Synthesis of Fused Imidazole-Containing Ring Systems via Dual Oxidative Amination of C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.joc.6b01517

A general and efficient method for a metal-free one-pot synthesis of highly substituted fused imidazole-containing 5,5- and 5,6-fused bicyclic heterocycles is described. Starting from commercially available substrates and reagents, the reaction proceeds through two C-N bond formations and an oxidative dehydrogenation to form highly substituted products in good to excellent yield.

Full text of DOI:10.1021/acs.joc.6b01517

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Note
Synthesis of Fused Imidazole-Containing Ring Systems
via Dual Oxidative Amination of C(sp3)-H bonds
Georgette Castanedo, Yanzhou Liu, James J. Crawford, and Marie-Gabrielle Braun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01517 • Publication Date (Web): 16 Aug 2016
Downloaded from http://pubs.acs.org on August 18, 2016
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Synthesis of Fused Imidazole-Containing Ring Systems via Dual Oxidative Amination of C(sp )-H bonds.
Georgette Castanedo,* Yanzhou Liu, James J. Crawford and MarieꢀGabrielle Braun
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.
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ABSTRACT: A general and efficient method for a metalꢀfree oneꢀpot synthesis of highly substituted fused imidazole conꢀ
taining 5,5 and 5,6 fused bicyclic heterocycles is described. Starting from commercially available substrates and reagents, the
reaction proceeds through two C–N bond formations and an oxidative dehydrogenation to form highly substituted products
in good to excellent yield.
Fused heterocyclic ring systems containing bridgehead nitrogens are not only biologically relevant but are valuable building
1
blocks in medicinal chemistry and present a persistent synthetic challenge (Figure 1). Typical approaches to their synthesis
2
involve acylation of orthoꢀnitrogen containing arylmethylamines and subsequent cyclodehydration (Scheme 1, A.). Several
recent publications have reported routes to polyꢀsubstituted 5,6 fused imidazo[1,5ꢀa]pyridines in one pot through CH arylaꢀ
3
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3
5ꢀ8
tion, multiꢀcomponent condensation and C(sp )ꢀH amination, however methods to access 5,5 and 5,5,6 fused ring sysꢀ
tems remain scarce and often suffer from limitations such as lack of commercial availability of starting materials, long synꢀ
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thetic routes, harsh reaction conditions, complex isolation procedures and limitations in scope (Scheme 1, B-E.).
1
Figure 1 Examples of fused imidazole-containing rings in medicinal chemistry
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In the course of one of our medicinal chemistry programs, we became interested in testing the effect of replacing an imidꢀ
azo[1,5ꢀa]pyridine core with a variety of 5,5 fused bridgehead nitrogen containing heterocycles. In studying the existing
methods, we found a number of inadequacies including the aforementioned drawbacks. We envisioned that a general method
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to
synthesize
5,5
imidazole
containing
fused
ring
systems
would
be
valuable
from both a synthetic as well as a medicinal chemistry perspective. Herein we report a robust and chemoselective method for
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their synthesis in a oneꢀpot fashion from commercially available starting materials (Scheme 1, F.).
Scheme 1. Summary of Methods to Synthesize Fused Imidazole Ring Systems
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Pioneering work by Yan et al. demonstrated the first example of a metalꢀfree sequential dual oxidative amination of C(sp )ꢀH
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bonds to synthesize imidazo[1,5ꢀa]pyridines. With this as a foundation, we sought to optimize the transformation to be apꢀ
plicable for the synthesis of a broad range of fused ring systems. At the outset of our investigation, we were able to demonꢀ
strate that the reaction could be performed in standard vials, negating the requirement for a Schlenk tube and making it more
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experimentally convenient. We found that the order of addition was also important, with the best results obtained when the
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iodine source and oxidant were added to a solution of heteroaromatic substrate and amine in solvent. With these adjustꢀ
ments in place, we began our evaluation of the reaction conditions (see SI, Table 1). Beginning with ethyl 2ꢀ(thiazolꢀ2ꢀ
yl)acetate (1a, 1.0 equiv), 3ꢀbromobenzylamine (2a, 2.0 equiv), iodine source (1.0 equiv) and TBHP (3.0 equiv) in DMA
(
0.5 M), we were pleased to observe formation of ethyl 5ꢀ(3ꢀbromophenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate 3a as the
primary product. Furthermore, NIS appeared to be the best iodine source of those screened for 5,5 fused ring formation. In
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our examination of the effect of solvent (see SI, Table 2), we found that ACN was marginally better in terms of yield of 3a,
but ultimately DMF was selected because of its superior solubilizing ability. With our newly optimized conditions in hand,
we proceeded to probe the amine scope (Table 1).
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Table 1: Amine Scope of imidazo[5,1-b]thiazole core
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Isolated % yields reported. Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), NIS (0.5 mmol), TBHP (1.5 mmol), Solvent
a
b
c
d
(
0.5 M), rt, 18 h. ACN as solvent, 0.5 mmol and 6.0 mmol scale in DMF gave same yield, 1.1 equiv of amine, Reaction
heated at 80 °C for 18 h.
