Bis(amino)cyclopropenylidenes as organocatalysts for acyl anion and extended umpolung reactions

Article abstract of DOI:10.1002/anie.201307167

Back to BACs: In the pursuit of novel carbene organocatalysts, bis(amino)cyclopropenylidenes (BACs) were explored as alternatives to N-heterocyclic carbenes. They were effective in catalyzing the Stetter reaction, and displayed unique advantages over the

Full text of DOI:10.1002/anie.201307167

Angewandte
Chemie
DOI: 10.1002/anie.201307167
Synthetic Methods
Hot Paper
Bis(amino)cyclopropenylidenes as Organocatalysts for Acyl Anion and
Extended Umpolung Reactions**
Myron M. D. Wilde and Michel Gravel*
The use of N-heterocyclic carbenes (NHCs) as organocata-
lysts has gained considerable attention in recent years
because of their unique properties and modes of reactivity.[1]
In addition to their use as acyl anion equivalents in the
reversal of reactivity (umpolung) of aldehydes,[2] they have
also been utilized in the extended umpolung of a-function-
alized aldehydes,[3] in the umpolung of activated olefins,[4] and
as nucleophilic catalysts.[5] As a result of this versatility,
significant effort has gone into the design of NHC catalysts
that are tailored to particular reactions and reaction types. To
date, the most commonly used precatalysts all feature a five-
membered nitrogen-containing heterocyclic core, as present
in 2-thiazolium, 1,2,4-triazolium, imidazolium, and imidazo-
linium salts. The usefulness of each of these NHC families is
now well established and new substitution patterns are
constantly being introduced to improve or modulate reac-
tivity. Although many studies have shown the catalytic
properties of NHCs to be greatly influenced by often subtle
steric and electronic effects, the search for new properties and
complementary reactivity would benefit from the introduc-
tion of entirely new catalytic architectures.[6]
which have proven elusive toward isolation and character-
ization.[11] This stability is due not only to the bulky isopropyl
substituents, but also to the electron-donating nitrogen
substituents, the p-aromatic character of the singlet state,
and to a significant degree of s-aromaticity.[12] Thus, even
sterically unhindered BACs (such as 4) may have a sufficient
lifetime in solution to participate in organocatalytic reactions
(Scheme 1). Despite the apparent improbability of BACs
Scheme 1. Formation of an enolamine between a BAC and an alde-
hyde.
forming the required strained enolamine (5),[13] the possibility
of using carbene catalysts that are readily accessible and less
sterically hindered than commonly used 1,2,4-triazolium salts
prompted this study. To our knowledge, there is no report on
the use of BACs as organocatalysts apart from a brief mention
by Tamm and co-workers, who used the hindered chiral BAC
2 in a benzoin reaction.[14] Herein, we describe our prelimi-
nary results on the use of BACs in representative umpolung
reactions. As detailed below, differences between the reac-
tivity of these carbenes and those derived from thiazolium
and triazolium salts are striking and should spur further
investigations.
The bis(amino)cyclopropenium motif, which was first
explored in the 1970s,[7–9] received renewed attention in 2006
when Bertrand and co-workers successfully characterized by
X-ray crystallography the free carbene bis(diisopropylami-
no)cyclopropenylidene (iPrBAC) derived from bis-
(amino)cyclopropenium salt 1 (Figure 1).[10] The thermal
stability of this carbene stands in contrast to the NHCs
derived from commonly used thiazolium and triazolium salts,
The bis(amino)cyclopropenium salt iPrBAC·HBPh4 (1)
was prepared from commercial tetrachlorocyclopropene
according to a known procedure (Scheme 2).[10a] Preparation
and isolation of the less hindered salt EtBAC·HBPh4 (3)
proved more difficult because the procedure reported by
Yoshida[8a,b] afforded mainly tris(diethylamino)cycloprope-
nium chloride (6)[15] and only small amounts of 3, the
purification of which failed. Addition of the amine at
À788C in the first step was found to be necessary to minimize
Figure 1. Bis(amino)cyclopropenium salts.
[*] M. M. D. Wilde, Prof. M. Gravel
Department of Chemistry
University of Saskatchewan
110 Science Place
Saskatoon, SK S7N 5C9 (Canada)
E-mail: michel.gravel@usask.ca
Homepage: http://www.usask.ca/chemistry/groups/gravel/
[**] We thank Prof. Claude Legault (Universitꢀ de Sherbrooke) for
helpful discussions, Dr. Eduardo Sꢁnchez-Larios for early work, and
Dr. Gabriele Schatte for X-ray analysis, as well as NSERC, CFI and
the University of Saskatchewan for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307167.
Scheme 2. Preparation of bis(amino)cyclopropenium salts 1 and 3.
