Thiazolium-catalyzed additions of acylsilanes: A general strategy for acyl anion addition reactions

Article abstract of DOI:10.1021/jo060699c

A strategy utilizing N-heterocyclic carbenes (NHCs) derived from thiazolium salts has been developed for the generation of carbonyl anions from acylsilanes. Synthetically useful 1,4-diketones and N-phosphinoyl-α- aminoketones have been prepared in good to excellent yields via NHC-catalyzed additions of acylsilanes to the corresponding α,β-unsaturated systems and N-phosphinoylimines. These organocatalytic reactions are air- and water-tolerant methods to execute robust carbonyl anion addition reactions. Additionally, polysubstituted aromatic furans and pyrroles have been efficiently synthesized in a one-pot process using this carbonyl anion methodology. The addition of alcohols to the reaction renders the process catalytic in thiazolium salt. In an effort to synthesize a potential intermediate along the proposed reaction pathway, silylated thiazolium carbinols have been identified to provide good yields of carbonyl anion addition products when subjected to the standard reaction conditions in the presence of suitable electrophiles.

Full text of DOI:10.1021/jo060699c

Thiazolium-Catalyzed Additions of Acylsilanes: A General Strategy
for Acyl Anion Addition Reactions
Anita E. Mattson, Ashwin R. Bharadwaj,1 Andrea M. Zuhl, and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
ReceiVed April 1, 2006
A strategy utilizing N-heterocyclic carbenes (NHCs) derived from thiazolium salts has been developed
for the generation of carbonyl anions from acylsilanes. Synthetically useful 1,4-diketones and
N-phosphinoyl-R-aminoketones have been prepared in good to excellent yields via NHC-catalyzed additions
of acylsilanes to the corresponding R,â-unsaturated systems and N-phosphinoylimines. These organo-
catalytic reactions are air- and water-tolerant methods to execute robust carbonyl anion addition reactions.
Additionally, polysubstituted aromatic furans and pyrroles have been efficiently synthesized in a one-pot
process using this carbonyl anion methodology. The addition of alcohols to the reaction renders the
process catalytic in thiazolium salt. In an effort to synthesize a potential intermediate along the proposed
reaction pathway, silylated thiazolium carbinols have been identified to provide good yields of carbonyl
anion addition products when subjected to the standard reaction conditions in the presence of suitable
electrophiles.
Introduction
ponent coupling reactions.28-31 A valuable synthetic tactic that
NHCs are capable of catalyzing is the polarity reversal, or
Umpolung,32 of carbonyl-containing compounds. Umpolung
strategies are highly useful methods to form carbon-carbon
bonds through unconventional modes of reactivity. The polarity
reversal of carbonyl units generates carbonyl or acyl anions, a
N-Heterocyclic carbenes (NHCs) have been shown to be
highly useful compounds able to participate in a number of
diverse reactions.2-9 Because of their unusual electronic char-
acteristics, they are unique molecular architectures for the
development of new organometallic processes,7,10-13 catalysts
in organocatalytic reactions,7,8,14-27 and reagents in multicom-
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10.1021/jo060699c CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/21/2006
J. Org. Chem. 2006, 71, 5715-5724
5715

Mattson et al.
SCHEME 1. Catalytic Acyl Anion Addition Reactions with
Aldehydes Employed as Acyl Anion Precursors
SCHEME 2. N-Heterocyclic Carbene-Catalyzed Generation
of Acyl Anions
fluoride or cyanide anions. In 1981, the Heathcock laboratory
reported the use of fluoride (KF, tetrabutylammonium fluoride)
to promote alkylation of the carbonyl carbon of acylsilanes with
various alkyl halides.49 These findings were followed by
disclosures from Degl’innocenti and co-workers showing the
conjugate additions of acylsilanes to enones catalyzed by either
fluoride or cyanide.50 More recently, Johnson has reported
asymmetric cross-benzoin reactions of acylsilanes and aldehydes
catalyzed by cyanide or metallophosphite species.36 These
nucleophilic phosphorus compounds have also been shown to
promote conjugate additions of acylsilanes to unsaturated
carbonyl compounds.51
Beginning in 2002, our laboratory has focused on developing
strategies to catalyze carbonyl anion addition reactions under
more neutral reaction conditions than those previously reported.
On the basis of the pioneering work by Heathcock and
Degl’innocenti, we chose acylsilanes to investigate as a unique
carbonyl anion precursor. It is well established that NHC
catalysis can be used to generate acyl anion equivalents from
aldehydes,8,9,15,35 and we envisioned applying this same approach
to acylsilanes. At the onset of our investigations, it was
reasonable to propose that an NHC would undergo nucleophilic
addition to an acylsilane (1) and promote a 1,2-silyl group shift
(Brook rearrangement)52,53 from carbon to oxygen, thus render-
ing the carbonyl carbon nucleophilic (Scheme 2). However,
when compared to smaller nucleophiles such as fluoride and
cyanide anions, it was unclear whether a larger five-membered
heterocycle such as a thiazolium would add to the carbonyl
carbon of an acylsilane. Indeed, heteroazolium carbenes/
zwitterions had not been used to promote Brook rearrangements
of acylsilanes prior to our findings. As mentioned, these overall
neutral carbenes/zwitterions have found utility as organocatalysts
in a variety of reactions, can be generated in situ from stable
precursors, tolerate air and moisture, and are generally nontoxic.
useful class of reactive intermediates. Many important biological
processes utilize carbonyl anions generated from the corre-
sponding R-keto acids via an NHC derived from thiamine
pyrophosphate, a cofactor of vitamin B1.
