Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles by a Gold-Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition

Article abstract of DOI:10.1002/adsc.201500905

Oxazoles are important motifs within bioactive and functional materials. Complex, fully substituted and functionalised 4-aminooxazoles are accessed by an efficient intermolecular reaction between an ynamide and an N-acylpyridinium N-aminide in the presence of a gold catalyst. The formal [3+2] dipolar cycloaddition employs a nucleophilic nitrenoid approach to access the 1,3-N,O-dipole character in a controllable fashion. The selectivity for a cycloaddition pathway provides a stark contrast against the indiscriminate reactivity of electrophilic acyl nitrenes. Protocols for the formation of acyl-functionalised aminides are reported from accessible precursors including carboxylic esters and acids. The function of these aminides in the oxazole-forming reaction has been explored and it is shown that substantial elaboration is accommodated despite proximity to the reactive centre. As a result functional oxazole-based motifs, such as chiral oxazoles with biologically pertinent substitution patterns, are readily accessible. The use of ynamide types that are unexplored or little used in gold catalysis has been evaluated. Unusual all-heteroatom substitution patterns around the oxazole are shown to be accessible using thio-ynamides. The study shows that a close stoichiometry of reactants is suitable alongside relatively low loadings of the bench-stable precatalysts in practically straightforward multi-mmol scale reactions. The efficiency and flexibility of this regioselective intermolecular preparation is demonstrated in the ready synthesis of oxazoles with substantial structural and functional group variation.

Full text of DOI:10.1002/adsc.201500905

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DOI: 10.1002/adsc.201500905
Very Important Publication
Efficient and Flexible Synthesis of Highly Functionalised
4-Aminooxazoles by a Gold-Catalysed Intermolecular Formal
[3+2]Dipolar Cycloaddition
Andrew D. Gillie,+a Raju Jannapu Reddy,+a and Paul W. Daviesa,*
a
School of Chemistry, University of Birmingham, Birmingham, B15 2TT, U.K.
Fax: (+44)-(0)121-414-4403; e-mail: p.w.davies@bham.ac.uk
+
Both authors contributed equally.
Received: September 28, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500905.
ꢀ2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
Abstract: Oxazoles are important motifs within bio- oxazole-based motifs, such as chiral oxazoles with
active and functional materials. Complex, fully sub- biologically pertinent substitution patterns, are readi-
stituted and functionalised 4-aminooxazoles are ac- ly accessible. The use of ynamide types that are un-
cessed by an efficient intermolecular reaction be- explored or little used in gold catalysis has been
tween an ynamide and an N-acylpyridinium N-ami- evaluated. Unusual all-heteroatom substitution pat-
nide in the presence of a gold catalyst. The formal terns around the oxazole are shown to be accessible
[3+2]dipolar cycloaddition employs a nucleophilic using thio-ynamides. The study shows that a close
nitrenoid approach to access the 1,3-N,O-dipole char- stoichiometry of reactants is suitable alongside rela-
acter in a controllable fashion. The selectivity for tively low loadings of the bench-stable precatalysts
a cycloaddition pathway provides a stark contrast in practically straightforward multi-mmol scale reac-
against the indiscriminate reactivity of electrophilic tions. The efficiency and flexibility of this regioselec-
acyl nitrenes. Protocols for the formation of acyl- tive intermolecular preparation is demonstrated in
functionalised aminides are reported from accessible the ready synthesis of oxazoles with substantial struc-
precursors including carboxylic esters and acids. The tural and functional group variation.
function of these aminides in the oxazole-forming re-
action has been explored and it is shown that sub-
stantial elaboration is accommodated despite prox- Keywords: cycloaddition; dipoles; gold; oxazoles;
imity to the reactive centre. As a result functional ynamides
Introduction
plications by simplifying the preparation of function-
alised oxazoles or by providing access to previously
Substituted 1,3-oxazoles are important components of untapped substitution patterns are therefore desira-
bioactive natural products,[1] pharmaceuticals,[2] agro- ble.