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the trisubstitution of tetrachlorocyclopropene. The recrystal-
lization of 3 was also more difficult than that of 1, and it was
found that the use of methanol effectively removed all
phosphorus-containing by-products while selectively provid-
ing 3 in a fine crystalline form. This modified one-pot
procedure reliably provides 30–40% yield of 3 on a gram
scale.
The catalytic properties of 1 and 3 were first examined by
using the intermolecular Stetter reaction.[16] Various alde-
hydes were reacted with trans-chalcone, the latter being
a useful benchmark because it has been used in a number of
reported Stetter reactions. A preliminary base screening
showed that the use of tertiary amines does not lead to any
reaction, presumably because the precatalysts are not depro-
tonated under these conditions. However, both DBU and
cesium carbonate proved highly effective in precatalyst
activation. The large difference in catalytic efficiency between
1 and the less hindered 3 became readily apparent upon
reaction with methyl p-formylbenzoate (Table 1, entries 1–3).
Scheme 3. Stetter reaction of p-methoxybenzaldehyde employing differ-
ent carbene precursors. Yields of 13 are given for each of the three
catalysts (3, 11, and 12).
use of thiazolium salt 11 or triazolium salt 12 under otherwise
identical conditions. The use of simple b-alkyl substituted
ketone acceptors in the Stetter reaction also represents
a significant challenge. The more electrophilic b-alkyl nitro-
olefins[18] and alkylidene malonates[17b,19] have been
employed, but these acceptors do not provide direct access
to the ubiquitous and useful 1,4-diketone motif. Gratifyingly,
the Stetter reaction between methyl p-formylbenzoate and
enone 14 provided an excellent yield of the addition product
under the catalysis of bis(amino)cyclopropenium salt 3
(Scheme 4). By contrast, the use of thiazolium salt 11 or
Table 1: Stetter reaction using precatalysts 1 and 3.[a]
Entry
R
Catalyst Cat.
loading (x)
Product Yield [%][b]
1
2
3
4
5
6
p-CO2MeC6H4
p-CO2MeC6H4
p-CO2MeC6H4
2-furyl
m-MeOC6H4
C6H5
1
1
3
3
3
3
10
7
7
7
8
9
<10[c]
24
98
99
72
65
30
10
10
10
20
10
[a] All reactions were run with 1–1.7 equiv of aldehyde. Reactions in
entries 1,3, and 4 were run for 1.5-3 hrs. Reactions in entries 2, 5, and 6
were run for 16 h. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. [b] Yield of
isolated pure product. [c] Product not isolated.
Scheme 4. Stetter reaction of an alkyl-substituted acceptor employing
different carbene precursors. Yields of 15 are given for each of the
three catalysts (3, 11, and 12).
Indeed, only small amounts of the Stetter product were
obtained using 1, even at a loading of 30 mol% and after an
extended reaction time. By contrast, the product was obtained
in nearly quantitative yield using 10 mol% of 3. This result
highlights the importance of steric hindrance in this family of
catalysts, as well as the necessity to prepare unhindered ones
through a reliable route. Other aromatic and heteroaromatic
aldehydes could be used successfully in Stetter reactions
catalyzed by 3 (Table 1, entries 4–6). Interestingly, and in
contrast to analogous reactions using thiazolium and triazo-
lium salts, the formation of benzoin products during the
course of the reaction was not observed.[17]
Stetter reactions involving particularly challenging sub-
strates were then performed using 3 as the catalyst, and
compared to reactions using the commonly employed salts 11
and 12. Bis(amino)cyclopropenium salt 3 efficiently catalyzes
the Stetter reaction of even electron-rich aldehydes such as p-
methoxybenzaldehyde (Scheme 3). The use of electron-rich
aldehyde substrates represents an ongoing challenge in
various NHC-catalyzed processes. This often-encountered
difficulty is illustrated by the poor yields obtained through the
triazolium salt 12 only afforded slow and incomplete con-
version to the Stetter product. In the case of triazolium 12, the
competing benzoin product was obtained in 73% yield. In the
reactions catalyzed by 3 (Schemes 3 and 4), the mixture
remained remarkably clean throughout, consisting essentially
of product, catalyst, and unreacted starting material. In line
with with previous results using 3, and in contrast to reactions
using catalysts 11 and 12, no competing benzoin by-products
were observed.
The reactivity of thiazolium- and triazolium-based cata-
lysts is known to be affected by the bulkiness of the aldehyde
reactant.[18c,20] By contrast, the unhindered nature of the
reactive carbene center in EtBAC may make it relatively less
susceptible to steric factors. To test this hypothesis, competi-
tion reactions were performed between furfural and methyl 4-
formylbenzoate in the presence of trans-chalcone (Table 2).
As anticipated, the use of EtBAC·HBPh4 (3) as precatalyst
led preferentially to Stetter product 7, formed from the more
hindered but more electron-poor methyl 4-formylbenzoate.
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Table 2: Aldehyde competition reaction.