Two established catalytic acyl anion addition reactions are
the benzoin condensation33-36 (1,2-addition of a carbonyl anion
to an aldehyde, Scheme 1, eq 1) and the Stetter reaction37-42
(1,4-addition of a carbonyl anion to an R,â-unsaturated system,
eq 2). In these processes, a catalyst, such as cyanide or an NHC,
is used to generate an acyl anion equivalent from an aldehyde.
Unfortunately, because of the highly reactive nature of alde-
hydes, a significant amount of self-condensation side products
are often formed when they are employed as acyl anion
precursors. The intrinsic reactivity of the starting aldehyde is
advantageous when generating a carbonyl anion species via
addition of an NHC, but this aspect is limiting in that multiple
products are observed when electrophiles that are less reactive
than aldehydes are employed.
Acylsilanes43-48 are useful molecules that have been utilized
as unconventional acyl anion precursors. Acylsilanes are more
sterically congested than aldehydes because of the substitution
on silicon, and this attenuated reactivity precludes side reactions
associated with additions to carbonyl groups. The standard
method to convert acylsilanes into carbonyl anions typically
involves the addition of charged nucleophilic species, such as
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In preliminary communications, we have reported the addition
of acylsilanes to R,â-unsaturated systems and imines to generate
the corresponding 1,4-diketones54 and R-aminoketones55 using
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5716 J. Org. Chem., Vol. 71, No. 15, 2006

Thiazolium-Catalyzed Additions of Acylsilanes
SCHEME 3. Acylsilane Addition Reactions Catalyzed by
NHCs
SCHEME 4. Acylsilane Additions to Chalcone with
Catalytic Thiazolium Salt
TABLE 1. Optimization of Acylsilane Additions to Chalcone with
Stoichiometric Thiazolium Salta
SCHEME 5. Catalytic Sila-Stetter Reaction with Exogenous
Alcohol
entry
base
solvent
yield (%)b
1
2
3
4
5
DBU
NEt3
THF
THF
THF
CH2Cl2
PhCH3
71
40
0
39
0
(Scheme 4). A more surprising result was obtained when no
product was observed with a stoichiometric amount of catalyst
3b.
KOtBu
DBU
DBU
A comparison of catalysts 3a and 3b reveals that the free
alcohol (an artifact of the conversion of thiamine into structures
such as 3a) may be the cause for the difference in reactivity.
To explore whether a free alcohol was necessary for the reaction,
4 equiv of 2-propanol was added to an acylsilane addition
reaction containing 30 mol % of 3a (Scheme 5). We were
pleased to find that the straightforward addition of an exogenous
alcohol improved the yield of 4 to 77% with only 30 mol % of
3a. Further confirmation of the importance of an alcohol additive
was observed when thiazolium 3c was employed with 4 equiv
of 2-propanol: these reaction conditions provided the same yield
as with 3a. These results show the counterion has a minimal
effect on the outcome of the acylation reactions.
a Reaction performed at 0.8 M for 12-24 h at reflux in the solvent
indicated. b Isolated yield after chromatographic purification.
NHC catalysts derived from commercially available thiazolium
salts (Scheme 3). This full account describes in detail the
development of our NHC-catalyzed acylsilane addition reactions,
including an examination of the catalyst structure and mecha-
nistic studies.
Results and Discussion
Development of a Successful NHC Catalyst System. Our
investigation of NHC-catalyzed acyl anion additions began with
a survey of reaction conditions to carry out 1,4-additions of
acylsilanes to chalcone. Our choice of pursuing the synthesis
of 1,4-dicarbonyl compounds via a carbonyl anion addition was
driven by the utility of these molecules in organic synthesis.
After significant experimentation, we discovered that a sto-
ichiometric amount of thiazolium salt 3a and DBU (1,8-
diazobicyclo[5.4.0]undec-7-ene) successfully promotes the ad-
dition of benzoyltrimethylsilane 1a to chalcone to produce 1,4-
dicarbonyl 4 in a good yield after 12 h of reflux in THF (71%,
Table 1, entry 1). With the desired bond-forming process
achieved, a brief survey of bases and solvents indicated that
DBU and THF were optimal. Methylene chloride provided only
a 39% yield product, most likely because of the low reaction
temperature (entry 4). The use of toluene as a solvent resulted
in a heterogeneous mixture that afforded no product formation
(entry 5).
