Understanding the reactivity of acyl anion equivalents: The epoxide ring opening case

Article abstract of DOI:10.1002/ejoc.201001680

Acyl anion equivalents (umpolung) are the practitioner's first choice en route to 1,3-hydroxy keto compounds from epoxides. Why? This investigation evaluates computationally and experimentally the reactivity of a near comprehensive range of acyl anion equ

Full text of DOI:10.1002/ejoc.201001680

FULL PAPER
DOI: 10.1002/ejoc.201001680
Understanding the Reactivity of Acyl Anion Equivalents: The Epoxide Ring
Opening Case
Wilhelm A. Eger,[a] Rebecca L. Grange,[a] Heiko Schill,[a] Régis Goumont,[b]
Timothy Clark,[c] and Craig M. Williams*[a]
Keywords: Umpolung / Epoxides / Acyl anion equivalent / Carbonyl equivalent
Acyl anion equivalents (umpolung) are the practitioner’s first
choice en route to 1,3-hydroxy keto compounds from epox-
ides. Why? This investigation evaluates computationally and
experimentally the reactivity of a near comprehensive range
of acyl anion equivalents using epoxide ring opening as a
test vehicle. Reactivity understanding, reactivity order, sur-
prise failures in performance, along with unprecedented, but
far from superior, reactivity of TosMIC is presented for the
first time.
Introduction
Since the umpolung[1] technique (acyl anion equivalent,
AAE) was first suggested by Corey[2] and Seebach,[3] AAEs
1,[4] especially dithiane 4a and 2-substituted derivatives (i.e.
4b),[5] have become valuable tools for the functionalization
and incorporation of ketone and formyl functionalities
(Scheme 1). Sulfur-containing AAEs (e.g. 4–10)[6–12] are
uniquely effective in forming carbon–carbon bonds by ring
opening of epoxides 2 to give the important latent 1,3-hy-
droxy keto substitution pattern seen in 3 and 12 (Scheme 1
and Scheme 2). The most significant subsequent develop-
ments in this area have been the use of dithianes (i.e. 4)
with concomitant Brook Rearrangement by Smith,[13] the
development of the Tietze[14a]–Smith[13,15] linchpin reaction
(derived in part from the work of Schaumann[14b]), and in-
troduction of the Smith anion-relay chemistry.[16]
Scheme 1. Sulfur containing AAEs 4–10 that ring open epoxides 1
intermolecularly providing the important latent 1,3-hydroxy keto
substitution pattern 3.
However, subsequent coupling of the substituted dithi-
ane 11 (Scheme 2) with an epoxide, aldehyde or alkyl halide
can be problematic, as first reported by Corey and Seebach,
and later by others (Scheme 2).[2c,2i,17] Two complications
Scheme 2. Undesired S-alkylation (i.e. sulfonium salt 13 formation)
should the deprotonation pathway fail.
can arise: deprotonation of the dithiane 11 can fail, as in- nylated dithianes,[20] partially oxidized dithioketals (i.e. 9
vestigated by Nakata[18] and Lipshutz,[19] and alkylation of and 10),[21] or a Brook rearrangement,[13a,15] but S-alky-
a sulfur atom by the electrophile can occur, affording sulfo- lation can be unavoidable if anion formation is unsuccess-
nium salts 13, as observed by Corey and Seebach.[2c,2i] ful. Our group has previously experienced this problematic
Remedies for the former problem include the use of distan- issue first hand.[22]
With a desire to gain a general understanding of AAE
[a] School of Chemistry and Molecular Biosciences, University of reactivity and overcome, or avoid, S-alkylation we searched
Queensland
the literature, which to our surprise unveiled a substantial
Brisbane, 4072, Queensland, Australia
paucity of work in this area. For example, there were no
comparative reactivity studies of known AAEs and no clear
understanding or description as to why sulfur was a com-
mon functional group element. Thus we embarked on a
near comprehensive investigation of non-sulfur, and sulfur
containing AAE functional group types so as to better
understand AAE reactivity using the process of epoxide
E-mail: c.williams3@uq.edu.au
[b] Institut Lavoisier-Franklin, Université de Versailles
45 avenue des Etats Unis, 78035 Versailles cedex, France
[c] Computer-Chemie-Centrum and Interdisciplinary Center for
Molecular Materials, Friedrich-Alexander-Universität Er-
langen-Nürnberg
Nägelsbachstrasse 25, 91052, Erlangen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001680.