chemicals,[3] functional materials,[4] and catalysts.[5]
Assembling highly substituted oxazoles in a rapid,
Their function as synthetic intermediates underpins flexible and efficient manner that also accommodates
a variety of useful transformations in target driven substantial functional group variation remains a chal-
synthesis.[6] Substantial diversity is seen in the type of lenge.[8] Recent advances into more convergent inter-
substituents at the 2-, 4- and 5-positions across the molecular oxazole assembly include the reactions of
varied applications of oxazoles, with heteroatom-sub- nitriles with metal carbenes derived from a variety of
stituted motifs of particular relevance in tuning the precursors including diazo compounds,[9] iodonium
properties of oxazoles.[7] Methods that enable such ap- ylides[10] and alkynes in formal [2+2+1]approaches.[11]
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Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles
In this context, our group reported a mechanistically
distinct [3+2]dipolar cycloaddition for the formation
of azoles.[24] Trisubstituted 4-aminooxazoles are
formed by a gold-catalysed reaction between N-acyl-
pyridinium-N-aminides 1, functioning as a nucleophilic
1,3-N,O dipole equivalent, and ynamides
2
(Scheme 1).[24a,25,26,27]
The use of bench-stable aminides 1 as 1,3-N,O-di-
polar equivalents contrasts with their innate and well-
explored 1,3-C,N-dipolar character. Such reactivity
has been exploited across a variety of transformations
in order to elaborate the pyridinium ring through
Scheme 1. The gold-catalysed oxazole synthesis from yna-
mides and N-acylpyridinium-N-aminides.[24a]
metal-mediated
or
cycloaddition
processes
Related transformations employ aryloximes[12] or (Scheme 2).
amides,[13] with partners also including a-halocarbon-
Of particular relevance is the propensity of these
yls,[14] propargylic carboxylates[15] and propargylic al- aminides to undergo intermolecular [3+2]dipolar cy-
cohols,[16] as well as oxidative reactions with 1,3-dicar- cloadditions with electron-deficient alkynes[28] or ter-
bonyls or alkynes and amines.[17,18] 5-Amino- and 5- minal alkynes in the presence of silver salts and palla-
alkoxyoxazoles have been accessed by multicompo- dium[29] or copper[30] catalysts to yield pyrazolo[1,5-
nent reactions with isocyanides.[19]
a]pyridines, or pyrido[1,2-a]indazoles from benzyne
In stark contrast to their broad utility for heteroar- precursors.[31] Stereoselective [3+3]-couplings with vi-
omatics such as 1,2,3-triazoles,[20] the use of alkyne- nylogous rhodium carbenes,[32] or between cyclopro-
based [3+2]dipolar cycloadditions has gained little panes and (iso)quinolinium-N-aminides[33] are also
traction in 1,3-oxazole preparation. Only very limited known. Other transformations include stereoselective
success has been achieved on generating the acyl ni- reductions,[34] directed C H functionalisations,
in-
[35]
À
trenes required as the 1,3-N,O-dipoles in the presence tramolecular cyclisations with tethered enolates or
of an alkyne due to the indiscriminate reactivity of thiocyanates,[36] as well as photochemical elimination
these electrophilic species.[21,22] A recent advance of pyridine to form electrophilic acyl nitrenes, or ring-
allows the formation of 2,4-disubstituted oxazoles expansion to diazepines.[37] Ring-opening N,O-cyclo-
from terminal alkynes and acyl azides via a copper- addition to cyclopropenones/-imines was described
stabilised acyl nitrene.[23]
from three aminides (R1 =OMe, OEt, Ph).[38]
Scheme 2. A summary of transition metal-catalysed and/or cycloaddition reactions of N-acylpyridinium-N-aminides.
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Andrew D. Gillie et al.
The combination of gold-activated ynamides and
nucleophilic nitrenoids able to develop into 1,3-di-
poles has since proved to be fertile ground for the de-
velopment of regiocontrolled intermolecular azole
formation.[27] Effective methods have been reported
for the formation of diazine and pyridine-fused imida-
zoles from N-arylaminides,[24c] and pyrroles from iso-
xazoles,[44] azirenes or vinyl azides.[45]
In the initial communication of the oxazole forma-
tion we showed that N-sulfonyl- or cyclic N-carba-
mate-derived ynamides bearing a variety of hydrocar-
bon substituents including other p-systems could be
employed, while aminides with methoxy, ethyl, vinyl,
or p-rich or neutral aryl groups were appropriate
(Scheme 1).[24a] The ability to access fully substituted
oxazoles by the convergent coupling of two orthogo-
nal units of nominally similar complexity led us to
study this reaction further. Here we report our explo-
ration into the wider potential of this ynamide-based
assembly of densely functionalised 4-aminooxazoles
in an efficient, convergent and practically straightfor-
ward fashion.