A key variable we were interested in examining was the
structure of the heteroazolium catalyst. The reactivity of an NHC
can significantly be affected by steric and electronic properties;
therefore, an examination of potential catalysts was carried out
to determine the best NHC to effect the desired conjugate
addition. To our surprise, NHCs derived from imidazolium and
triazolium compounds fail to produce significant amounts of
the desired product 4 (Table 2, eq 4). Surprisingly, the catalyst
derived from benzothiazolium 3d does not provide any of the
desired product, thereby underscoring the subtle electronic
effects that control the interaction of the heteroazolium-derived
carbene with the acylsilane as well as the carbon-carbon bond
forming process. Additionally, no decomposition of the chalcone
or acylsilane is observed with 3d. There is no product formation
with the sterically hindered catalyst resulting from imidazolium
salt 3e, although some acylsilane is consumed. Interestingly,
benzaldehyde is the only product resulting from the reaction
catalyzed by 3e and no benzoin products were observed by gas
chromatography. The benzimidazolium-derived catalyst (3f)
affords nearly complete conversion of the acylsilane, but only
a 5% yield of 1,4-diketone 4 is observed. Triazolium-derived
catalysts 3g and 3h had similar results, with little product
formation and little recovered acylsilane. These observations
emphasize how slight perturbations in the heteroazolium core
and nitrogen substitution can cause drastic differences in
reactivity.
After successful formation of 4 in the stoichiometric process,
we focused on developing a catalytic acylsilane addition
reaction. On the basis of our knowledge of the Stetter reaction,
we suspected that the process should be catalytic in thiazolium
salt; however, when the amount of 3a was reduced from 1 equiv
to 30 mol %, only a 43% yield of the product was isolated
(54) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem.
Soc. 2004, 126, 2314-2315.
(55) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363-4366.
J. Org. Chem, Vol. 71, No. 15, 2006 5717

Mattson et al.
TABLE 2. Examination of Catalyst Structurea
TABLE 3. Catalytic Sila-Stetter Reaction with Acylsilane 1a and
â-Aryl Unsaturated Phenyl Ketonesa
entry
R1
R2
yield (%)b
product
1
2
3
4
5
6
7
8
9
Ph
Ph
1-naphth
4-BrPh
4-ClPh
2-ClPh
4-MePh
3-OMePh
4-OMePh
4-HOPh
4-ClPh
4-OMePh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
82
80
72
66
74
68
84
75
77
50c
5
6
7
8
9
10
11
12
13
14
10
Ph
a Reaction performed at 0.8 M for 12-24 h. b Isolated yield after
chromatographic purification. c Based on 70% conversion.
TABLE 4. Catalytic Sila-Stetter Reaction with Acylsilane 1a and
â-Aryl Unsaturated Phenyl Ketonesa
entry
acylsilane
R1
R2
yield (%)b
product
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
CH3
CH3
CH3
Ph
Ph
Ph
77
82
70
61
70
63
4
15
16
4
17
18
4-ClPh
4-CH3Ph
Ph
CH3
cyclohexyl
a Reaction performed at 0.8 M for 12-24 h. b Isolated yield after
chromatographic purification.
a Reactions performed at 0.5 M for 24 h. b Yields and conversions
obtained by GC unless otherwise noted. c Isolated yield after purification.
d Mes ) Mesityl.
there are no stringent precautions to exclude moisture in any
of these reactions.
The influence of the acylsilane structure on the reaction was
also examined (Table 4, eq 6). Because the addition of a
thiazolium-derived carbene/zwitterion is an important step in
the overall process, the substitution of the silyl group should
influence the accessibility to the carbonyl carbon atom. Ac-
cordingly, both alkyl and substituted aryl acylsilanes were
investigated as acyl anion precursors. Acylsilane 1b containing
an electron-withdrawing substituent in the para position provided
the best results, generating 15 in 82% yield (Table 4, entry 2).
Interestingly, 1b is the most reactive acyl anion precursor we
have surveyed. This may be due to the ability of this analogue
to offer additional stabilization to the carbonyl anion equivalent
that is generated in the reaction. Acylsilanes with alkyl groups
at R1 (1e and 1f) are successful substrates and generate 1,4-
diketone products 17 and 18 in good yields (entries 5 and 6).
These entries indicate that the reaction can accommodate
acylsilanes with enolizable protons. Additionally, dimethylphe-
nyl acylsilane 1d proved to be a suitable acyl anion precursor
yielding 61% of 4 (entry 4).
Investigation of Acylsilane Additions to R,â-Unsaturated
Electrophiles. With an operative catalytic process identified,
we proceeded to examine the scope of the addition reaction of
various acylsilanes to R,â-unsaturated systems. After our initial
success with chalcone (2a), we screened numerous unsaturated
amides and esters as electrophiles with no success. A current
requirement of our acylsilane conjugate additions is that the
electrophile needs to be an R,â-unsaturated ketone or a highly
reactive ester. Utilizing an unsaturated acyl pyrrole as the
electrophile produced a complex mixture of compounds with
no desired carbonyl anion products. Additionally, no desired
product was observed when a cyclic ester and amide, maleic
anhydride, and N-methyl maleimide were examined. Additions
to alkylidene malonates were met with limited success as low
conversions prevented high yields of product from being
isolated. Our attempts to add to nitroalkenes failed because the
starting materials decomposed under these reaction conditions.
