General Entry into o-,o′-Heteroatom-Linked N-(Hetero)aryl-Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar Cycloaddition

Article abstract of DOI:10.1002/adsc.201700249

A general redox-neutral approach into the o-,o′-heteroatom-linked N-(hetero)aryl-imidazole family of heteroaromatics has been developed. New types of heteroatom substituted carbimidoyl nitrenoids are efficiently realised from robust, bench-stable N-(heteroaryl)-pyridinium-N-aminides by formal gold-catalysed [3+2]-dipolar cycloadditions across ynamides. Broad structural variety and functional group tolerance allows rapid access into diverse functionalised scaffolds, as exemplified by the preparation of 8 different heteroaromatic cores. (Figure presented.).

Full text of DOI:10.1002/adsc.201700249

Title: General Entry into o-,o’-Heteroatom-Linked N-(Hetero)aryl
Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar
Cycloaddition
Authors: Miguel Garzón, Elsa Arce, and Raju Jannapu Reddy
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700249
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
General Entry into o-,o’-Heteroatom-Linked N-(Hetero)aryl
Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar
Cycloaddition
Miguel Garzón,a Elsa M. Arce,a Raju Jannapu Reddya and Paul W. Daviesa,*
a
School of Chemistry, University of Birmingham, Birmingham, B15 2TT, UK
Fax: +44 (0)1214144403; E-mail: p.w.davies@bham.ac.uk
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201#########
accommodate the requisite structural variety in a
Abstract. A general redox-neutral approach into the o-,o’-
heteroatom-linked N-(hetero)aryl imidazole family of formal [3+2]-dipolar cycloaddition (Scheme 1a).
heteroaromatics has been developed. New types of
heteroatom substituted carbimidoyl nitrenoids are
efficiently realised from robust, bench-stable N-(heteroaryl)
pyridinium N-aminides by formal gold-catalysed [3+2]-
dipolar cycloadditions across ynamides. Broad structural
variety and functional group tolerance allows rapid access
into diverse functionalised scaffolds, as exemplified by the
preparation of 8 different heteroaromatic cores.
Keywords: cycloaddition; dipoles; gold; nitrogen
heterocycles; nucleophilic nitrenoids
The
o-,o’-heteroatom-linked
N-(hetero)aryl
imidazole structural motif A (Figure 1) covers an
array of important tricyclic fused-heteroaromatic
systems. The synthetic utility and application of some
of these structures have been widely demonstrated.
For instance, in the benzo[d]imidazo[2,1-b]thiazole
series, uses include PET-imaging to detect Aβ
plaques which are symbols of Alzheimer’s disease,[1]
inhibitors of tumorigenesis (Triflorcas)[2] or FLT-3,[3]
and antiapoptotic,[4] antibacterial[5] and antimicrobial
agents (Figure 1).[6] In contrast, the potential of other
structures within this class has scarcely been explored.
A variety of synthetic routes into certain members of
this structurally-related family are known, those
involving formation of the shared imidazole ring
commonly feature oxidative coupling or the
condensation of an aromatic amine with an α-halo-
carbonyl equivalent.[7] Here we report a new
practically straightforward and non-oxidative strategy
that allows ready access into structural and functional
group diversity across the general structural motif A.
We questioned whether a general route into the
tricyclic motif A could be realised using a
nucleophilic nitrenoid approach to assemble the
imidazole ring common to this scaffold.[8] N-
Heteroaryl pyridinium N-aminides B were identified
as potential 1,3-N,N-dipole equivalents that could
Figure 1. The common o,o’-heteroatom-linked N-
(hetero)aryl imidazole motif with examples of
benzo[d]imidazo[2,1-b]thiazole based compounds found in
A
biomedical applications.
We recently reported the synthesis of imidazo-
fused azines by gold-catalyzed formal cycloaddition
reactions based on the use of nucleophilic nitrenoids
(Scheme 1b).[9] The cycloaddition, and the N,N-
dipole character of an imidoyl nitrene, is thought to
arise by the attack of N-azinyl pyridinium N-aminide
C onto an electrophilic π-complex D. The resulting
vinyl gold carbenoid intermediate E cyclises to the
aurated heterocycle F on elimination of the pyridine
nucleofuge, then followed by the elimination of
gold.[10] The explored aminides such as C contain an
imidoyl nitrenoid embedded within a π-deficient ring.