Scheme 3. Mechanistic outline of gold-catalysed [3+2]dipo-
lar cycloaddition.[24]
Results and Discussion
The N-acylpyridinium-N-aminides
The function of these species as nucleophilic acyl
nitrene equivalents in the formation of oxazoles is ini- In order to access diversity at the 2-position of the ox-
tiated by a regioselective intermolecular attack onto azoles an expedient route into aminides is needed
a gold-activated ynamide A governed by the influence that accommodates substantial variation of the acyl
of the gold keteniminum resonance form A’ substituent on the N-acylpyridinium-N-aminide. Rela-
(Scheme 3).[24,25,39,40] Vinyl gold carbenoid B is formed tively little study has been undertaken into the prepa-
À
with the N C-4 bond of the oxazole skeleton.
ration and reactivity of species with significant func-
À
The O C-5 bond is proposed to result from a 4-p tional group variation at the N-acyl group as it gener-
electrocyclisation of an unusual bisheteroatom-con- ally acts as a protecting or directing group in other
taining aurated system. This step could be considered applications. Of the known disconnections (Scheme 4)
to proceed via stepwise elimination of the pyridine we focused on those preparative methods involving
nucleofuge, through an intermediate C when the reac- formation of the N-acyl bond (Path A),[24,34c–e,36,37,46]
[47]
À
tive centres are cis across the newly formed C=N rather than the N N bond (Path B) or the pyridini-
bond. The ready inclusion of alkyl groups at C-5 de- um ring (Path C),[34c–e] as they appeared to offer the
spite the relative ease of gold carbenes to undergo most potential for a streamlined route into these sys-
3
[41]
À
1,2-insertion into adjacent C(sp ) H bonds
indi- tems from readily and generally accessible carboxylic
cates a fast ring closure and led us to propose that acid-derived precursors.
cyclisation occurs with some synchronicity to elimina-
tion of the pyridine. For elimination to occur on for-
À
mation of B the N N bond must align with the vinyl
gold p-system. Reconfiguration about the nitrogen
centre brings the acyl group towards being in plane
À
with the aurated carbon centre. C O bond formation
can occur as positive charge develops around the ex-
tended p-system with release of the nucleofuge, which
is shown in an idealised form as D. Similar mechanis-
tic rationales were subsequently proposed in the syn-
thesis of furans from S-ylides and terminal alkynes by
formal gold-catalysed [3+2]dipolar cycloaddi-
tion.[42,43]
Scheme 4. Disconnections for the formation of aminides.
Path A: formation of the N-acyl bond; Path B: N N bond
formation; Path C: assembly of the pyridinium ring.
a
À
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Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles
Table 1. Synthesis of N-acylpyridinium-N-ylides.[a]
[a]
Reaction conditions: 4 (1.0 equiv.), 5 (1.1–2.0 equiv.), K2CO3 (2.0–2.4 equiv.) in MeOH (0.13M in 4) at room temperature
for 3 days. Isolated yields after purification by flash chromatography unless otherwise noted.
No further purification required after filtration.
Purified by filtration and then recrystallisation.
Carboxylic acid (1.0 equiv.) was treated with ClCO2Et (1.1 equiv.) and NEt3 (1.1 equiv.) in CH2Cl2 (0.1M in acid) for 1 h
[b]
[c]
[d]
before adding 4 (1.1 equiv.), K2CO3 (2.4 equiv.) and MeOH as co-solvent and stirring at room temperature for 24 h.
Conditions as in [a] except using dry MeCN as solvent under an argon atmosphere.