Our investigations of the chalcone substrate scope began with
an examination of various substituted derivatives (Table 3, eq
5). The addition reaction can tolerate both electron-donating
and electron-withdrawing substituents on either aryl group,
delivering good to high yields of product in all cases (66-82%,
entries 1-9). Even a free hydroxyl group provides the desired
1,4-diketone 14, albeit in a slightly reduced yield (50%, entry
10). Because 2-propanol is a key constituent in the reactions,
The scope of the sila-Stetter reaction was further examined
by employing various classes of R,â-unsaturated carbonyl
electrophiles (Table 5, eq 7). Even with multiple nucleophilic
species in solution (e.g., DBU, 2-propanol, thiazolium carbene/
zwitterion), a surprising number of highly reactive conjugate
acceptors that are prone to polymerization provide moderate
yields of 1,4-dicarbonyl products. Diethyl fumarate and dimethyl
5718 J. Org. Chem., Vol. 71, No. 15, 2006

Thiazolium-Catalyzed Additions of Acylsilanes
TABLE 5. Acylsilane Additions to â,â-Unsaturated Esters and
TABLE 6. Examples of Furans Prepared in a One-Flask
Synthesisa,b
Ketonesa
a All reactions performed at 1.0 M for 24 h. See Supporting Information
for details. b Isolated yields after chromatographic purification.
pounds,57,58 we envisioned that our addition reaction could be
the first step in a direct, one-flask process to access polyaromatic
furans without the need for a transition-metal catalyst. Thus,
the 1,4-dicarbonyl compounds synthesized by the thiazolium-
catalyzed conjugate addition of acylsilanes could be directly
converted to furans in a one-pot process upon simple addition
of an acid.
We were pleased to find that straightforward addition of acetic
acid to the reaction after 100% conversion of the conjugate
acceptor followed by stirring at reflux for 8 h yielded the desired
furan product 25 (Table 6, eq 8). In this process, both alkyl
and aryl acylsilanes successfully participate in the one-pot
reaction with a variety of chalcone derivatives, providing
excellent yields of highly substituted furans (74-84%). Notably,
these yields are for a two-step process yielding greater than 90%
per step.
Encouraged by the efficiency of our simple furan synthesis,
this one-flask strategy has been applied to the synthesis of 2,3,5-
trisubstituted pyrroles.59 The addition of a primary amine to a
1,4-dicarbonyl compound in the presence of acid accesses
pyrroles in good yield and is known as the Paal-Knorr
cyclization.60-62 The combination of our conjugate addition with
a Paal-Knorr reaction in a single flask would constitute the
multicomponent assembly of polyaromatic pyrroles. Rapid
access to various substituted pyrroles is a continuing goal in
organic chemistry because these heterocycles are important
motifs in natural products,63-66 therapeutic compounds,67,68 and
materials.69-71 Accordingly, new synthetic approaches to access
a Reactions performed at 0.8 M for 12-24h. b Isolated yield after
chromatographic purification. c 64% conversion. d 59% conversion.
malonate are competent substrates generating the corresponding
products 19 and 20 in good yield (entries 1 and 2). Highly
reactive substrates lacking substitution in the â-position such
as ethyl acrylate and methyl vinyl ketone undergo these
nucleophilic acylation reactions to generate 21 and 22 in 72%
and 75% yields (entries 3 and 4). Finally, additions to alkyl
chalcone derivatives 2f and 2g produce the desired 1,4-diketones
in moderate yields (entries 5 and 6). In this system, alkyl
chalcones are less reactive than aryl chalcones and the lower
yields are a result of the reactions not going to completion under
numerous conditions surveyed. In an effort to aid in the
conversion of the alkyl chalcones, acylsilane 1b containing the
p-Cl substituent was employed because it is the most reactive
acyl anion precursor that we have examined.
One-Pot Synthesis of Furans and Pyrroles. With a robust
and efficient preparation of 1,4-dicarbonyl compounds devel-
oped, we became interested in applying this new Umpolung
methodology to a one-flask synthesis of highly substituted
heterocycles. Initially, our efforts were directed toward the
synthesis of furans because these important heterocycles are
easily accessible from 1,4-diketones and are found in natural
products, pharmaceuticals, and materials.56 Although there are
many strategies available to synthesize these valuable com-
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J. Am. Chem. Soc. 1999, 121, 54-62.
(66) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783.
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Giannaccini, G.; Lucacchini, A. J. Med. Chem. 1990, 33, 2646-2651.
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200.
J. Org. Chem, Vol. 71, No. 15, 2006 5719

Mattson et al.
TABLE 7. Select Examples of Pyrroles Synthesized in a One-Pot
Sila-Stetter Processa,b
TABLE 8. Survey of Amines for Pyrrole Synthesisa
a All reactions performed at 0.8 M for 16 h. See Supporting Information
for details. b Isolated yields after chromatographic purification.
pyrroles continue to be an area of intense research.72-75 Our
multicomponent approach is similar to the furan synthesis above
in efficiency and avoidance of expensive and/or toxic transition-
metal catalysts.