Compound 3a was isolated in 68% yield in ACN and 57% yield in DMF with no column purification, with the product isoꢀ
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lated following trituration of the reaction mixture. We were able to demonstrate the scalability of the reaction by achieving
the same yield (57%) at 1 gram (6 mmol) scale in DMF. The method tolerates both electronꢀdonating (hydroxy 2c, methoxy
2
3
d) and electronꢀwithdrawing groups on the amine (halogens 2a and 2b, ester 2e, nitrile 2f and sulfone 2g). Examples 3a and
b contain halogens that can act as a synthetic handle for further elaboration. We were very gratified to see that the free hyꢀ
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droxyl group in 3c was benign under the reaction conditions. The orthoꢀmethoxy substituent in 3d demonstrated that the
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reaction can also tolerate increased steric demand on the amine substrate. The exceptional chemoselectivity and functional
group tolerability of the reaction was further evidenced by examples 3e-g, where an ester, nitrile and sulfone were not affectꢀ
ed under these reaction conditions. Interestingly, amine substrates 2h–k with additional potentially reactive nitrogens were
also tolerated in the reaction (examples 3h–k). Although pyridinꢀ2ꢀylmethanamine had not been demonstrated as a viable
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amine substrate on prior occasions with similarly proposed mechanisms,
the corresponding product, 3h, was obtained,
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albeit in low yield, through adjusting the number of equivalents of the amine substrate from 2.0 to 1.1. The scope was further
expanded to include aliphatic amines as in 3l and 3m. In addition, the allylic moiety in 3m is a multifaceted group that is
poised to undergo further functionalization. Although the isolated yields were somewhat low for several of the examples in
this table, we were delighted to synthesize a wide variety of highly complex, polyꢀsubstituted imidazo[5,1ꢀb]thiazoles with
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exceptional chemoselectivity and diversity in one step with broad functional group tolerance.
Our attention then turned to investigating the scope of heteroaromatic substrate (Table 2). Electronꢀdonating and withꢀ
drawing groups (Me, CF , Br) were tolerated at multiple positions on the imidazo[5,1ꢀb]thiazole as seen in examples 4b–d.
3
Initially we chose to mask the free amino group of the heteroaromatic substrate in 4e with a tertꢀbutoxycarbonyl (Boc) group
as we were concerned that it might hinder product formation. We were subsequently able to show that this is not the case, as
the free amino group was tolerated under the reaction conditions as shown by 4f and 4g. Additionally, we were unable to find
any prior instances of this imidazo[5,1ꢀb][1,3,4]thiadiazolꢀ2ꢀamine core in the literature. The Weinreb amide was also a
competent substrate in this reaction shown by 4h in 54% yield and is a versatile handle for additional manipulation. Furtherꢀ
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more, the tertiary amide 4g can potentially be readily converted to an aldehyde. Imidazo[1,5ꢀa]imidazole 4i was lower
yielding at 34% but our oneꢀstep synthesis, which allowed for more structural diversification, offered advantages over the
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e
previously reported 4ꢀstep method to make this ring system. Similarly, the polyꢀsubstituted imidazo[1,5ꢀb][1,2,4]triazole 4j,
whose starting material and subsequent product contains a free NH, was poorly exemplified in the literature but easily preꢀ
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pared in 40% yield with this method. As demonstrated by 4k–m, benzothiazole, benzimidazole and benzoxazole were all
competent substrates in the reaction to form the corresponding fused 5,5,6 ring systems. In some cases, low yields can be
potentially be explained by the pK of the nitrogen in the heteroaromatic substrate, which offers a relative estimation of its
a
nucleophilicity. In particular, for methyl 2ꢀ(benzo[d]oxazolꢀ2ꢀyl)acetate (1m), used to synthesize 4m in 13% yield, the pK is
a
18
on the order of 0.5. Several other examples of heteroaromatic substrates whose nitrogen atom has a negative or unknown
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pK value failed to yield any product (such as isoxazole, 1,2,4ꢀoxadiazole and benzo[d]isothiazole). We were able to obꢀ
a
serve formation of imidazo[5,1ꢀb][1,3,4]oxadiazole 4s but it rapidly decomposed during isolation, presumably due to instaꢀ
2
0
bility of the product.
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Table 2: Heteroaromatic Substrate Scope
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Isolated % yields reported. Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), NIS (0.5 mmol), TBHP (1.5 mmol), Solvent
a
b
c
(
0.5 M), rt, 18 hrs. Reaction heated at 80 °C for 18 h 1.1 eq of amine used, Product was observed but not isolated due to
rapid decomposition.
After demonstrating the successful synthesis of a variety of complex fused 5,5 and 5,5,6 imidazoleꢀcontaining bicycles, we
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wanted to further demonstrate the robustness of the method through extension to fused 5,6 systems. To that end, with exꢀ
amples 4n–r, we were able to show that highly substituted 5,6 fused imidazole ring systems including imidazo[1,5ꢀ
a]pyrimidine, imidazo[1,5ꢀa]pyrazine, imidazo[1,5ꢀc]pyrimidine and 1,2,3,4ꢀtetrahydroimidazo[1,5ꢀa][1,8]naphthyridine
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could all be accessed using this method. Although the oneꢀpot synthesis of the imidazo[1,5ꢀc]pyrimidine core was not comꢀ
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patible with a prior method, we were gratified to isolate 4p in 81% yield. In addition, 4q demonstrated that a reactive funcꢀ
tional group (chlorine) on the pyrazine substrate remained undisturbed, and offered an option for further elaboration if necesꢀ
sary.