[e]
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Our initial study employed a protocol based on that
The functionalised N-acylpyridinium-N-ylides 6a–n
of Knaus using N-aminopyridinium iodide and acid were then evaluated in the gold-catalysed synthesis of
chlorides with aqueous NaOH.[24,34c–e] While this oxazoles using a standard ynamide 8a in the presence
worked well for a number of substrates, the use of of bench-stable dichlorogold(III)picolinate as precata-
acid chlorides is not ideal for overall process efficien- lyst[52] in toluene at 908C. The generality of the oxa-
cy, functional group compatibility, or practicality. In zole synthesis proved to be considerable: Despite
addition, some optimisation was found to be required their varied functionality all the aminides reacted to
on moving between different substrates to avoid er- give the corresponding oxazoles 9a–n in generally
ratic recovery of product between batches due to good to excellent yields (Table 2). Importantly, an in-
water solubility in certain cases (such as R=OMe tramolecular reaction between the nitrenoid centre
prepared from dimethyl dicarbonate).
and the appended functionality was not observed to
On evaluating a number of procedures, we found interfere with the effective intermolecular reaction, in
that adapting Streith[46a,b] and Kakehiꢁs[36] protocols af- contrast to the reactivity expected from electrophilic
forded a practically straightforward and expedient nitrenoids.
method. This could be generally applied for more
elaborate substrates bearing different acyl functional tained in excellent yield, even with a reduced ylide
groups from readily accessible electrophiles. and catalyst loading to that previously reported
While the 2-methoxyoxazole 9a was readily ob-
A variety of aminides 6 were prepared from elec- (entry 1),[24a] the 2-tert-butoxy analogue 9ba was un-
trophiles 5 including chloroformate (Table 1, entry 1), stable and was not isolated in pure form (entry 2).
di-tert-butyl dicarbonate (entry 2) and alkyl esters However the 2-tert-butoxyoxazole 9bb prepared from
(entries 3-10) by stirring them with commercially N-phenyl ynamide 8b could be isolated and fully char-
available aminopyridinium iodide 4[48] in methanol acterised, although it also degraded over time
with K2CO3 at room temperature. Other solvents (entry 3). Attempts to use 9b as a precursor to a 4-N-
were also effective, but methanol was generally supe- substituted oxazol-2-one via acid-catalysed elimina-
rior on grounds of solubilisation and its ready remov- tion of isobutene proved unsuccessful, affording com-
al on work-up. Work-ups are straightforward with plex mixtures in all cases.
evaporation, solvent exchange, and filtration to
Acid labile groups, such as N-Boc groups 9d, 9ka–e,
remove excess salts, followed by either flash chroma- 9la–e and acetal 9f were well tolerated in the catalysis
tography or recrystallisation. Products 6a, b, h were process.[53] 4,5-Disubstituted oxazoles can also be gen-
pure after the first filtration.
erated through this method using the N-formylpyridi-
A one-pot protocol was developed to streamline nium-N-aminide 6g (entry 9). p-Rich and p-deficient
the synthesis of aminides in cases where the free car- aromatics, where starting materials and products are
boxylic acid form is more readily accessible than the both potentially viable ligands to transition
ester. The acid is stirred with ethyl chloroformate in metals,[54,55,56] react smoothly affording 9h–j despite
the presence of triethylamine for an hour before addi- the presence of Lewis basic atoms (Table 2, en-
tion of 4, K2CO3 and methanol (entries 11–14). More tries 10–12).
sensitive electrophiles such as isocyanate or isothio-
The use of secondary aniline urea derivative 6n re-
cyanate can also be used by switching the solvent to sulted in the formation of the 2,4-diamino-substituted
dry acetonitrile to access the (thio)urea type ylides 6n oxazole 9n. In contrast, the related thiourea deriva-
and 7 in high yield (entries 15 and 16).[49]
tive 7 did not react.