To optimize this conjugate addition/Paal-Knorr sequence,
various acids were added directly along with aniline to a
thiazolium-catalyzed reaction between 1 and 2 after 100%
conversion of 2. With p-toluenesulfonic acid (TsOH) after 8 h
at reflux, moderate to good yields of the pyrroles can be isolated.
In this manner, a wide array of highly substituted pyrroles can
be readily prepared (Table 7, eq 9). The reaction is tolerant of
various substituted chalcones, including both electron-donating
and electron-withdrawing substituents. Additionally, pyrroles
were easily generated from an assortment of alkyl and aryl
acylsilanes in high yield. To gain an additional element of
diversity, the amine was investigated (Table 8, eq 10). Substi-
tuted anilines proved to be suitable substrates, as both electron-
donating and -withdrawing analogues generated the desired
pyrroles in high yield (entries 1-3). Both straight chain and
branched alkylamines successfully participate in the cyclization
reactions to yield the desired products in 63-82% yields (entries
5-8). Chiral pyrroles 47 and 48 were generated in good yield
from optically active amines (entries 9 and 10).
Although this multihour process affords good yields of
pyrroles, we felt that a more efficient means of heating could
reduce the time required and thus improve the overall process.
The use of microwave heating76-78 significantly reduces the
a Reaction conditions: 20 mol % of 4 and 30 mol % of DBU, 4 equiv
of i-PrOH; 0.8 M at 70 °C for 8 h. Amine, TsOH, and 4 Å sieves were
then added for an additional 8 h. b Isolated yield after purification.
(71) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.;
Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992-4993.
(72) Merlic, C. A.; Baur, A.; Aldrich, C. C. J. Am. Chem. Soc. 2000,
122, 7398-7399.
(73) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074-2075.
overall time for this two-step, single-flask process (Scheme 6).
The first heating cycle for 15 min at 160 °C combines 1a and
R,â-unsaturated ketone 2 in the presence of 20 mol % of 3a,
30 mol % of DBU, and 4 equiv of 2-propanol. This sequence
(74) Wang, Y. L.; Zhu, S. Z. Org. Lett. 2003, 5, 745-748.
(75) Takaya, H.; Kojima, S.; Murahashi, S. I. Org. Lett. 2001, 3, 421-
424.
(76) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389-
392.
(77) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org.
Chem. 2005, 5277-5288.
(78) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283.
5720 J. Org. Chem., Vol. 71, No. 15, 2006

Thiazolium-Catalyzed Additions of Acylsilanes
TABLE 9. Effect of Acylsilane Structure on Addition to Iminesa
SCHEME 6. One-Pot Pyrrole Synthesis in the Microwave
is followed by the addition of aniline and TsOH, and a second
15 min heating cycle at 160 °C smoothly affords the desired
pyrrole (36) in 55% yield in only 30 min. This streamlined
approach generates the target heterocycle in 3% of the time
required using conventional heating (30 min vs 16 h).
Investigation of Acylsilane Additions to Imines. The
successful conjugate additions of acylsilanes confirmed that
NHCs could promote carbonyl anion reactions. After exploring
different unsaturated ketones as electrophiles in these 1,4-
additions, we turned our attention toward developing the related
1,2-addition manifold. Acylsilane additions to activated imines
would enable the direct preparation of R-aminoketone products,
valuable compounds in synthetic and medicinal chemistry.79-81
Although powerful methods exist to generate R-amino acids
from imines, such as the Strecker reaction,82-84 the options to
directly synthesize protected R-aminoketones are limited.
The optimal conditions were established using a similar
catalyst system that was developed for the 1,4-addition reactions.
Chloroform and 2-propanol combined with the carbene derived
from thiazolium salt 3c and DBU provided an excellent yield
of R-aminoketone 51 (93%, Table 9, entry 1). It is important to
note that the phosphinoyl protecting group is crucial for success
in these reactions. The other imines surveyed (N-Bz, N-sulfinyl,
N-sulfonyl) were unsuccessful in this process. For these nu-
cleophile-catalyzed reactions, a careful balancing of reactivity
must be present: the ultimate electrophile (conjugate acceptor
or imine) cannot interact irreversibly with the nucleophilic
catalysts. The unique characteristics of N-phosphinoylimines85
in these acylsilane additions vs other imines underscore this
point.
a All reactions performed at 0.5 M for 12-24 h. See Supporting
Information for details. b Isolated yields after silica gel chromatography.
(Table 10, eq 12). Imines containing electron-withdrawing
substituents on the aryl ring, such as 4-Cl and 2-Cl, are suitable
substrates generating high yields of the corresponding R-ami-
noketone products (entries 1 and 4). The imine derived from
para-anisaldehyde produced an excellent yield of 58 (86%, entry
3). The reaction can also successfully incorporate heterocycles,
such as thiophene, into the final product in high yield (80%,
entry 5). The use of N-phosphinoylimines derived from alkyl-
substituted aldehydes did not generate 1,2-addition products
because the presence of an enolizable proton allows for facile
conversion to the more stable enamide. In an attempt to avoid
this problem by generating only small concentrations of reactive
imine during the reaction, Charette’s method using sulfinic acid
adducts of imines was employed.86 Unfortunately, no desired
products were observed using the imine precursors.