For the desired formation of heterocycles A, N,N-
dipole character is required from
a
π-rich
environment of donor-heteroatom substituted
carbimidoyl nitrenoids B. A strong influence from the
donor atom was expected: enhancing the abilities
1
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
Table 1. Surveying a nucleophilic nitrenoid approach to
access o,o’-heteroatom-linked N-aryl imidazole by gold-
catalysed formal [3+2]-dipolar cycloaddition.
Entry Catalyst
Solvent
T
time
(˚C) (h)
90 24
Yield
(%)[a]
1
2
3
DTBPAuX 1,4-dioxane
DTBPAuX 1,2,-DCB
DTBPAuX m-xylene
(26)
44
44
81
76
59
84
84[b]
-
125 24
120 24
1,4-dioxane 90 24
1,2,-DCB
CH3C6H5
1,2,-DCB
1,2,-DCB
1,2,-DCB
C6H5Cl
4
5
6
7
8
9
PicAuCl2
PicAuCl2
PicAuCl2
PicAuCl2
PicAuCl2
None
90
90
125 24
125 24
125
24
24
6
10
Zn(OTf)2
100 24
-
[a]
Isolated yield after purification by column
1
chromatography. Yield in parenthesis calculated by H-
NMR spectroscopy against a known quantity of 1,2,4,5-
tetramethylbenzene. Reaction run in an open flask with
[b]
undried solvent.
Scheme 1. Unveiling the carbimidoyl nitrene character of
N-heteroaryl pyridinium N-aminides for cycloaddition.
of the product and starting aminide to sequester the
electrophilic catalyst would retard reactivity while
aromaticity-disrupting cyclisation is a critical step
(Scheme 1b). Despite these concerns, and the absence
of any previous studies into the reactivity of aminides
B, the excellent structural and functional group
compatibility that has been observed in our[9,11] and
others[12] studies into mechanistically-distinct formal
cycloadditions with nucleophilic nitrenoids, prompted
us to probe this route as a means to access the
valuable heterocyclic motif A.
Figure 2. Crystal structure of 3a with ellipsoids drawn at
the 50% probability level.
We commenced our study using ynamide, 1a
and the pyridinium N-(2-benzoxazolyl)aminide 2.[13]
On reaction with the phosphite gold(I) catalyst
[11b,14]
was needed to achieve full conversion. In addition,
the transformation proved to be robust with no loss of
yield observed when the reaction was run without any
precautions taken to exclude air or moisture (Entry 8).
No cycloaddition product was observed either in the
absence of catalyst or when Zn(OTf)2 was employed
as the catalyst (Entries 9-10).[16-18]
Reacting aminide 2 across a range of ynamides
1a-j gave single regioisomers of isolated products
(Scheme 2).[19] The higher temperature conditions
(1,2-DCB at 125 ˚C) were predominantly used in
DTBPAu·NCCH3.SbF6
the desired imidazo-
[2,1-b]benzoxazole 3a did form, albeit with modest
conversion even at elevated temperature in either m-
xylene or 1,2-DCB (Table 1, Entries 1-3). Using
bench-stable picolinateAuCl2 as a precatalyst at 90 ˚C
(Entries 4-6) saw greatly improved conversion and a
high yield of 3a as a single regioisomer (Figure 2).[15]
A similar yield of 3a was achieved in a
substantially-reduced reaction time on running the
reaction at 125 ˚C in 1,2-dichlorobenzene (DCB)
(Entry 7). Notably, only a slight excess of aminide 2
2
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
We then sought to explore the wider potential of
the formal [3+2]-dipolar cycloaddition by using
elaborated aminides B to access more varied
structural types across the fused tricyclic motif A.
The reported synthesis of 2 employed substitution of
the 2-haloheterocycle with N-amino-pyridinium
iodide.[13] As chemo- and regio-selectivity issues can
render the synthesis of suitably halogenated fused-
heterocycles inefficient or impractically lengthy, we
also sought a complementary method. To this end, we
investigated whether methylthio heterocycles 4 would
be suitable precursors as they can be prepared from
the readily accessible o-halo or o-hydroxy aromatic
amine motif, by reaction with a CS2 equivalent
followed by S-methylation (Scheme 3).[24]
A variety of novel, and functionalised, 2-
methylthiobenzo(thio/oxa)zoles and aza-analogues 4
were prepared (see ESI). In most cases, clean
reactions occurred with N-amino pyridinium iodide
and potassium carbonate in methanol, affording a
range of new N-heteroaryl pyridinium N-aminides 6-
13 as bench-stable crystalline materials (Scheme 3).