In addition to displaying the broad scope of the amine and heteroaromatic substrates, we were able to use this methodology
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to improve upon a synthesis of an imidazo[1,5ꢀb]pyridazine intermediate that had been employed in the synthesis of NFꢀκβ
1d
inducing kinase (NIK) inhibitors (Scheme 2). Using methylꢀ2ꢀpyridazinꢀ3ꢀyl)acetate 1t as a common starting material, 4t
was synthesized in 78% yield following a trituration, avoiding any column chromatography, rather than in 4 steps and 17%
overall yield with the previous literature route.
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d
Scheme 2. Improved Route to Literature Intermediate (Example 4t)
With the objective of further elucidating the reaction mechanism, we isolated and characterized several reaction intermediꢀ
ates encountered during our scope investigations. Imine intermediate 5 was obtained in 50% yield when the reaction was
performed at room temperature (Scheme 3, A.), but conversion to product 3k (Table 1) could be effected with heating to 80
°C from the outset. Similarly, secondary amine 6 was isolated in 43% yield (Scheme 3, B.), while formation of product 4g
22
(
Table 2) was realized when the reaction was heated to 80 °C. The isolation of both imine 5 and secondary amine 6 as reacꢀ
5,8,13,23
tion intermediates support the previously reported proposed mechanistic pathways.
We also observed when the hetꢀ
eroaromatic substrate was a ketone and the starting material was primarily in the enol form (as indicated by NMR), preferenꢀ
tial and unexpected formation of a 2,4,5 substituted oxazole 7 was seen in 44% yield over our desired imidazobenzimidazole
4
u, obtained in 22% yield (Scheme 3, C.). We are currently investigating whether we can alter the conditions to bias the reꢀ
action outcome. In addition, mechanistic studies are underway in an attempt to elucidate the reaction mechanism beyond
what has been previously reported.
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Scheme 3. Isolated Potential Reaction Intermediates and By-Products
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Isolated % Yields Reported. Standard Reaction Conditions: 1 (0.5 mmol), 2 (1 mmol), NIS (0.5 mmol), TBHP (1.5 mmol),
Solvent (0.5 M), rt, 18 h.
Attempts to expand the scope beyond ester, ketone, amide and Weinreb amide moieties at C–4 of the imidazole ring met
with some limitations. In the case of the nitrile, instead of 4v, we saw the benzo[d]thiazole ring nitrogens react preferentially
2
4
over the secondary amine nitrogen to give 8 in 40% yield (Scheme 3, D.). Additional heteroaromatic substrates containing
electron withdrawing groups such as CF , SO Ph and symmetrical benzo[d]thiazole rings (with CH in between) also failed
3
2
2
to give product, which we attributed to insufficient captodative resonance stabilization of the proposed radical reaction inꢀ
5
,8,14
termediate.
In summary, we were able to develop a highly chemoselective, robust, and general method to synthesize a variety of hisꢀ
torically difficult to access, complex polyꢀsubstituted fused 5,5 and 5,6 imidazole containing heterocycles in moderate to
excellent yields. A wide array of functional group tolerance on both the heteroaromatic and amine substrates was demonꢀ
strated. Additionally, our method allowed access to fused heterocycles which had not been previously reported in the literaꢀ
ture. We believe this method has the capability of being impactful in such fields as medicinal chemistry, agrochemicals and
materials as it allows for rapid synthesis of a diverse range of fused heterocycles.
EXPERIMENTAL SECTION
General Information. Unless otherwise indicated, all commercial reagents and solvents were used without additional purifiꢀ
1
cation. Anhydrous solvents were used in reaction optimization and scope. HꢀNMR spectra were recorded with a 400 or 500
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spectrometer. Chemical shifts (in ppm) were referenced to tetramethylsilane (δ = 0 ppm) in DMSOꢀd or CDCl as an internal
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standard (2.5 or 7.26 ppm). CꢀNMR spectra were obtained by the same NMR spectrometer and were calibrated with
DMSOꢀd or CDCl (δ = 39.51 or 77.2 ppm). HRMS was recorded on an Orbitrap Q Exactive mass spectrometer. In situaꢀ
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3
79
tions where final compounds contain Bromine, Br with the exact mass of 78.9183 was used in the calculation. Thinꢀlayer
chromatograms were performed on Silica gel 60 F254 aluminumꢀbacked plates and visualized with UV light. Reactions were
monitored by walkup a LCMS/UV system using 2ꢀ98% acetonitrile/0.1% formic acid (or 0.01% Ammonia) over 2.5 min
(short method) or 5.5 min (long method). Flash column chromatography purifications were performed on automated systems
equipped with 254 and 280 nm wavelengths. Reverse phase purification of compound 4m was carried out by HPLC with a
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gradient of 5−95% acetonitrile/water (with 0.1% formic acid or 0.1% NH OH) over 10 min at 60 mL/min. The starting mateꢀ
4
rials were commercially available with the exception of 1e, 1h, 1p and 1q. Ethyl 2ꢀ(1ꢀmethylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀ
yl)acetate used in synthesis of compound 4l was prepared as described in Chapman, D.D.; Elwood, J.K.; Hesltine, D.W.;
Hess, H.M.; Kurtz, D.W. J. Org. Chem., 1977, 42, 2474.
