Dual nucleophilic/electrophilic capture of in situ generated iminium ethers: Towards the synthesis of functionalized amide building blocks

Article abstract of DOI:10.1002/chem.201203293

Rearranging its feathers: The transformation of simple linear amides into a diverse range of branched, functionalized products by conversion to iminium esters is followed by sequential treatment with nucleophiles and electrophiles (see scheme). The method takes advantage of a novel Claisen rearrangement and the use of aromatic substrates greatly facilitates the formation of the intermediate iminium ether.

Full text of DOI:10.1002/chem.201203293

DOI: 10.1002/chem.201203293
Dual Nucleophilic/Electrophilic Capture of In Situ Generated Iminium
Ethers: Towards the Synthesis of Functionalized Amide Building Blocks
Bo Peng, Daniel H. OꢀDonovan, Igor D. Jurberg, and Nuno Maulide*[a]
Iminium ethers (or oxazacarbenium ions) are desirable re-
active intermediates due to their ambident electrophilicity
and ability to react with a wide range of nucleophiles.[1]
These species are ideally suited to applications that require
the rapid generation of structural diversity because a single
iminium ether can potentially give rise to a large variety of
different products. Iminium ethers have also been used for
the preparation of natural products and bioactive mole-
cules.[2] However, their synthetic utility has been limited by
the relatively small range of useful methods for their gener-
ation. Common procedures rely on the inter- or intramolec-
Scheme 1. Traditional strategies for the preparation of iminium ethers.
ular O-alkylation of amides by using strong electrophiles
(Scheme 1a),[3] the N-alkyla-
tion of oxazolines (Sche-
me 1b),[4] and more recently,
Aubꢀꢁs procedure for prepar-
ing iminium ethers through the
Schmidt reaction of ketones
with 2-azidoethanol (Sche-
me 1c).[5] Many of these meth-
ods are limited to a narrow
range of substrates and there-
fore new and more flexible ap-
proaches for the generation of
Scheme 2. Formation of the iminium ether 2a by the Claisen rearrangement of amide 1a.
iminium ethers remain highly
desirable.
Our group has recently described the domino Claisen re-
arrangement of w-allyloxy, -propargyloxy and -benzyloxy
amides through the corresponding keteniminium salts for
the synthesis of a-substituted lactones in the presence of
triflic anhydride (Tf2O) and 2,4,6-collidine.[6] During recent
investigations, we were surprised to observe that iminium
ether 2a could be isolated from this reaction in pure form
confirm the structure of iminium ether 2a by X-ray crystal-
lography.
Encouraged by the isolation of 2a, we sought to develop
this reaction as a novel method for the generation of a-allyl
iminium ethers and to exploit their unique reactivity to facil-
itate the conversion of linear amides such as 1a into
branched, highly functionalized products in a single opera-
tion (Scheme 3).
by omitting the final hydroACTHNURTGNEUlGN ysis step (Scheme 2). Mechanisti-
cally, the formation of 2a can be explained by an intramo-
lecular cyclization onto the transient keteniminium salt fol-
lowed by a [3,3] Claisen rearrangement. After purification
and counter-ion exchange we were able to unambiguously
In line with the ambident electrophilicity of iminium
ethers, we envisaged that “hard” (non-stabilized) nucleo-
[a] Dr. B. Peng, Dr. D. H. OꢁDonovan,+ Dr. I. D. Jurberg,+
Dr. N. Maulide
Max-Planck-Institut fꢂr Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mꢂlheim an der Ruhr (Germany)
Fax : (+49)2083062999
E-mail: maulide@mpi-muelheim.mpg.de
[+] These authors contributed equally to this work.
Scheme 3. The generation and reaction of iminium ethers to afford a-al-
lylated products.
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Chem. Eur. J. 2012, 18, 16292 – 16296