All variations of the procedure were performed on
The reactions of (hydroxy)proline-based 6k/l and
upwards of 1 mmol and use an efficient stoichiometry other amino acid derivatives proceeded smoothly (en-
of reagents. In all cases the aminides were bench tries 13–24). Generally fast reactions (circa 1 h) were
stable and readily stored and handled at room tem- seen with these aminides across a variety of ynamides
perature.[50]
8a–d. The use of chiral amine-derived ynamide 8e
Ready inclusion of functionality at the acyl position was explored to access oxazoles 9ke/9le with stereoge-
of the aminide was possible under these protocols. In nicity at two of the oxazole substitution points. A
addition to alkoxy groups 6a/b,[51] secondary carba- good yield was obtained albeit with a considerably
mates and secondary unsaturated carboxylic amides slower reaction (15 h), presumably due to the greater
6c–e were well tolerated, as were an acetal 6f, steric bulk around the ynamide. Deprotection of the
a benzyl ether 6l, the formyl group 6g and heteroaro- N-Boc groups to afford the free pyrrolidine deriva-
matics 6g–j including basic nitrogens. The ester of tives was successfully achieved in both series from
a p-rich aromatic reacted slowly, however, in cases 9ka/9la in 98% and 91% yield, respectively (see the
where the inherent reactivity of the ester is too low, Supporting Information). As a result, this de novo ox-
the one-pot transformation from the free carboxylic azole synthesis provides entry into elaborated ver-
acid can be used effectively as seen with the thio- sions of structural types exploited in peptidomimet-
phene derivative 6j (entries 10 vs. 11).
ics[57] and found in bioactive natural products such as
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Table 2. Synthesis of substituted oxazoles from a range of functionalised N-acylpyridinium-N-aminides.[a]
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Andrew D. Gillie et al.
[a]
Reaction conditions: 6 (stated equiv.), 8a (1.0 equiv.) and dichlorogold(III)picolinate in toluene (0.1M in 8a) at 908C
under an argon atmosphere for 1–24 h (see the Supporting Information). Isolated yields after purification by flash chro-
matography. Ns=4-nitrobenzensulfonyl; Ms=methanesulfonyl.
9ba could not be isolated in sufficient purity due to apparent degradation.
9bb undergoes degradation to a complex mixture within 24 h.
[b]
[c]
[d]
51% isolated by direct recrystallisation of the reaction mixture with a further 26% recovered following column chroma-
tography of the filtrate.
[e]
A crystal structure of 9ka showed two crystallographically independent molecules arising from rotation about the oxa-
zole-4-sulfonamido bond (see the Supporting Information).
the peptide-derived oxazoles diazonamide A and agents, and optimum simplicity in terms of atom-
muscoride A,[58] while chiral pyrrolidines tethered to economy and work-up with evaporation of free pyri-
imine nitrogens are used successfully as bifunctional dine, the potential for improving these processes by
organocatalysts.[59]
modifying the pyridine shows some promise. It is
With the gold-catalysed reaction accommodating
significant variety at the acyl group of the ylide, toler-
ance to modification at the pyridinium was also brief-
ly examined. While increasing the complexity and
mass of the pyridine nucleofuge is undesirable in
terms of substrate economy and ease of work-up,
such substitutions are commonly employed in related
gold-catalysed oxygen transfer reactions.[60,61] Substitu-
tion around the pyridine moiety potentially affects
the solubility and nucleophilicity of the aminide, the
cyclisation step through changing the leaving group
ability, and the concentration of active catalyst pres-
ent due to interaction with the released pyridine.