General Procedure A. To a stirring solution of the heteroaromatic substrate (0.5 mmol) in N,Nꢀdimethylformamide (2
mL/mmol, 0.5 M) was added the benzylamine derivative (1.0 mmol, 2.0 equiv), NIS (0.5 mmol, 1.0 equiv) and finally TBHP
(70% aq, 1.5 mmol, 3.0 equiv) dropwise. The reaction mixture was subsequently stirred overnight (18 hours) whereupon it
was quenched by a saturated Na S O solution (2.0 mL) to reduce any excess iodine followed by addition of a saturated amꢀ
2
2
3
monium chloride solution (10 mL) and extraction with dichloromethane (10 mL). The organic layer was dried with magnesiꢀ
um sulfate, filtered and concentrated to afford crude fused imidazole bicyclic product which was purified via flash column
chromatography using a heptanes/iPrOAc or 3:1 iPrOAc:MeOH to heptanes gradient.
General Procedure B. Changes from above procedure as follows: After quenching reaction with a saturated Na S O soꢀ
2
2
3
lution, a solid precipitated from the aqueous solution which was further diluted with water (10 mL), collected by filtration
and triturated by sonicating or rinsing the solid in a slurry of methanol. The solid was reꢀcollected by filtration and dried unꢀ
der vacuum to afford pure fused imidazole bicyclic product without the necessity of column purification.
Ethyl 2ꢀ[5ꢀ(tertꢀbutoxycarbonylamino)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]acetate (1e). To a suspension of ethyl 2ꢀ(5ꢀaminoꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl)acetate (500 mg, 2.67 mmol, 1.0 equiv) in dichloromethane (0.25 M, 10.7 mL) at room temperature was addꢀ
ed diꢀtertꢀbutyl dicarbonate (661 mg, 1.1 equiv,) and 4ꢀdimethylaminopyridine (34 mg, 0.1 equiv). After stirring 18 h at
room temperature, the reaction mixture was washed with 1 N HCI and the organic layer was dried with magnesium sulfate,
filtered and concentrated. The crude was purified via flash column chromatography using a heptanes:iPrOAc gradient to afꢀ
1
ford 430 mg (56%) of ethyl 2ꢀ[5ꢀ(tertꢀbutoxycarbonylamino)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]acetate as a white solid H NMR (400
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13
MHz, DMSOꢀd ) δ 11.81 (s, 1H), 4.19 – 4.11 (m, 4H), 1.49 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀ
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
d ) δ 168.8, 161.6, 156.2, 152.7, 81.9, 61.1, 35.0, 27.8, 14.0. HRMS (ESI) [M+H] calc. C H N O S: 288.1018, found:
6
11 18
3
4
2
88.1013.
NꢀmethoxyꢀNꢀmethylꢀ2ꢀthiazolꢀ2ꢀylꢀacetamide (1h). To a solution of 2ꢀthiazoleacetic acid (400 mg, 2.68 mmol, 1.0 equiv)
in DMF (0.5 M) was added N,Oꢀdimethylhydroxylamine hydrochloride (2.0 equiv), HATU (1.1 equiv) and DIPEA (4.0
equiv). The reaction was stirred for 30 minutes and quenched with a saturated ammonium chloride solution then extracted
with DCM. The organic layer was dried with magnesium sulfate, filtered and concentrated and purified by column chromaꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
tography using a heptanes:iPrOAc gradient to afford 450 mg (90%) of NꢀMethoxyꢀNꢀmethylꢀ2ꢀthiazolꢀ2ꢀylꢀacetamide. H
13
NMR (400 MHz, CDCl ) δ 7.73 (d, J = 3.4 Hz, 1H), 7.30 (d, J = 3.3 Hz, 1H), 4.24 (s, 2H), 3.74 (s, 3H), 3.25 (s, 3H).
C
3
+
NMR (101 MHz, CDCl ) δ 169.4, 162.8, 142.1, 120.0, 61.7, 36.6, 32.4. HRMS (ESI) [M+H] calc. C H N O S: 187.0541,
3
7
11
2
2
found: 187.0536.
