulting thiazolium zwitterion.11 Thus, accessing a
pathway to produce nucleophile 5 cleanly in the presence of the
nitroalkene is clearly a key requirement for success. To assess this
approach, we began by examining the addition of thiazolium
carbinols (1) to nitroalkene 2a (Table 1).
Our initial investigations demonstrated that â-nitro ketone 6 could
be isolated, using tetrabutylammonium triphenyl difluorosilicate to
generate the carbonyl anion equivalent in situ at -40 °C (entry 1).
Encouraged by the direct installation of a carbonyl unit at low
temperature via this new process, the reaction was further enhanced
by the addition of thiourea additive 9. Our incorporation of a
thiourea was based on the additions to nitroalkenes recently reported
by Takemoto.12 This unique fluoride/thiourea combination afforded
an improved 66% yield of 6 (entry 2). Tetramethylammonium
fluoride (TMAF)13 was superior in terms of reaction times and
simplicity of purification, but the yields remained unsatisfactory.
To improve the process, silyl protecting groups were evaluated.
Triethylsilyl (TES)-protected carbinols afforded increased yields
of 6 compared to trimethylsilyl (TMS) variants, while more robust
tert-butyldimethyl (TBS) analogues prevented the nitroalkene from
being completely consumed. With the optimal fluoride source and
protecting group in hand, placement of an electron-withdrawing
group on the protected thiazolium carbinol increased the yield to
78% (entry 5). Finally, commercial thiocarbanilide (8) was a
convenient additive and provided good yields of 7 (75%, entry 6).
We began by surveying catalytic methods that installed carbonyl
groups using aldehydes6 or acylsilanes7 as nucleophilic precursors.
However, the heteroazolium-derived catalysts generated in situ for
these processes typically require basic conditions, and our attempts
with this approach afforded only low levels of â-nitro ketones (3),
primarily due to rapid base-induced decomposition of the nitroalk-
ene. Prompted by the paucity of efficient means to directly add
carbonyl anions to this sensitive electrophile class, we hypothesized
that accessing carbonyl anion reactivity without an amine base
would be successful. In our previous studies with thiazolium-
catalyzed additions of acylsilanes, we have observed that thiazolium
carbinols, such as 1, operate as storable and stoichiometric carbonyl
anions when exposed to an amine base.8 We reasoned that these
easily prepared carbinols9 might act as nucleophilic acyl reagents
when exposed to a fluoride source, thereby selectively accessing
carbonyl anions without amine bases (Scheme 1).
Table 1. Fluoride Promoted Carbonyl Anion Additions to
Nitroalkene 2a
entry
R
X
fluoride source
additive
yield (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
4-Cl-Ph
4-Cl-Ph
Me
Me
Me
Et
Bu4N•Ph3SiF2
Bu4N•Ph3SiF2
Me4N•F
none
33
66
53
59
78
75
9
9
9
9
8
Me4N•F
Et
Me4N•F
Me4N•F
Et
Scheme 1
Investigation into the reaction scope was carried out with the
optimal combination of fluoride source (TMAF) and thiourea 8
(Table 2, eq 3). Various nitroalkenes are competent substrates in
the addition reaction, including branched and straight chain variants
(entries 1-4). The nucleophilic acylation of a cyclic nitroalkene
occurs smoothly with excellent diastereoselectivity to yield trans
product 13 (20:1 dr, entry 5). Remarkably, formation of a quaternary
In this process, the resulting alkoxide 4 could undergo a 1,2-
hydrogen shift to generate 5, an intermediate described by Breslow
in the benzoin reaction.10 Alternatively, alkoxide 4 could also
collapse to eject the thiazolium zwitterion and thus not undergo
the desired addition reaction. Importantly, generating intermediate
9
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J. AM. CHEM. SOC. 2006, 128, 4932-4933
10.1021/ja056565i CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Nucleophilic Acylation of Nitroalkenes with Protected
Thiazolium Carbinols
In summary, the first direct nucleophilic addition of a carbonyl
unit to nitroalkenes has been reported. In the presence of a fluoride
anion, silyl-protected thiazolium carbinols do not undergo scission
to an aldehyde and thiazolium zwitterion, but instead access
carbonyl anion reactivity via a presumed 1,2-hydrogen shift. This
distinct fluoride-activated acyl anion strategy is divergent from the
typical combinations of heteroazolium salts and bases and thus
allows for the use of reactive nitroalkenes as substrates. Addition-
ally, newly formed stereocenters in this reaction can be controlled
by a chiral thiourea. The enantioselective process implicates key
interactions between thiourea and nitro functionality during carbon-
carbon bond formation. Mechanistic investigations and the further
exploration of these silyl-protected thiazolium carbinols as sto-
ichiometric carbonyl anions will be reported in due course.
Acknowledgment. This article is dedicated to the memory of
Professor Nabi Magomedov and his family. Support for this work
has been provided by the NSF (CAREER 0348979) and the ACS-
PRF. K.A.S. thanks Abbott Laboratories, Amgen, Boehringer
Ingelheim, and 3M for generous support, and Wacker Chemical
Corp. for providing organosilanes. A.E.M. acknowledges an ACS
Division of Organic Chemistry Fellowship sponsored by Eli Lilly.
A.M.Z. is a 2005 Pfizer Summer Undergraduate Research Fellow.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
a Diastereoselectivity ) 6:1 when achiral thiourea 8 is replaced by 18.
Table 3. Survey of Thiazolium Carbinols
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