Several derivatives 10(I–VIII) were prepared in
order to test whether there was a substantial benefit
to be realised through modifying the pyridinium that
might outweigh the detriment to atom economy and
practicality. Modifications included non-sterically af-
fecting-activating groups, 3-halo-substitutions, sterical-
ly hindered and quinolinium systems.[46c]
Table 3. Screening of N-acylpyridinium-N-aminides with
modified pyridines.[a]
Entry
8
10
Time [h]
11
Yield of 11[b]
The relative efficacy of the ylides was probed using
a 1.1:1 stoichiometry of ylide to ynamide. All the
ylides except lutidine derivative 10(IV) reacted effec-
tively with ynamide 8a (Table 3, entries 1–8). Use of
the less reactive a-methylbenzylamine derived yna-
mide 8e saw greater differentiation between ylide effi-
cacies and no reaction went to completion within 5 h
(Table 3, entries 9–16). The para-methyl 10(II), meta-
chloro 10(VI) and isoquinolinium 10(VII) derivatives
gave similar conversions to the parent pyridinium
10(I), whereas para-methoxy 10(III) and quinolinium
10(VII) saw significantly lower conversions. The
meta-bromopyridine derivative 10(V) was the only
system to perform substantially better than 10(I), and
led to a good yield of the oxazole, albeit with some
unreacted starting material, when the reaction was
run for 24 hours. No reaction was seen using the even
more bulky ynamide 8f. Indeed, as far as we are
aware ynamides such as 8f have not been employed
in gold catalysis, whilst those related to 8e have only
been utilised in an intramolecular fashion.[62]
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8a
8a
8a
8a
8e
8e
8e
8e
8e
8e
8e
8e
8e
8f
8f
I
II
1
1
1
1
1
1
1
1
5
5
5
5
5
5
5
11a
11a
11a
11a
11a
11a
11a
11a
11e
11e
11e
11e
11e
11e
11e
11e
11e
11f
11f
88%
89%
82%
NR
III
IV
V
VI
VII
VIII
I
II
III
V
VI
VII
VIII
I
V
I
>95%
>95%
>95%
85%
45%
52%
23%
67%
51%
16%
46%
53%
75%
NR
9
10
11
13
14
15
16
17
18
19
20
24
24
24
24
V
NR
[a]
All reactions carried out using
(1.1 equiv.) and dichlorogold(III) picolinate (5 mol%) in
toluene (0.1M in 8) at 908C under an argon atmosphere.
Yields determined by H NMR using 1,2,4,5-tetramethyl-
8
(1.0 equiv.), 10
[b]
1
While the use of unsubstituted pyridine has clear
benefits in terms of preparation from commercial re-
benzene as internal standard.
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Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles
Scheme 5. Gram-scale reaction with reduced loading of ami-
nide and catalyst and no precautions against oxygen or
moisture.
worth noting that the nature of the acyl substituent
also affects the efficacy of the ylides as demonstrated
in the reactions of 8e with aminides 6k/l (Table 2),
such that the conjunction of pyridine and acyl modifi-
cation can be considered for process optimisation as
needed for specific targets.
The chemoselectivity demonstrated at the 2-posi-
tion was accompanied by excellent practicality. The
reactions of aminides 6a–n were run across a range of
scale, often using reduced catalyst loading of 1 or
2 mol%, and/or a decreased excess of aminide with
respect to ynamide, from 1.5 to 1.1 equivalents
(Table 2). The tolerance of this process was further
tested by running a reaction with no precautions
taken against atmosphere, using undried toluene di-
rectly from bulk supply in an open reaction flask, on
a 1.0 g (4.8 mmol) scale of ynamide 8a with only
1 mol% catalyst (18 mg) and only 1.1 equivalents of
ylide 10(I). While the reaction was slowed and was
further left for an extended period, the reaction still
proceeds with 59% of oxazole 11a isolated in addition
to 30% of recovered ynamide (Scheme 5).
Scheme 6. Exploration of varying the ynamide N-substitu-
ent. Isolated yields after flash chromatography.
The Ynamide
Having established substantial structural and func-
tional group variation in the aminides our attention
turned to the nature of the ynamides used in this pro-
cess. Cyclic carbamate- and sulfonamide-derived yna-
mides with N-alkyl, aryl, allyl, propargyl and benzyl
substituents were used in the initial study. (Hetero)-
Aryl, vinyl, alkynyl and alkyl substituents could all be
Scheme 7. Ynamides containing structural variation at the
C-terminus.
accommodated at the C-terminus of the ynamides tion pathway previously reported with N-tert-butyl
translating to varied substitution at the 5-position in carbamate ynamides.[63] The lactam derivative 13 re-
the oxazole (Scheme 1).[24a] With broad coverage of acted slowly affording only ketone 17, again likely
such types already established, we were interested in from an intramolecular cyclisation of the carbonyl
examining ynamide substitution patterns that were oxygen followed by hydration.[64]
either rarely explored or unknown in gold catalysis or
that might introduce competing pathways.