COMMUNICATION
philes would react with the central sp2 oxazacarbenium
atom C1 under ionic control (Nu1, Scheme 3 a), whereas
“softer” or more hindered nucleophiles might react at C4,
Table 1. Iminium ether generation and subsequent nucleophilic capture
to form amides 3–10.
À
accompanied by ring opening and cleavage of the O C4
bond (Nu2, Scheme 3 b). Herein, we report the development
of a one-pot procedure for the generation of iminium ethers
via the Claisen rearrangement of amides and their subse-
quent reaction with a diverse range of nucleophiles.
Amides 1a, 1b, and 1c were subjected to the Claisen rear-
rangement by using conditions previously reported by our
group.[6] In a one-pot procedure, the crude iminium ether
was then reacted in situ with the appropriate nucleophilic
reagent (Table 1).
This sequence could be used for the preparation of a
broad range of products, including a-allyl lactones 3, b-
allyl-a,w-amino alcohols 4, and a-allyl amide derivatives 5–
10. Both classes of nucleophiles (Nu1 and Nu2, Scheme 3) re-
acted with linear amides 1a and 1b, whereas the branched
substrate 1c could only be successfully united with the first
class of nucleophiles (Nu1, H2O, and NaBH4), presumably
due to the added steric hindrance at C4.
Entry Nu (conditions)
Product, yield [%] (d.r.)
3a, 90[a]
3b, 57[a]
H2O (aq. NaHCO3, RT,
3c, 71 (5:1)[a]
1
2
16 h)
4a, 72[b]
4b, 41[b]
4c, 73
(>9:1)[b]
NaBH4 (MeOH, RT, 16 h)
5a, 62[c]
5b, 82[d]
The reduction product 4c was generated with a diastereo-
ACHTUNGTRENNUNGisomeric ratio (d.r.) of >9:1, whereas the corresponding lac-
tone 3c was formed with a slighlty lower d.r. of 5:1. It is
likely that the mildly basic hydrolytic conditions used to pre-
pare 3c facilitate epimerization of the intermediate iminium
ether.
Notably, different reactions required some modification of
conditions, with solvent effects proving to be particularly im-
portant. Acetonitrile was usually superior for reactions the
involving six-membered iminium ether 2b, which we ascribe
to the improved rate of nucleophilic substitution (versus
degradation) of intermediate 2b in a polar aprotic solvent.
Similarly, the yields of reactions involving the five-mem-
bered iminium ether 2a were usually higher than those in-
volving 2b. This is likely due to the fact that the latter six-
membered species proved less stable than its homologue
under most conditions.
3
4
5
NaCN (1208C, mW, 5 min)
PPh3 (1208C, mW, 1 h)
6a, 58[e]
6b, 40[d]
7a, 72[c]
7b, 85[d]
NaSPh (1208C, mW, 5 min)
8a, 56[c]
8b, 42[d]
6
7
NaN3 (RT, 24 h)
By an appropriate choice of nucleophile, this sequence
À
À
can be used to generate new C S (using NaSPh), C N
À
(NaN3, aliphatic amines) and even C C bonds (NaCN).
NaN3 proved to be a particularly effective nucleophile; its
reactions proceeded at room temperature whereas all other
nucleophiles targeting the C4 position (Nu2, Scheme 3) re-
quired microwave irradiation. We observed that increasing
the amount of NaN3 employed from 1.1 to 2.0 equivalents
generally led to the formation of deallylated products, possi-
bly via SN2’ nucleophilic attack by the azide anion on the
allyl chain of the iminium ether. Reactions involving triphe-
nylphosphine (Table 1, entry 4) are also noteworthy, as this
nucleophile has not been previously reported to react with
iminium ethers. The products if these reactions are particu-
larly interesting as they provide structurally elaborate pre-
cursors ripe for subsequent Wittig reactions.
9a, 73[e]
9b, 47[d]
10a, 47[e]
10b, 46[d]
(1208C, mW, 5 min)
8
(1208C, mW, 5 min)
[a] i) CH2Cl2, ii) biphasic mixture of CH2Cl2/aq. NaHCO3 (1:1).
[b] i) CH2Cl2, ii) MeOH. [c] i) CH2Cl2, ii) DMF. [d] i) and ii) MeCN. [e] i)
and ii) CH2Cl2.
We then proceeded to examine the reaction of diastereo-
meric iminium ether 2d with the same series of nucleophiles
(Scheme 4). Our previous studies[6] showed that lactone 3d
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N. Maulide et al.
The O-benzyl analogue 1 f
was found to react under simi-
larly mild conditions. However,
the major product of this trans-
formation was not the expect-
ed iminium ether 2 f or its rear-
omatized congener;[7e] instead,
the isomeric compound 11 was
generated in 65% yield
(Scheme 5).
Although
11
proved inert to hydrolysis and
did not afford the expected
lactone product, it was possible
to confirm its structural assign-
ment by X-ray crystallography.
Scheme 4. Reactions of the diastereo-enriched iminium ether 2d.
The formation of 11 can be
explained by initial generation
was generated with a diastereomeric ratio of 9:1 following
hydrolysis of 2d with bicarbonate solution. Although switch-
ing to nucleophiles other than water generally provided a
lower degree of diastereomeric enrichment, the d.r. re-