While the 7-fluorobenzothiazolyl sulfide 4c was
unreactive, use of its corresponding arylsulfone (5c)
provided ready access into the desired aminide 8.
[a]
Using conditions A and at 0.2 mmol scale at [0.1 M]
relative to 1 unless otherwise specified. Yields of isolated
product after flash chromatography. [b] Using conditions B.
Scheme 2. Synthesis of fused imidazo[2,1-b]-benzoxazoles
and -benzothiazoles across different ynamides[a]
order to achieve faster conversion with reactions
generally complete within 4 h.
N-Alkyl, -benzyl and -allyl substituents are all
tolerated (e.g. 3(a-f)) including
a
bulky α-
methylbenzyl substituent (3c) shown to substantially
reduce the effectiveness of other gold-catalysed
reactions.[11a] The desired intermolecular reaction to
afford 3d outperformed thermal intramolecular aza-
Claisen rearrangement of N-allyl-ynsulfonamide 1d,
even at 125 ˚C.[20] N-Phosphoryl ynamides react as
smoothly as yne-sulfonamides (cf. 3a and 3e).[21]
Changing the ynamide C-substituent allows
ready access to a variety of C-3 substitution patterns
on the heteroaromatic, including electron-rich (3f)
and electron-poor (3g) groups. Though the reactive
enynamide 1h degraded at 125 ˚C (3h formed in 35%
yield), the 3-alkenyl-heterocycle 3h was formed in
good yield under the less vigorous reaction conditions
(90 ºC in 1,4-dioxane). Cyclopropyl-substituted 3i
was obtained in good yield, though other alkyl-
substituted ynamides afforded complex mixtures.[22]
Thioynamide 1j reacts smoothly to give the 2-amino-
3-thioether products 3j, bearing a useful thioether
group for later derivatisation.[23]
[a] N-Aminopyridinium iodide (1.00 equiv.), 4 (1.04 equiv.),
K2CO3 (2.80 equiv.) at [0.1 M]. Yield of isolated product
after flash chromatography. TCT = 2,4,6-trichloro-1,3,5-
triazine. Py = Pyridine.
Scheme 3. The use of arylthioethers to allow synthesis of
functionalised and diverse N-(heteroaryl)aminides[a]
Pleasingly, the formal cycloaddition proved to
be general across a broad spectrum of N-heteroaryl
pyridinium N-aminides, either prepared from
arylthioethers or substitution of halogenated
3
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
[a] Using conditions A and at 0.2 mmol scale at [0.1 M] relative to 1 unless otherwise specified. Yields of isolated product
after flash chromatography. [b] Using conditions B. [c] No reaction under conditions A. [d] Reaction run at 2.5 mmol scale.
Scheme 4. Novel and functionalised N-(heteroaryl)aminides in formal [3+2] dipolar cycloaddition across ynamides.[a]
heterocycles (14-17, See ESI) (Scheme 4). The
attached donor atom impacted substantially on the
reactivity of the imidoyl nitrenoid, with both
Substitution was well-accommodated at each of
the 4-, 5-, 6- and 7-positions across the imidazo[2,1-
b]benzothiazole and imidazo[2,1-b]benzoxazole
series on reaction with various ynamides under the
standard conditions (Scheme 4). Notably, having the
nucleophilic nitrenoid centre in-, or out of- direct
conjugation to a strongly withdrawing nitro group
had little practical impact (24a vs 25a).
The new aminides incorporating pyridine rings
10-13 also proved to be effective dipole equivalents
allowing rapid access to the fused triheterocyclic
scaffolds 26-29 under the standard conditions
(Scheme 4). In these cases, the reaction profile was
significantly altered by the position of the additional
aza group. The 4- and 7-aza analogues 11 and 10
reacted smoothly, affording the products 26 and 27 in
benzothioxazole-
and
benzimidazole-derived
aminides 14[13] and 15 less reactive than 2, but still
allowing access into imidazo[2,1-b]benzothiazole 18a
and imidazo[1,2-a]benzimidazole 19a under the more
vigorous reaction conditions.
These reactions could be directly scaled-up to
prepare more than
a
gram of imidazo[2,1-
b]benzothiazole 18k in high yield. This approach
allows ready access into bi-heteroaryl linkages
though use of the appropriate alkyne derivative as
demonstrated in the use of an N-alkynylindole
affording 2-(N-indolyl)-imidazo-fused system 18l, or
the thiophene 18m.