In contrast, phosphoramidate-derived ynamides 14,
recently introduced by Hsung and co-workers as at-
The stabilising unit on the nitrogen was first tested tractive alternatives to the N-sulfonyl patterns, proved
(Scheme 6). In contrast to cyclic carbamates, the acy- effective.[65] Oxazoles 18 were formed in high yield
clic methyl carbamate-derived 12 did not give any ox- even with more functionalised aminides 6k and 6l.
azole, instead yielding a small amount of oxazolone Despite such systems not having been previously em-
16 from an intramolecular cyclisation and fragmenta- ployed in gold catalysis, the reaction of N-alkynylin-
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Andrew D. Gillie et al.
dole 15 was effective, albeit slow, affording the 4-(N-
indolyl)oxazole 19.
Alternative substitution was investigated through
ynamides synthesised from 2,2-dichloroenamides 20
(Scheme 7).[66] Formation of the lithium acetylides
and trapping with suitable electrophiles provided
access to the ester 21a–d, ketone 21e, phosphonate
21f, secondary alcohol 21g and methyl 21h substitu-
tion patterns (Scheme 7). In addition, unusual thio-
ynamides 21i-m could be prepared in an analogous
fashion by trapping with either elemental sulfur fol-
lowed by methyl iodide, or the use of S-phenyl benze-
nesulfonothioate.[67] Terminal and silyl-substituted
ynamides 22–24 were also synthesised using known
methods.[24a,68]
The reactivity of these ynamides in the oxazole syn-
thesis was assessed using a low 1.1 equivalence of an
aminide (Scheme 8). Oxazoles 25a–e with a carboxylic
ester at the 5-position were successfully formed. The
3-bromopyridine-derived aminide 10(V) was again
used to afford a decent yield from the chiral ynamide
21d. However, the keto, phosphonate and secondary
alcohol derivatives 21e–g did not react cleanly and no
oxazoles were isolated. A 5-methyloxazole 25f was
also formed in a reasonable yield using the N-allyl
ynamide despite the potential for 1,2 insertion or aza-
Claisen initiated rearrangement.[69]
The use of thio-ynamides, previously unexplored in
gold catalysis, proved particularly successful with gen-
erally high yields obtained of the resulting 5-thio-oxa-
zoles 25g–o. A 5-sulfonyloxazole was also prepared
from 25h by oxidation with mCPBA (see the Support-
ing Information). Notably, in combination with suita-
ble aminides, this route can be used to readily access
oxazoles 25n and 25o with all-heteroatom substitution
patterns with 25o having a different heteroatom on
each position.
Terminal ynamide 22 reacted smoothly to give the
2,4-disubstitued oxazole 25r. Silylated ynamides 23
and 24 did not react to give 5-silyloxazoles. Disubsti-
tuted oxazole 25r was formed in 30% yield alongside
unreacted ynamide (26%) when trimethylsilyl-substi-
tuted 23 was reacted with 10(I), likely via desilylated
ynamide 22. Attempts to isolate pure 2-bromoyna-
mides from the bromination of terminal ynamides or
elimination of HBr from dibromoenamides were un-
successful due to their instability.[70] However, the im-
mediate use of a partially-purified product of HBr
elimination from 26 afforded 5-bromooxazole 27. De-
spite the modest yield over the two steps the use of
a crude mixture further highlights the tolerance of the
oxazole-forming catalysis.
Scheme 8. Exploration of the ynamide C-substituent.
The successful oxazole formation from ynamides choice of ylide proved critical as in the presence of
21a–d with an electronic ꢂpush-pullꢁ substitution pat- 6a, 21b reacts to give pyrazolo[1,5-a]pyridine 28 and
tern contrasts with the known reactions of N-acylpyri- no oxazole (Scheme 9).[31b]
dinium-N-aminides as 1,3-C,N dipoles in the presence
Control reactions showed that heating a mixture of
of dimethyl acetylenedicarboxylate.[28] However, the ynamide 21b with aminide 6a resulted in the forma-
234
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Adv. Synth. Catal. 2016, 358, 226 – 239

FULL PAPERS
Efficient and Flexible Synthesis of Highly Functionalised 4-Aminooxazoles
Conclusions
Practically straightforward protocols for the formation
of N-acylpyridinium-N-aminides are reported. Sub-
stantial variation at the acyl position can be achieved
from accessible precursors including carboxylic esters
and acids. In the presence of a gold-activated yna-
mide, an N-acylpyridinium-N-aminide functions as
a N-nucleophilic 1,3-N,O dipole/acyl nitrene equiva-
lent for a formal [3+2]dipolar cycloaddition to give 4-
aminooxazoles.