2548
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Understanding the Reactivity of Acyl Anion Equivalents
ring opening as a test vehicle. Results of which are reported To this end, exhaustive attempts to find a reactivity trend
herein.
based on calculations regarding the reaction mechanism
using Density-Functional Theory (DFT) at the M05-
2X[38,39]//6-311+G(2d,2p)[40] level failed. However, the NBO
(Natural Bond Order) approach[41,42] at the same level of
theory proved vital for this type of analysis in connection
with the calculation of proton affinities (Table 1). The com-
putational data listed in Table 1 indicate that the reactivity
of acyl anions should be in an increasing order starting
from entry 1 through to 8. The initial surprise, however,
was that the calculated proton affinities, which represent
anion stability and are related to pKa, do not correlate with
the net atomic charge on carbon. The experimental values
of acidity (pKaDMSO) (Table 1) reinforce this finding, for ex-
Results and Discussion
Before computational or experimental analysis could be
performed, an extensive survey of the literature for AAEs,
beyond 4–10 listed above (Scheme 1), was undertaken. In
addition, carbanions known to open epoxides were consid-
ered for their potential to become new AAEs by suitable
substitution to the desired oxidation state.
Surprisingly, only two non-sulfur containing acyl anion
equivalents (14[23] and 15[24]) and only one non-nucleophilic
sulfur containing AAE (16[25]) have been reported to open
epoxides (Figure 1). Unfortunately, AAEs 15 and 16 are not
general because of their preexisting substitution. However,
methylene counterparts 17 and 18[26] as well as 19[27] (and
20[28]) were identified as substitutes for 15 and 16, respec-
tively. Considering that the TMS-acetonitrile anion opens
epoxides[29] readily, derivative 21[30] was selected, as were
compounds 22 and 23[31] based on the work of
Schöllkopf[32] that anions of methyl isonitriles routinely ring
open epoxides. Methylenebis(benzotriazole) 24[33] and the
oxazolin-5-one 25[34] were also selected. Nitromethane 26
maintains AAE status,[35] but an early report,[36] later con-
firmed by others,[37] suggested that reactions with epoxides
fail, so that 26 was not investigated. Lastly, TosMIC 29,
which has no reported activity with epoxides, was included
in the study because of its long history as an AAE.
ample, both entries 5 and 6 (Table 1) are known to react
DMSO
with epoxides, but differ by nearly 20 pKa
units.
Three principal interactions stabilize anions: inductive ef-
fects produced by the neighboring heteroatoms, π-delocal-
ization and negative hyperconjugation (donation from the
nC lone pair into a neighboring σ*XY orbital, where X is
a neighboring heteroatom and Y an atom bonded to it).
Substituent stabilization of carbanions has long been a
topic of interest for computational work. Note that the
question as to whether carbanions can be stabilized by πpǞd
interactions only arises within the LCAO approximation
and is therefore unimportant.[43] Calculations for sulfur-,[44]
phosphorus-[45] and silicon-substituted anions[46] have
shown that including d-orbitals in the basis set is very im-
portant, as they help describe the higher polarizability of
second-row elements. Therefore, both polarization effects
and negative hyperconjugation stabilize the charge in acyl
anions bearing second-row substituents and are more im-
portant than the inductive effects that dominate for more
electronegative first-row substituents.
Even though there is evidence of the existence of negative
hyperconjugation,[50] most of the stabilization effect can be
attributed to polarization of the heteroatoms in the case of
sulfur.[51] On the other hand, first row atoms are far less
polarizable, so that oxygen and nitrogen can only stabilize
anions weakly inductively and by π-conjugation to delo-
calize the negative charge. As a result, the pKa values of N-
and O-substituted substrates are very high, but even if they
could be deprotonated, their negative charge would be more
delocalized and they therefore probably would not be able
to perform nucleophilic attack effectively.
Coordination of the heteroatoms (e.g. tosyl) can lead to
enhanced negative hyperconjugation. This led to the misun-
derstanding that negative hyperconjugation might be the
cause for higher acidity.[50b] However, not only the anion,
but also the acyl compound have underlying hyperconjuga-
tional effects that cancel and therefore do not enhance acid-
Figure 1. Acyl anion equivalents 14–29.