Methyl 2ꢀ(2ꢀmethoxypyrimidinꢀ4ꢀyl)acetate (1p). To a 0.5 M solution of methyl 2ꢀ(2ꢀchloropyrimidinꢀ4ꢀyl)acetate (460
mg, 2.5 mmol, 1.0 equiv) in MeOH (0.5 M) was added sodium methoxide (2.0 equiv, 30% mass in MeOH). The reaction was
stirred for 24 hours at room temperature, then diluted with a saturated ammonium chloride solution (20 mL) and extracted
with DCM (20 mL). The organic layer was dried with magnesium sulfate, filtered and concentrated and purified by column
chromatography using a heptanes:iPrOAc gradient to afford 100 mg (22%) of methyl 2ꢀ(2ꢀmethoxypyrimidinꢀ4ꢀyl)acetate as
1
an oil. H NMR (400 MHz, CDCl ) δ 8.47 (d, J = 5.0 Hz, 1H), 6.96 (d, J = 5.0 Hz, 1H), 4.01 (s, 3H), 3.76 (s, 2H), 3.74 (s,
3
13
+
3
H). C NMR (101 MHz, CDCl ) δ 169.7, 165.7, 165.3, 159.4, 114.8, 54.9, 52.4, 43.2. HRMS (ESI) [M+H] calc.
3
C H N O : 183.0770, found: 183.0764.
8
11
2
3
Methyl 2ꢀ(5ꢀchloropyrazinꢀ2ꢀyl)acetate (1q). To a solution of 2ꢀ(5ꢀchloropyrazinꢀ2ꢀyl)acetic acid (509 mg, 3.0 mmol, 1.0
equiv) in DMF (0.5 M) was added potassium carbonate (3.0 equiv) and iodomethane (1.1 equiv). The reaction was stirred at
room temperature for 1 h, then quenched with a saturated solution of ammonium chloride and DCM. The organic layer was
dried with magnesium sulfate, filtered and concentrated. The crude was purified via flash column chromatography using a
1
heptanes:iPrOAc gradient to afford 290 mg (53%) of methyl 2ꢀ(5ꢀchloropyrazinꢀ2ꢀyl)acetate as a white solid. H NMR (400
13
MHz, CDCl ) δ 8.52 (s, 1H), 8.51 (s, 1H), 3.88 (s, 2H), 3.75 (s, 3H). C NMR (101 MHz, CDCl ) δ 169.6, 150.0, 148.7,
3
3
+
1
43.2, 143.0, 52.7, 40.6. HRMS (ESI) [M+H] calc. C H ClN O : 187.0274, found: 187.0269.
7 8 2 2
Ethyl 5ꢀ(3ꢀbromophenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3a). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.5 mmol) was reacted
with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure B. The reaction was performed in acetonitrile on a
1
0
.5 mmol scale to give 68% yield and in DMF on a 0.5 mmol and 6 mmol scale both to give 57% yield. H NMR (400 MHz,
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DMSOꢀd ) δ 8.37 (d, J = 4.2 Hz, 1H), 8.07 – 8.04 (m, 1H), 7.95 – 7.91 (m, 1H), 7.68 – 7.64 (m, 1H), 7.59 (d, J = 4.2 Hz,
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
H), 7.52 – 7.46 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.3, 141.1,
6
+
1
36.5, 131.5, 131.2, 130.9, 128.7, 125.0, 122.1, 120.5, 120.2, 119.9, 59.7, 14.2. HRMS (ESI) [M+H] calc. C H BrN O S:
14
12
2
2
350.9803, found: 350.9808.
Ethyl 5ꢀ(3ꢀiodophenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3b). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.5 mmol) was reacted
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
with 3ꢀiodobenzylamine 2b (2.0 equiv) according to general procedure B to give 133 mg (67%) of a light tan solid. H NMR
(
400 MHz, DMSOꢀd ) δ 8.40 (d, J = 4.2 Hz, 1H), 8.24 – 8.22 (m, 1H), 7.97 – 7.93 (m, 1H), 7.86 – 7.82 (m, 1H), 7.60 (d, J =
6
4
1
.2 Hz, 1H), 7.36 – 7.31 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSOꢀd ) δ
6
+
61.5, 141.2, 137.5, 136.5, 134.7, 131.2, 131.0, 125.5, 120.5, 120.5, 120.2, 95.4, 60.0, 14.4. HRMS (ESI) [M+H] calc.
C H IN O S: 398.9664, found 398.9659.
1
4
12
2
2
Ethyl 5ꢀ(3ꢀhydroxyphenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3c). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.5 mmol) was reactꢀ
ed with 3ꢀhydroxybenzylamine 2c (2.0 equiv) according to general procedure A to give 100 mg (69%) of a light orange solꢀ
1
id. H NMR (400 MHz, DMSOꢀd ) δ 9.75 (s, 1H), 8.30 (d, J = 4.1 Hz, 1H), 7.58 (d, J = 4.2 Hz, 1H), 7.40 – 7.30 (m, 3H),
6
13
6
1
2
.94 – 6.83 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.6, 157.8,
6
+
40.8, 138.3, 130.3, 130.2, 120.3, 120.2, 120.0, 117.0, 116.3, 113.2, 59.9, 14.5. HRMS (ESI) [M+H] calc. C H N O S
14
13
2
3
89.0647, found: 289.0641.