Elaboration at the acyl position does not interfere
in the effective function of these aminides in the oxa-
zole-forming process. The ready inclusion of function-
ality in proximity to the reactive centre highlights the
control and chemoselectivity offered by the nucloe-
philic nitrenoid approach in contrast to that associat-
ed with electrophilic nitrenes.
The reactants derived from an unsubstituted pyri-
dine show excellent performance across a wide
breadth of both aminide and ynamide variations, and
are considered the most convenient and effective gen-
eral starting point for this transformation. The effica-
cy of the dipolar cycloaddition can however be al-
tered by modifying the pyridine moiety which pro-
vides an avenue for further process optimisation as
dictated by specific target needs.
Ynamide variations such as thio-ynamides have
been explored for the first time in gold catalysis.
These prove to be effective systems for the oxazole-
forming process along with ꢂpush-pullꢁ ynamides as
well as N-phosphoramide ynamides and N-indole-de-
rived ynamines. This study highlights how richer sub-
stitution patterns might be accessed across the in-
Scheme 9. Competing pyrazole formation.
tion of 28, although slower than in the presence of creasing number of gold-catalysed cycloadditions em-
gold. In contrast, no reaction was seen on heating 21b ploying ynamides.
with aminide 10 in the absence of catalyst.
In conjunction with elaboration of both the aminide
The divergence in reaction outcome can be ration- and the ynamide, this strategy provides an efficient,
alised by competing pathways following s- versus p- practically straightforward and convergent access into
activation of the ynamide. Conjugate addition to form complex oxazoles. The reactions employ a close stoi-
the zwitterion B followed by cyclisation to C is viable chiometry of reactants, relatively low loadings of the
but reversible. Elimination of carbon monoxide and bench-stable precatalyst and are tolerant to air and
expulsion of the acyl substituent with deprotonation moisture on a multi-mmol scale. The reaction pro-
provides a thermodynamically favourable aromatisa- vides access into the 2,4- and 4,5-disubstitution pat-
tion pathway when the acyl substituent is a good leav- terns as well as the 2,4,5-trisubstitution pattern.
ing group.[30b] The viability of this pathway is unsur- Highly-substituted oxazoles can be prepared with sub-
prising given the electropositivity of the catalyst used stantial structural and functional group variation that
and its ability to function as both a p- and s-Lewis can enable application and utility of this important
acid. However, when the acyl substituent is a poor heteroaromatic motif.
leaving group [e.g., phenyl or CH(OMe)2 anion] the
driving force for disruption of the pyridinium aroma-
ticity is removed (B–C) and the reaction funnels back
through the oxazole forming pathway (E/F), either
through the ynamide or a direct interconversion of
tautomeric intermediates B/F.
Adv. Synth. Catal. 2016, 358, 226 – 239
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
235

FULL PAPERS
Andrew D. Gillie et al.
thank Dr. Louise Male (University of Birmingham) for X-
ray crystallography. The facilities used in this research were
partially supported through Birmingham Science City AM2
by Advantage West Midlands and the European Regional
Development Fund.
Experimental Section
Representative Formation of Aminides from
Carboxylic Esters: Aminide 6f
N-Aminopyridinium iodide (666 mg, 3.0 mmol) and K2CO3
(995 mg, 7.2 mmol) were suspended in MeOH (23 mL) and
ester 5f (486 mg, 3.6 mmol) was added. The reaction mix-
ture was stirred for 3 days at room temperature and then
concentrated under reduced pressure. The crude residue was
suspended in 9:1 CH2Cl2/MeOH and filtered through a 5 cm
pad of basic alumina. The filtrate was concentrated under
reduced pressure and purified by flash column chromatogra-
phy on silica gel (100:0:1!90:10:1 CH2Cl2:MeOH:NEt3) to
yield aminide 6f as a white solid; yield: 496 mg (84%).
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Carboxylic Acids: Aminide 6j
A solution of N-Boc-4-trans-benzyloxy-l-proline (1.28 g,
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238
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