With the optimal conditions now identified, we examined the
scope of this 1,2-addition reaction with regard to the acylsilane
structure and imine substitution. First, the effect of the acylsilane
structure on the reaction was examined. In a vein similar to the
previous conjugate additions, the imine process can accom-
modate either alkyl or aryl acylsilanes, producing high yields
of product in all cases (Table 9, eq 11). An acylsilane with a
protected alcohol is a competent acyl anion precursor in the
reactions (entry 5).
Reaction Pathway. With the successful development of 1,2-
and 1,4-acylsilane addition reactions, we became interested in
a deeper understanding of the mechanism of these NHC-
catalyzed processes. We have advanced a plausible reaction
pathway based on the mechanism proposed for the benzoin
condensation (Scheme 7).35,87-94 The deprotonation of the
Various aromatic substituted N-phosphinoylimines were also
examined as electrophiles in the acylsilane addition reactions
(86) Cote, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5405-5410.
(87) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124-5131.
(88) Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J. T.; Jordan, F.
J. Org. Chem. 1994, 59, 7714-7722.
(79) Di Gioia, M. L.; Leggio, A.; Liguori, A.; Napoli, A.; Siciliano, C.;
Sindona, G. J. Org. Chem. 2001, 66, 7002-7007.
(80) Beguin, C.; Andurkar, S. V.; Jin, A. Y.; Stables, J. P.; Weaver, D.
F.; Kohn, H. Bioorg. Med. Chem. 2003, 11, 4275-4285.
(81) Haustein, K. O. Int. J. Clin. Pharm. Ther. 2003, 41, 56-66.
(82) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875-877.
(83) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2000, 39, 1279-1281.
(89) Chen, Y. T.; Jordan, F. J. Org. Chem. 1991, 56, 5029-5038.
(90) Barletta, G. L.; Zou, Y.; Huskey, W. P.; Jordan, F. J. Am. Chem.
Soc. 1997, 119, 2356-2362.
(91) Jordan, F.; Kudzin, Z. H.; Rios, C. B. J. Am. Chem. Soc. 1987,
109, 4415-4416.
(92) Rios, C. B.; Chung, A.; Jordan, F. Biochemistry 1988, 27, 3107-
3107.
(84) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 5634-5635.
(85) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205-1227.
(93) Jordan, F. Nat. Prod. Rep. 2003, 20, 184-201.
(94) Kluger, R. Chem. ReV. 1987, 87, 863-876.
J. Org. Chem, Vol. 71, No. 15, 2006 5721

Mattson et al.
TABLE 10. Examination of Acylsilane Additions to Phosphoyl
Iminesa
TABLE 11. Effect of Alcohol on Acylsilane Additions to Chalconea
entry
alcohol
EtOH
i-PrOH
t-BuOH
(CF3)2CH2OH
phenol
pKa (DMSO)
yield (%)b
1
2
3
4
5
28
29
29
18
18
56
85
99
70
81
a All reactions performed at 0.8 M for 24 h. b Yields obtained by GC.
O-silyl heterocycle I remain uncertain, the geminal substitution
on the nucleophilic carbon I renders a nucleophilic addition at
this point in the catalytic cycle energetically unfavorable.
Instead, it is plausible that a desilylation of I occurs in the
presence of DBU and an alcohol (such as 2-propanol) to yield
III, a less sterically hindered acyl anion equivalent able to
undergo addition reactions with greater facility. Enol/enamine
structures similar to III were first invoked as the carbonyl anion
species in the seminal work on the mechanism of the benzoin
reaction by Breslow and thus were termed “Breslow intermedi-
ates”. The nucleophilic addition of III to the electrophile forms
the key carbon-carbon bond which is followed by collapse of
the carbonyl to regenerate the thiazolium catalyst and produce
the acylated product.
To gain an improved understanding of the addition reactions
described above, we investigated the role of the alcohol in the
reaction and carried out a synthesis and investigation of potential
intermediate II. We were initially puzzled by the observation
that thiazolium salts such as 3b lacking a hydroxyl group
afforded no product without 2-propanol. However, after deter-
mining that a full equivalent of a hydroxyl group must be present
on the thiazolium or as an additive for the reaction to proceed
to 100% conversion, we concluded that the alcohol is involved
in the generation of the carbonyl anion and not catalyst turnover.
2-Propanol had been the alcohol of choice; however, a more
thorough investigation revealed that the alcohol structure had
only a moderate effect on the yield (Table 11, eq 13).
Interestingly, more sterically hindered alcohols such as tert-
butyl alcohol are slightly better additives, providing a quantita-
tive yield of 1,4-diketone 4 (entry 3). Surprisingly, the acidity
of the alcohol additive has a minimal impact on the overall
process. On the basis of experiments monitored by GC, the
alcohol additive is the ultimate silyl acceptor. These data support
the hypothesis that the alcohol additive promotes desilylation
of I: enolsilanes are known to be mild silylating agents,95-97
whereas silyl ethers (such as O-silylated versions of IV) are
less prone to donate a silyl group. However, this observation
does not confirm that intermediates such as I undergo desily-
lation because silyl group transfer after addition of I to an
electrophile cannot be ruled out at this time. The elusive nature
of compounds such as I (vide infra) has made the delineation
of the exact role of the alcohol additive difficult.
a All reactions performed at 0.5 M for 12-24 h. See Supporting
Information for details. b Isolated yields after silica gel chromatography.