Ethyl 5ꢀ(2ꢀmethoxyphenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3d). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.46 mmol) was reꢀ
1
acted with 2ꢀmethoxybenzylamine 2d (2.0 equiv) according to general procedure A to give 102 mg (74%) of a yellow oil. H
NMR (400 MHz, CDCl ) δ 7.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.44 (ddd, J = 8.3, 7.5, 1.8 Hz, 1H), 7.38 (d, J = 4.2 Hz, 1H), 7.10
3
–
7.05 (m, 1H), 7.01 (dd, J = 8.4, 1.0 Hz, 1H), 6.96 (d, J = 4.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.42 (t, J = 7.1
13
Hz, 3H). C NMR (101 MHz, CDCl ) δ 162.7, 156.7, 139.8, 137.2, 132.2, 131.1, 121.4, 121.2, 120.2, 118.7, 117.1, 111.2,
3
+
6
0.5, 55.6, 14.7. HRMS (ESI) [M+H] calc. C H N O S: 303.0798, found: 303.0792.
15
15
2
3
Ethyl 5ꢀ(3ꢀ(methoxycarbonyl)phenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3e). To a solution of HCl salt of methyl 4ꢀ
aminomethyl)benzoate hydrochloride 2e (1.0 mmol, 200 mg) in acetonitrile was added was added Amberlyst 21 (380 mg).
The suspension was stirred at room temperature for 30 min, then filtered and washed with CH Cl to remove the resin. The
(
2
2
filtrant was collected and concentrated in vacuo. The residue was then redissolved in DMF (1 mL) and was reacted with
ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol, 90 mg) according to general procedure A to give 103 mg (62% yield) of a white
solid. 1H NMR (400 MHz, CDCl ) δ 8.49 (t, J = 1.8 Hz, 1H), 8.19 – 8.07 (m, 2H), 7.85 (d, J = 4.2 Hz, 1H), 7.59 (td, J = 7.8,
3
13
0
.6 Hz, 1H), 7.13 (d, J = 4.2 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). C NMR (101 MHz,
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+
CDCl ) δ 166.5, 162.6, 132.1, 131.7, 131.1, 130.3, 130.1, 129.4, 127.4, 119.5, 118.6, 61.0, 52.5, 14.8. HRMS (ESI) [M+H]
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
calc. (C H N O S): 331.0753, found: 331.0747.
16
15
2
4
Ethyl 5ꢀ(4ꢀcyanophenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3f). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol, 90 mg) was
reacted with 4ꢀ(aminomethyl)benzonitrile 2f (1.0 mmol, 130 ꢁL) according to general procedure A to give 116 mg (78%
1
yield) of a white solid. H NMR (400 MHz, CDCl ) δ 8.01 – 7.99 (m, 2H), 7.85 (d, J = 4.2 Hz, 1H), 7.79 – 7.77 (m, 2H),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
7
.19 (d, J = 4.2 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ 162.3, 141.5,
3
+
1
37.0, 133.8, 133.0, 127.1, 122.9, 120.3, 118.4, 112.6, 61.2, 14.7. HRMS (ESI) [M+H] calc. (C H N O S): 298.0650,
15
12
3
2
found: 298.0645.
Ethyl 5ꢀ(4ꢀ(methylsulfonyl)phenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3g). To a solution of HCl salt of (4ꢀ
methylsulfonylphenyl)methanamine 2g (1.0 mmol, 220 mg) in acetonitrile was added was added Amberlyst 21 (380 mg).
The suspension was stirred at room temperature for 30 min, then filtered and washed with DCM to remove the resin. The
filtrant was collected and concentrated in vacuo. The residue was then redissolved in DMF (1 mL) and was reacted with
ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol, 90 mg) according to general procedure A to give 140 mg (80% yield) of a white
1
solid. H NMR (400 MHz, CDCl ) δ 8.11 – 8.05 (m, 4H), 7.87 (d, J = 4.2 Hz, 1H), 7.20 (d, J = 4.2 Hz, 1H), 4.48 (q, J = 7.1
3
Hz, 2H), 3.11 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, CDCl ) δ 162.2, 141.4, 140.6, 136.8, 134.6, 128.2,
3
+
1
27.3, 122.8, 120.2, 118.3, 61.0, 44.5, 14.6. HRMS (ESI) [M+H] calc. (C H N O S ): 351.0473, found: 351.0468.
15
15
2
4 2
Ethyl 5ꢀ(pyridinꢀ2ꢀyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3h). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.5 mmol) was reacted
1
with 4ꢀpyridylmethanamine 2h (1.1 equiv) according to general procedure A to give 45 mg (30%) of a red solid. H NMR
(
400 MHz, DMSOꢀd ) δ 8.84 (d, J = 4.2 Hz, 1H), 8.71 – 8.68 (m, 1H), 8.17 – 8.14 (m, 1H), 8.00 – 7.95 (m, 1H), 7.63 (d, J =
6
13
4
1
2
.0 Hz, 1H), 7.47 – 7.43 (m, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.4,
6
+
49.1, 148.1, 141.6, 137.5, 136.7, 123.4, 122.1, 120.5, 120.3, 120.2, 60.0, 14.4. HRMS (ESI) [M+H] calc. C H N O S
1
3
12
3
2
74.0650, found: 274.0645.