mained relatively high in the case of poorly basic nucleo-
philes such as triphenylphosphine (5:1) and sodium borohy-
dride (7:1). However, nucleophiles necessitating longer reac-
tion times or more basic nucleophiles such as piperidine
generally led to reduction of the d.r., likely due to epimeri-
zation of the intermediate iminium ether.
of iminium ether 2 f through the expected benzyl-Claisen re-
arrangement, followed by a Cope-type sigmatropic rear-
rangement.[8] Remarkably, this reaction sacrifices aromatici-
ty in one of the two phenyl rings, while simultaneously gen-
erating a sterically-crowded quaternary carbon center, and
proceeds under mild conditions at room temperature.
We also envisaged that iminium ethers generated by the
Claisen rearrangement might behave as competent pro-nu-
cleophiles through deprotonation at C2, thereby generating
an N,O-ketene aminal.[9] After some experimentation, we
found that it is possible to deprotonate the in situ formed
A further substrate class that we examined incorporates a
phenyl ring within the alkyl
tether, thereby restricting con-
formational freedom in the
substrate. Interestingly, the O-
allyl amide 1e was quantita-
tively converted to iminium
ether 2e after just five minutes
at
room
temperature
(Scheme 5); these conditions
are remarkably mild given that
the same transformation for
iminium ethers 2a–d generally
requires microwave irradiation
at 1208C in order to proceed.
The facility with which this re-
action takes place is likely a
result of reduced conforma-
tional flexibility, resulting in
significant pre-organization for
the cyclization/Claisen rear-
rangement events, perhaps
combined with the favorable
formation of a conjugated ke-
teniminium salt intermediate.
Nucleophilic capture of 2e was
also
possible
(Scheme 5),
giving rise to isochromanone
3e or the aromatic aminoalco-
hol 4e.
Scheme 5. Claisen–Cope rearrangement of 1 f to produce iminium ether 11. An ORTEP drawing of 11·OTf is
shown, ellipsoids are presented at the 50% probability level.
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Dual Nucleophilic/Electrophilic Capture of In Situ Generated Iminium Ethers
COMMUNICATION
for his valuable advice regarding the aromatic substrates discussed in
Scheme 5.
2a and combine it with benzyl bromide to afford the alkylat-
ed intermediate 2g, which, following hydrolysis, leads to the
corresponding lactone 3g (Scheme 6). This transformation
represents a sequential addition of both an electrophile
(BnBr) and a nucleophile (H2O) to the iminium ether 2a
that was generated initially. It was also possible to react the
putative, newly formed iminium ether 2g with nucleophiles
other than water, as evidenced by the preparation of nitrile
5g. Remarkably, product 5g is formed as a result of three
Keywords: amides · Claisen rearrangement · iminiums ·
keteniminium · rearrangement
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À
À
À
À
formation of a new C S, C N, C P, or C C bond in a single
operation. The investigation of conformationally restricted
substrates incorporating an aromatic ring (1e and 1 f) re-
vealed that this modification greatly facilitates the formation
of the iminium ether, even leading to intriguing products of
dearomatization. We have also demonstrated that the imini-
um ethers may be utilized in a deprotonation–alkylation se-
quence followed by reaction with nucleophiles, thereby car-
rying out three complexity-generating reactions in a single,
one-pot operation. The ability to use amide electrophilic ac-
tivation to generate reactive intermediates that are amena-
ble to complexity-increasing cascades of bond-forming
events is an exciting line of research, which is currently
being further pursued in our laboratories.
Acknowledgements
We are grateful to the Max-Planck-Society and the Max-Planck-Institut
fꢂr Kohlenforschung for generous support of our research programs. This
work was funded by the Ecole Polytechnique (Fellowship to I.D.J.) and
the Fonds der Chemischen Industrie (Sachkostenzuschuss to N.M.). We
further acknowledge the invaluable support of our NMR, HPLC, and
GC Departments and Dr. R. Goddard (MPI Mꢂlheim) for crystallo-
graphic analysis. The authors also acknowledge J.-W. Lee (MPI Mꢂlheim)
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1984, 84, 205–247; b) S. Blechert, Synthesis 1989, 71–82; c) L. A. Pa-
quette, Angew. Chem. 1990, 102, 642–660; Angew. Chem. Int. Ed.
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N. Maulide et al.
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Received: September 14, 2012
Published online: November 14, 2012
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Chem. Eur. J. 2012, 18, 16292 – 16296