4
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
excellent yields after one hour. The 5-aza analogue
12 reacted more slowly, requiring 8 h for complete
conversion, while the 6-aza analogue 13 reacted
sluggishly with relatively low conversion even on
prolonged heating. This relative reactivity profile can
tentatively be assigned to the ability of the additional
basic nitrogen site, in either starting materials or
products, to act as a ligand to sequester the active
gold species and reduce effective catalyst
concentration. Both 5- and 6-positions are more
sterically accessible than the o-substituted 4- and 7-
positions; while the 6-aza group is further activated
by the position of the π-donating aminide or
imidazole in 13 or 29 respectively.
The applicability of this aminide-based
nucleophilic nitrenoid approach to access new
heterocyclic motifs was next tested using caffeine as
a precursor. Selective bromination at C-2[25] followed
by substitution of 30 with N-amino-pyridinium iodide
generated the aminide 31 in high yield (Scheme 5).
As 31 degraded on prolonged heating at elevated
temperature, the gold-catalysis was run under the
lower temperature conditions affording the densely
functionalised cycloaddition adduct 32 in good yield,
as apparently the first synthesised example of fused
imidazo[1,2-e]purine derivatives.
scale. The route tolerates substantial structural and
functional group elaboration allowing for rapid build-
up of structural complexity and molecular diversity.
The reactivity and wider applicability of these formal
cycloaddition processes is underway in our laboratory.
Experimental Section
Representative
formation
of
aminides
from
arylthioethers: A mixture of N-aminopyridinium iodide
(235 mg, 1.06 mmol) and potassium carbonate (411 mg,
2.97 mmol) in methanol [10 mL, 0.1 M] was stirred at
room temperature for 30 min until a permanent purple
suspension
appeared.
2-(Methylthio)thiazolo[5,4-
b]pyridine (4e, 201 mg, 1.10 mmol) was added and the
reaction mixture was stirred at room temperature for 24 h.
The solvent was removed under reduced pressure and the
residue dissolved in CH2Cl2 and washed with NaOH(aq.)
[2.5M]. The aqueous phase was extracted with CH2Cl2 and
the combined organic phases were dried over MgSO4,
filtered and the solvent removed under reduced pressure.
The residue was purified by flash chromatography over
silica gel [CH2Cl2:methanol (95:5)] affording aminide 10
as a bright yellow solid (194 mg, 0.85 mmol, 80%).
Representative procedure for the formation of o-,o’-
heteroatom-linked N-(hetero)aryl imidazoles: A heat
gun-dried Schlenk tube under an argon atmosphere was
charged with aminide 10 (54.6 mg, 0.24 mmol),
dichloro(2-pyridinecarboxylate)gold (4.1 mg, 5 mol%) and
ynamide 1n (71.5 mg, 0.20 mmol) in dry 1,2-
dichlorobenzene [0.1 M relative to the ynamide] and the
mixture was stirred under argon at 125 °C for 1 h. The
reaction mixture was then allowed to cool before being
added directly onto a silica gel column and purified by
flash chromatography [hexane:ethyl acetate (4:1)]
affording 26n as a white solid (93.3 mg, 0.19 mmol, 92%).
Experimental details and data are in the Supporting
Information along with copies of NMR spectra and the
crystal structure of 3a.
Acknowledgements
The authors thank the University of Birmingham (UoB) for a
studentship (MGS) AstraZeneca plc and UoB for a studentship
(EMA), the EC FP7 (SYNHET) for a Marie-Curie IIF (RJR). We
thank Scott Lamont (AstraZeneca plc) for discussions. The
authors acknowledge support from the Centre for Chemical and
Materials Analysis in the School of Chemistry at UoB and thank
Dr Louise Male (UoB) for X-ray crystallography.
Scheme 5. Rapid elaboration of caffeine into the
imidazo[1,2-e]purine by a formal cycloaddition approach.
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10.1002/adsc.201700249
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
COMMUNICATION
General Entry into the o-,o’-Heteroatom-Linked N-
(Hetero)aryl Imidazole Motif by Formal [3+2]-
Dipolar Cycloaddition
Adv. Synth. Catal. Year, Volume, Page – Page
Miguel Garzón, Elsa M. Arce, Raju Jannapu Reddy
and Paul W. Davies*
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