Ethyl 5ꢀ(pyridinꢀ4ꢀyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3i). Ethyl 2ꢀthiazolꢀ2ꢀylacetate 1a (0.5 mmol) was reacted
1
with 4ꢀpyridylmethanamine 2i (2.0 equiv) according to general procedure A to give 56 mg (41%) of a light yellow solid. H
NMR (400 MHz, DMSOꢀd ) δ 8.73 – 8.70 (m, 2H), 8.57 (d, J = 4.1 Hz, 1H), 7.94 – 7.91 (m, 2H), 7.69 (d, J = 4.2 Hz, 1H),
6
13
4
1
.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.4, 150.4, 142.1, 135.9, 135.7, 121.1,
6
+
21.0, 120.6, 120.0, 60.0, 14.4. HRMS (ESI) [M+H] calc. C H N O S 274.0650, found: 274.0645.
13
12
3
2
Ethyl 5ꢀ(thiazolꢀ2ꢀyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3j). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol, 90 mg) was
reacted with thiazolꢀ2ꢀylmethanamine 2j (1.0 mmol, 110 mg) according to general procedure A to give 77 mg (55% yield) of
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1
a yellow solid. H NMR (400 MHz, CDCl ) δ 8.65 (d, J = 4.2 Hz, 1H), 7.86 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
7
.13 (d, J = 4.2 Hz, 1H), 4.66 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ
3
+
1
62.2, 157.9, 143.4, 141.1, 133.5, 122.1, 121.4, 119.9, 119.0, 61.1, 14.7. HRMS (ESI) [M+H] calc. (C H N O S ):
11
10
3
2 2
280.0214, found: 280.0209.
Ethyl 5ꢀ(1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3k). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was reacted with (1ꢀmethylpyrazolꢀ4ꢀyl)methanamine 2k (2.0 equiv) according to general procedure A but instead of room
1
temperature was heated to 80 °C for 18 h to give 83 mg (60% yield) of an orange oil. H NMR (400 MHz, CDCl ) δ 7.95 (s,
3
1
H), 7.89 (s, 1H), 7.63 (d, J = 4.2 Hz, 1H), 7.08 (d, J = 4.2 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.43 (t, J = 7.1
13
Hz, 3H). C NMR (101 MHz, CDCl ) δ 162.5, 139.2, 136.7, 133.2, 129.2, 121.1, 119.1, 117.8, 112.5, 60.8, 39.4, 14.7.
3
+
HRMS (ESI) [M+H] calc. (C H N O S): 277.0759, found: 277.0754.
12
13
4
2
Ethyl 5ꢀcyclopropylimidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3l). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (1.5 mmol) was reacted
with cyclopropylamine 2l (2.0 equiv) according to general procedure A but instead of room temperature was heated to 80 °C
for 18 h to give 110 mg of an inseparable mixture of product and succinimide (31% yield, adjusted to 26% based on NMR)
1
of a redꢀorange oil. H NMR (400 MHz, CDCl ) δ *8.41 (bs, 1H), 7.51 (d, J = 4.2 Hz, 1H), 6.99 (d, J = 4.2 Hz, 1H), 4.40
3
(
q, J = 7.1 Hz, 2H), *2.76 (s, 2H), 2.01 (tt, J = 8.3, 5.0 Hz, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.20 – 1.05 (m, 2H), 1.08 – 0.90 (m,
13
2
H). C NMR (101 MHz, CDCl ) δ *177.3, 162.6, 141.4, 138.6, 119.9, 118.2, 117.0, 60.6, *29.7, 14.8, 8.1, 7.0. HRMS
3
+
(
ESI) [M+H] calc. (C H N O S): 237.0698, found: 237.0691.
11
13
2
2
Ethyl 5ꢀvinylimidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (3m). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (1.5 mmol) was reacted with alꢀ
1
lylamine 2m (2.0 equiv) according to general procedure A to give 140 mg (42% yield) of an orange amorphous solid. H
NMR (400 MHz, CDCl ) δ 7.64 (d, J = 4.2 Hz, 1H), 7.09 (d, J = 4.1 Hz, 1H), 6.80 (dd, J = 17.7, 11.6 Hz, 1H), 6.10 (d, J =
3
13
1
7.8 Hz, 1H), 5.55 (d, J = 11.6 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ
3
+
1
62.5, 139.9, 137.5, 123.9, 121.6, 119.2, 118.0, 117.9, 60.9, 14.7. HRMS (ESI) [M+H] calc. (C H N O S): 223.0541,
10
11
2
2
found: 223.0533.
tertꢀbutyl 5ꢀ(3ꢀbromophenyl)ꢀ3ꢀmethylimidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (4b). tertꢀbutyl 2ꢀ(4ꢀmethylthiazolꢀ2ꢀ
yl)acetate 1b (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A to give 160
1
mg (81%) of an orange solid. H NMR (400 MHz, DMSOꢀd ) δ 7.86 – 7.84 (m, 1H), 7.74 – 7.70 (m, 1H), 7.66 – 7.62 (m,
6
13
1
1
H), 7.48 – 7.43 (m, 1H), 7.08 – 7.06 (m, 1H), 2.08 (d, J = 1.2 Hz, 3H), 1.55 (s, 9H). C NMR (101 MHz, DMSOꢀd ) δ
6
+
60.7, 140.6, 137.3, 132.5, 132.2, 132.0, 129.8, 129.3, 129.1, 120.8, 114.1, 79.9, 28.0, 14.3. HRMS (ESI) [M+H] calc.