Computational Results
The reaction consists of two components; deprotonation ity.[52] The increase in acidity with higher oxidation of the
of the acyl anion and nucleophilic attack of the anion on sulfur atom is a resonance effect and thus decreases the nu-
the epoxide. The first depends on the pKa of the AAE and cleophilicity of the anion by reducing the negative charge
the second largely on the degree of localization of the nega- of the reacting carbon atom. This becomes clear in the case
tive charge on the anionic carbon atom. The ideal AAE of TosMIC 29 (Table 1, Entry 4).
would therefore feature strong stabilization of the anion
With this in mind, the reactivity of acyl anions from a
that does not involve delocalization of its negative charge. theoretical view point therefore not only depends on the
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C. M. Williams et al.
FULL PAPER
Table 1. Natural (NBO) charges (QC) at the carbon atom of either the naked ions or the lithium salts in THF (C-PCM), including proton
affinities [P(A), kcalmol–1].
DMSO
[a] Prior to this investigation a pKa
for TosMIC 29 had not been determined. Our own studies show that due to a lack of stability
in basic media, an accurate pKaDMSO for TosMIC 29 cannot be determined. An approximate range, however, can be obtained from NMR
studies of the ionization of TosMIC using various bases carried out in [D6]DMSO (See Supporting Information). [b] Entry 8 was chosen
because Schaumann reported[49] that it ring opens epoxides, however, the final product is a cyclopropane and not an addition product of
type 3.
pKa, but also on the effects that stabilize the corresponding albeit optimized yield of 32%, possibly from the in situ gen-
anion. Hence, charge-stabilizing effects that do not delo- erated imidazole 30 known to be formed by base-promoted
calize the charge at the carbon atom, such as inductive or dimerisation of TosMIC 29 (Scheme 3).[53] Considering that
polarization effects, enhance the reactivity, whilst delocal- many of the AAEs 14, 17–25 when reacted as the corre-
ization effects such as resonance or negative hyperconjuga- sponding anions with 1,2-epoxypentadecane failed, all the
tion decrease it. Consequently, a general rule can be pro- reactions were repeated in the presence of a compatible
posed: second-row substituents are superior to first row Lewis acid (BF3·Et2O, 1 equiv.). Amazingly all the results
substituents, as resonance effects are not important, remained the same except for that of TosMIC 29, which
whereas polarization effects are. As resonance effects de- afforded the desired ring-opened material 31 in 33% yield
crease the reactivity, any substituent that enhances reso- (51% based on recovered starting material). To the best of
nance decreases acyl anion reactivity [e.g. –S–MeϾ–S(O)2- our knowledge, this is the first example of TosMIC 29
Me], but does not necessarily prevent reaction with epox- opening an epoxide, which is surprising given its status as
ides. With this general rule in mind and considering the one of the classical AAEs.[54]
computational data shown in Table 1, we embarked upon
testing the general rule in the laboratory.
Experimental Results
For this investigation, enantiopure 1,2-epoxypentade-
canes, obtained from the addition of dodecylmagnesium
bromide to enantiopure epichlorohydrins, were chosen as a
convenient non-activated and non-volatile test vehicle. Pre-
vious work[22] had demonstrated that these epoxides un-
dergo smooth ring opening when reacted with either the
anion of dithiane 4a or the TMS-dithane 4b and as such
acted as a benchmark to dithiane reactivity.
To our astonishment, ten (14, 17, 18, 19, 20, 21, 22, 23,
24, and 25) of the eleven AAEs investigated were found not
to undergo reaction with 1,2-epoxypentadecane, even those
reported to ring-open epoxides i.e. 14[23] failed. In contrast,
TosMIC 29 gave the hydroxyalkenyl-imidazole 32 in poor SO2-C6H4-4-Me).