Entry
Catalyst
Product ratio 7/8[a]
Combined yield [%][b]
Scheme 7. Enantioselective Stetter reaction.
1
2
3
3
11
12
85:15
37:63
12:88
99
80
85
Supporting Information). This catalyst was then tested in an
enantioselective Stetter reaction between furfural and chal-
cone, for which excellent yield and moderate enantioselec-
tivity were achieved (Scheme 7). Enantioselective Stetter
reactions involving unsaturated ketones have been notori-
ously difficult to accomplish with a high degree of enantio-
selectivity using chiral triazolium salts.[17a,24] Current efforts
are thus aimed at designing more rigid BAC catalysts that can
better provide facial selectivity in the Stetter reaction of
enones.
In summary, BACs have been shown to be a viable and
effective family of catalysts for both acyl anion and extended
umpolung transformations. Stetter reactions involving noto-
riously unreactive substrates can be mediated with high
efficiency using BACs compared with their NHC counter-
parts. The short and modular nature of BAC synthesis lends
itself well to the rapid preparation of a diverse set of
precatalysts. The design of BACs with varying electronic
properties as well as various chiral scaffolds for enantiose-
lective applications is currently underway.
[a] Determined by 1H NMR spectroscopy on the crude reaction mixture.
[b] Isolated as a mixture of Stetter products 7 and 8.
In comparison, the use of thiazolium 11 or triazolium 12
favored Stetter product 8, formed from the less hindered
furfural. Control experiments show that these reactions are
under kinetic control (see the Supporting Information).
The success of the EtBAC-catalyzed Stetter reaction can
be transposed to our previously disclosed domino Stetter–
Michael reaction, as shown in Scheme 5.[17c,21] The preferred
Scheme 5. Domino Stetter–Michael reaction.
formation of the all-trans diastereomer 16 is presumably the
result of thermodynamic control under the basic reaction
conditions.
In addition to their ability to catalytically form acyl anion
equivalents as demonstrated in the Stetter reaction, BACs can
also display homoenolate-type reactivity in the presence of
enals. Indeed, when cinnamaldehyde was left to react with
catalytic amounts of 3 under basic conditions, cis-lactone 18
was formed through extended umpolung (Scheme 6).[22]
Experimental Section
Bis(diethylamino)cyclopropenium tetraphenylborate 3: Diethyl-
amine (2.36 mL, 22.5 mmol) was added dropwise to a solution of
tetrachlorocyclopropene (0.690 mL, 5.64 mmol) in dichloromethane
(100 mL) at À788C under nitrogen. The reaction mixture was warmed
to room temperature over 3 h, then cooled back to À788C.
Triphenylphosphine (1.48 g, 5.64 mmol) was then quickly added and
the mixture was warmed to room temperature. Distilled water
(20 mL) was added and the two-phase mixture was stirred vigorously
for 16 h. Sodium tetraphenylborate (1.93 g, 5.64 mmol) was then
added and the reaction was transferred to a separatory funnel with
dichloromethane. The organic layer was washed with 0.5m HCl,
saturated aqueous NaHCO3, and H2O, and then dried over Na2SO4
and concentrated in vacuo. The resulting crude oil was purified by
recrystallization first from methanol/water, then from CH2Cl2/Et2O.
The title compound was obtained as a white solid (920 mg, 32%).
M.p. 132–1338C; 1H NMR (500 MHz, CHCl3): d = 7.51 (br s, 8H),
7.03 (t, J = 7.1 Hz, 8H), 6.86 (t, J = 7.1 Hz, 4H), 4.46 (br s, 1H), 3.20
(q, J = 7.5 Hz, 4H), 3.10 (q, J = 7.5, 4H), 1.21 (t, J = 7.5, 6H),
1.11 ppm (t, J = 7.5, 6H); 13C NMR (125 MHz, CHCl3): d = 164.4 (C-
Scheme 6. Lactone formation through homoenolate reactivity.
B, q, 1JCB = 49 Hz), 136.2, 135.4, 125.9 (C-B, q, JCB=2.8 Hz), 122.0,
2
Although the yield of this unoptimized transformation is
modest, the ability of catalyst 3 to mediate both acyl anion
equivalent and homoenolate reactions is remarkable.
Given the straightforward and modular synthesis of BAC
precatalysts, we decided to highlight this aspect through the
rapid preparation of a chiral analogue. To this end, catalyst 19
was prepared in a single step from a chiral diamine[23] (see the
98.2, 48.1, 46.9, 14.2, 12.9 ppm; FTIR (KBr thin film): n˜max = 3108,
3053, 2984, 1895, 1589 cmÀ1; HRMS (ESI +): m/z: calcd for C11H21N2
+
[M]+: 181.1699; found: 181.1703.
Received: August 14, 2013
Revised: September 11, 2013
Published online: October 2, 2013
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Keywords: carbenes · cyclopropenylidenes · organocatalysis ·
Stetter reaction · umpolung
.
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