SCHEME 7. Proposed Reaction Pathway
thiazolium salt (TS) yields the nucleophilic carbene. The
addition of the NHC to an acylsilane generates a tetrahedral
intermediate which undergoes a 1,2-silyl group migration from
carbon to oxygen (Brook rearrangement). This thermodynami-
cally driven migration produces acyl anion equivalent I (after
electronic reorganization). The carbon with the silyloxy group
appended is now nucleophilic by virtue of the connecting
enamine and is most likely in equilibrium with II when in the
presence of an available proton. All attempts to observe and/or
isolate compounds such as I have been fruitless (vide infra).
Although the reactive characteristics of a species such as the
Synthesis and Examination of a Potential Reaction In-
termediate. To further probe the mechanism of these acylsilane
(95) Mcwilliams, J. C.; Clardy, J. J. Am. Chem. Soc. 1994, 116, 8378-
8379.
(96) Veysoglu, T.; Mitscher, L. A. Tetrahedron Lett. 1981, 22, 1303-
1306.
(97) Veysoglu, T.; Mitscher, L. A. Tetrahedron Lett. 1981, 22, 1299-
1302.
5722 J. Org. Chem., Vol. 71, No. 15, 2006

Thiazolium-Catalyzed Additions of Acylsilanes
SCHEME 8. Proposed First Step in Acylsilane Additions
SCHEME 10. Examination of II in Addition Reactions
SCHEME 9. Attempted Synthesis of Proposed Intermediate
I
SCHEME 11. Examination of II in Addition Reactions
additions, we attempted to synthesize a silylated Breslow
intermediate with a structure similar to I in our proposed reaction
pathway. Access to compounds such as I would allow us to
assess their ability to undergo addition reactions with or without
an alcohol present. This species is invoked in our reaction
pathway and could be produced in a manner very similar to the
first steps in the proposed catalytic cycles of the benzoin
condensation and Stetter reaction.35,87 In these Umpolung
processes, the addition of a thiazolium-derived catalyst to the
aldehyde followed by a 1,2-proton shift to generate the acyl
anion equivalent occurs. We suspected that a similar sequence
was occurring in our addition reactions in which the interaction
of a thiazolium carbene/zwitterion with acylsilane generates
intermediate I (Scheme 8). To probe whether I was involved
as an intermediate in the reaction, an independent synthesis was
required. This was attempted by first lithiating 4,5-dimethylthi-
azole at the 2-position using n-butyllithium and then reacting
with an aldehyde (Scheme 9). The resulting carbinol was
purified by simple recrystallization (ethyl acetate/hexanes) and
then protected with a trimethylsilyl group (TMS) in the presence
of triethylamine. Finally, the thiazolium salt was prepared by
straightforward alkylation with neat iodomethane at 80 °C.
Confirmation of the synthesis of desired intermediate II was
obtained by 1H and 13C NMR spectroscopy. We anticipated that
intermediate I could be generated by deprotonation of the
protected thiazolium carbinol II. Unfortunately, upon addition
of base (DBU, Et3N, iPr2EtN, KHMDS) to the thiazolium
carbinol, only decomposition was observed by TLC or 1H NMR.
However, because of the nature of the acylsilane addition
reactions, we speculated thiazolium salt II may be an intermedi-
ate in the process. As depicted in Scheme 7, this thiazolium
salt (II) could be in equilibrium with I and this pathway would
provide a different entry into the catalytic cycle.
products in good yield providing additional evidence for
intermediate II participating in the reaction.
Conclusions. A new strategy has been developed to generate
carbonyl anion equivalents from acylsilanes. We have demon-
strated that in the presence of an alcohol additive neutral NHCs,
generated in situ from commercially available thiazolium salts,
successfully catalyze the addition of acylsilanes to R,â-unsatur-
ated systems and N-phosphinoylimines to generate the corre-
sponding 1,4-diketones and R-aminoketones in good to excellent
yields. Furthermore, highly substituted furans and pyrroles can
be synthesized via efficient one-pot sila-Stetter/cyclization
sequences. Benzoin side-product formation is not observed in
these processes, strongly indicating that the acylsilane does not
self-condense under the reaction conditions. To probe the
mechanism of these new bond-forming reactions, a proposed
reaction intermediate was independently synthesized and ex-
amined under a variety of conditions. The expected products
are observed in all cases when this potential intermediate is
subjected to a variety of reaction conditions providing substantial
evidence for the proposed reaction pathway. Finally, an
investigation of the alcohol additive revealed that it is necessary
for successful generation of carbonyl anions with acylsilanes
and thiazolium salts and also plays the role of the final silyl
group acceptor. Continued investigation into the full potential
of this NHC/acylsilane combination is ongoing in our laboratory,
and the development of related NHC-catalyzed Umpolung
reactions is currently underway.