Scheme 3. Reaction of TosMIC 29 with pentadecene oxide (Ts =
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Understanding the Reactivity of Acyl Anion Equivalents
With this development NBO calculations on all AAEs, ensuing second substitution with propyl iodide[56] pro-
in the presence of boron trifluoride, were performed for ceeded in moderate to excellent yields (Scheme 4; Table 2).
comparison (Table 1). Pleasingly, the results show the same Unmasking the keto group from a disubstituted TosMIC
order of reactivity but not surprisingly enhanced reactivity derivative of type 39 has been reported and will not be repli-
(Table 1).
cated here.[55–57] Furthermore, although the anion of pro-
Unfortunately, the yield of 31 could not be improved pyl-substituted TosMIC is reported to undergo substitution
with increased equivalents of TosMIC 29, alternative ratios reactions with alkyl halides,[58] we found that in the case of
of BF3·Et2O, different Lewis acids (TiCl4, Et2AlCl, Et- epoxide ring opening, utilizing our optimized conditions,
AlCl2), higher temperatures, or longer reaction times. Fur- no reaction occurred.
ther attempts to improve the yield and effect simultaneous
silyl protection by a Brook rearrangement concentrated on
using the TMS- (or TBS-) TosMIC (i.e. 27 and 28) anions
(Scheme 3),[55] but manipulation of these AAEs was fraught
with difficulty. Protection of 31 as the TBS ether 33, how-
ever, proceeded in good yield (73%) and subsequent cou-
pling to 1-iodopropane[56] also occurred affording 34 in
high yield (83%, Scheme 3).
Scheme 4. Addition reaction of TosMIC and further reaction pos-
sibilities. See also Table 2.
Reaction of the TosMIC 29 anion with other epoxides in
the presence of BF3·Et2O afforded the corresponding ad-
Comparing the experimental results to the computionally
ducts of type 37 in 15–52% isolated yield (up to 59% based
predicted acyl anion reactivity (Table 1) it is clear that at
on recovered starting epoxide Table 2). The reaction, how-
least one sulfur atom is an absolute functional group
ever, seems to be limited to aliphatic epoxides, as 2-phenyl-
requirement for AAEs that are used for epoxide ring open-
oxirane (Entry 5, Table 2) failed to react, giving rise only to
ing. Sulfur oxidation state is of key importance. Increasing
decomposition products. Whereas a 1,2-disubtituted epox-
the oxidation state lowers reactivity and decreases overall
performance, for example, comparing dithiane 4a with
TosMIC 29.
It should be noted that this work has not considered
“two stage” masked AAEs as alternatives (i.e. oxidative de-
carboxylation,[59] oxidative desulfonation,[60] and nickel-cat-
ide only gave a low yield (Entry 6, Table 2), cyclic disubsti-
tuted epoxides are good substrates (Entries 7 and 8,
Table 2) although cyclooctene oxide (Entry 9, Table 2) sur-
prisingly failed to react at all. The TBS protection and the
alyzed cyclization[61]) nor the non-Umpolung class (i.e. di-
Table 2. Yield of the reactions with several epoxides corresponding
to Scheme 4.
thioesters[62]), metathesis class (i.e. cyclopropenone ace-
tals[63]) or α-metalated α-heteroatom substituted olefins[64]
as these are not strictly applicable to the current investiga-
tion.[65]
Conclusions
After an extensive computational and experimental sur-
vey of known AAEs, dithioketals, especially dithiane 4a and
its silyl derivatives 4b, still remain the most versatile. Al-
though it may be argued that this was already known prior
to this study it had not been proven. The current study pre-
dicted and verified the general rule, “Second row substitu-
ents are superior to first row substituents, as resonance ef-
fects decrease anion reactivity, but polarization effects help
stabilize the anions. As resonance effects decrease the reac-
tivity, any substituent that enhances resonance decreases
acyl anion reactivity [e.g.–S–MeϾ–S(O)2Me]” and subse-
quent performance. TosMIC 29, although the least reactive
sulfur-containing acyl anion equivalent toward epoxide ring
opening offers some relief to situations where dithianes fail
i.e. to avoid sulfonium salt 13 formation, but is not superior.
Finally, AAEs offer the synthetic chemist much value in
the design process of creative target-oriented synthesis. Di-
thianes have led the way, in this regard, but development of
further tools for this toolbox would be welcomed.
1
[a] Based on recovered starting material. [b] Yield estimated by H
NMR since product was contaminated by TosMIC 29. [c] Method
A: nBuLi, HMPA, nPrI. [d] Decomposition. [e] Method B: NaH,
nPrI. [f] No reaction.
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C. M. Williams et al.
FULL PAPER
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Received: December 14, 2010
Published Online: March 17, 2011
Eur. J. Org. Chem. 2011, 2548–2553
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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