Experimental Section
To probe this possibility, thiazolium carbinol II was employed
in two separate reactions, with chalcone (2a) and N-phosphi-
noylimine 50a using previously established reaction conditions
(Scheme 10, eqs 14 and 15). In both cases, the desired product
was obserVed in good yield lending support to the hypothesis
that II is an intermediate in these addition reactions. Interest-
ingly, the reactions readily occurred in the absence of heat. In
a second set of experiments, the thiazolium carbinol was added
to the reaction in place of the NHC precursor (Scheme 11, eqs
16 and 17). Gratifyingly, both reactions generated the desired
General Procedure for Thiazolium-Catalyzed Acylsilane
Additions to R,â-Unsaturated Systems. A screw-capped test tube
was charged with the thiazolium salt (30 mg, 0.119 mmol) and
placed under a positive pressure of nitrogen. Benzoyltrimethylsilane
(140 mg, 0.768 mmol) in THF (0.25 mL) was added by syringe to
the test tube followed by the addition of DBU (17 µL, 0.119 mmol).
The reaction mixture was heated to 70 °C after which the chalcone
(0.384 mmol) in THF (0.25 mL) was added by syringe followed
by the addition of 2-propanol (120 µL, 1.56 mmol). The reaction
was allowed to stir at 70 °C for 24 h. Upon completion by TLC
J. Org. Chem, Vol. 71, No. 15, 2006 5723

Mattson et al.
(40% ether/hexanes), the reaction was cooled to room temperature,
diluted with ethyl acetate (20 mL), and washed with water (20 mL).
The aqueous layer was washed with ethyl acetate (3 × 30 mL),
and the combined organic extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. The resulting residue was
purified by flash column chromatography on silica gel.
completion as determined by TLC (40% ether/hexanes). To the
solution was added amine (0.825 mmol, 3.0 equiv) followed by
addition of p-toluenesulfonic acid (104 mg, 0.55 mmol, 2.0 equiv)
in ethanol (0.5 mL) and 4 Å molecular sieves (spatula tip). The
reaction mixture remained heating at 70 °C for an additional 6 to
12 h or until consumption of diketone as determined by TLC (25%
ethyl acetate/hexane). Upon cooling to room temperature, the
reaction mixture was diluted with ethyl acetate (30 mL) and washed
with water (10 mL). The aqueous layer was washed with ethyl
acetate (3 × 30 mL), and the combined organic extracts were
washed with brine (10 mL) and dried over sodium sulfate, filtered,
and concentrated in vacuo. The resulting residue was purified by
flash column chromatography on silica gel.
General Procedure for Thiazolium-Catalyzed Acylsilane
Additions to N-Phosphinoylimines. A screw-capped tube was
charged with the thiazolium salt (20 mg, 0.08 mmol) and placed
under a positive pressure of nitrogen. Benzoyltrimethylsilane (84
mg, 0.47 mmol) in CHCl3 (0.25 mL) was added by syringe followed
by the addition of DBU (12 µL, 0.08 mmol). The reaction mixture
was heated to 60 °C after which the phosphoryl imine (0.26 mmol)
in CHCl3 (0.25 mL) was added by syringe followed by the addition
of 2-propanol (80 µL, 1.05 mmol). The reaction was allowed to
stir at 60 °C. Upon completion by HPLC, the reaction was cooled
to room temperature, diluted with methylene chloride (20 mL), and
washed with water (20 mL). The aqueous layer was washed with
methylene chloride (3 × 30 mL), and the combined organic extracts
were dried over sodium sulfate, filtered, and concentrated in vacuo.
The resulting residue was purified by flash column chromatography
on silica gel.
General Procedure for Thiazolium-Catalyzed Pyrrole Syn-
thesis. A screw-capped test tube was charged with the thiazolium
salt (14 mg, 0.055 mmol, 0.20 equiv) and placed under a positive
pressure of nitrogen. Benzoyltrimethylsilane (100 mg, 0.55 mmol,
2.0 equiv) in THF (0.25 mL) was added by syringe to the test tube
followed by the addition of DBU (13 µL, 0.083 mmol, 0.30 equiv).
The reaction mixture was heated to 70 °C after which the chalcone
(0.275 mmol, 1.0 equiv) in THF (0.25 mL) was added by syringe
followed by the addition of 2-propanol (83 µL, 1.10 mmol, 4.0
equiv). The reaction was allowed to stir at 70 °C for 12 h or until
Acknowledgment. Financial support for this work has been
partially provided by Northwestern University and the NSF
(CHE-0348979). K.A.S. gratefully acknowledges Amgen, Ab-
bott Laboratories (New Faculty Award), 3M (Nontenured
Faculty Award), and Boehringer-Ingelheim (New Investigator
Award in Organic Chemistry) for generous research support.
A.E.M. thanks the Division of Organic Chemistry for a graduate
fellowship sponsored by Eli Lilly. A.M.Z. was a Pfizer Summer
Undergraduate Research Fellow. We thank FMCLithium,
Wacker Chemical Company, Sigma-Aldrich, and BASF for
providing reagents used in this research.
Supporting Information Available: Detailed experimental
procedures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060699C
5724 J. Org. Chem., Vol. 71, No. 15, 2006