C H BrN O S 393.0272, found: 393.0267.
1
7
18
2
2
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Ethyl
The Journal of Organic Chemistry
5ꢀ(3ꢀbromophenyl)ꢀ3ꢀ(trifluoromethyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate
(4c).
Ethyl
2ꢀ[4ꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
trifluoromethyl)thiazolꢀ2ꢀyl]acetate 1c (0.5 mmol, 120 mg) was reacted with 3ꢀbromobenzylamine 2a (1.0 mmol, 130 ꢁL)
1
according to general procedure A to give 145 mg (69% yield) of a yellow solid. H NMR (400 MHz, CDCl ) δ 7.70 (brs,
3
1H), 7.63 (dd, J = 8.1, 3.1 Hz, 1H), 7.60 – 7.58 (m, 1H), 7.48 – 7.45 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 4.46 (q, J = 7.1 Hz,
13
2H), 1.43 (t, J = 7.1 Hz, 3H), C NMR (101 MHz, CDCl ) δ 162.2, 140.2, 138.7, 133.5, 133.4, 131.6, 129.6, 129.0 (q, J =
3
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.8 Hz), 124.6 (q, J = 4.9 Hz), 122.8, 122.6, 122.1, 118.6 (q, J = 270.4 Hz), 61.3, 14.7. HRMS (ESI) [M+H] calc.
(C H BrF N O S): 418.9677, found: 418.9673.
15
11
3
2
2
Methyl 2ꢀbromoꢀ5ꢀ(3ꢀbromophenyl)imidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxylate (4d). Methyl 2ꢀ(5ꢀbromoꢀ1,3ꢀthiazolꢀ2ꢀ
yl)acetate 1d (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure B to give 106
1
mg (51%) of an orange solid H NMR (400 MHz, DMSOꢀd ) δ 8.83 – 8.82 (m, 1H), 8.06 – 8.05 (m, 1H), 7.96 – 7.92 (m,
6
13
1
H), 7.70 – 7.67 (m, 1H), 7.51 – 7.46 (m, 1H), 3.85 (s, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.6, 139.1, 137.5, 132.0,
6
+
1
31.1, 130.8, 129.0, 125.6, 122.3, 122.1, 120.8, 107.2, 51.6. HRMS (ESI) [M+H] calc. C H Br N O S 414.8751, found:
13
9
2
2
2
414.8743.
Ethyl 5ꢀ(3ꢀbromophenyl)ꢀ2ꢀ((tertꢀbutoxycarbonyl)amino)imidazo[5,1ꢀb][1,3,4]thiadiazoleꢀ7ꢀcarboxylate (4e). Ethyl 2ꢀ[5ꢀ
(
tertꢀbutoxycarbonylamino)ꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl]acetate 1e (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0
1
equiv) according to general procedure B to give 210 mg (90%) of a white solid. H NMR (400 MHz, DMSOꢀd ) δ 12.56 (s,
6
1
9
1
H), 8.43 – 8.37 (m, 1H), 8.23 – 8.16 (m, 1H), 7.67 – 7.60 (m, 1H), 7.54 – 7.45 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.53 (s,
13
H), 1.33 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 160.9, 160.7, 152.8, 135.1, 134.5, 131.6, 130.9, 130.4,
6
+
27.9, 124.6, 122.0, 118.5, 83.2, 60.2, 27.7, 14.4. HRMS (ESI) [M+H] calc. C H BrN O S 467.0389, found: 467.0383.
18
20
4
4
Ethyl 2ꢀaminoꢀ5ꢀ(3ꢀbromophenyl)imidazo[5,1ꢀb][1,3,4]thiadiazoleꢀ7ꢀcarboxylate (4f). Ethyl 2ꢀ(5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ
2
1
7
ꢀyl)acetate 1f (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A to give
. 1
50 mg (82%) of a yellow solid H NMR (400 MHz, DMSOꢀd ) δ 8.44 – 8.40 (m, 1H), 8.23 – 8.19 (m, 1H), 8.01 (s, 2H),
6
13
.64 – 7.59 (m, 1H), 7.51 – 7.45 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd6)
+
δ 166.0, 161.2, 135.1, 133.3, 131.3, 130.9, 130.8, 127.8, 124.5, 122.0, 119.0, 60.1, 14.4. HRMS (ESI) [M+H] calc.
C H BrN O S 366.9864, found: 366.9846.
1
3
12
4
2
2
ꢀaminoꢀ5ꢀ(3ꢀbromophenyl)ꢀN,Nꢀdimethylimidazo[5,1ꢀb][1,3,4]thiadiazoleꢀ7ꢀcarboxamide
(4g).
2ꢀ(5ꢀaminoꢀ1,3,4ꢀ
thiadiazolꢀ2ꢀyl)ꢀN,Nꢀdimethylacetamide 1g was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general proꢀ
1
cedure A but instead of room temperature was heated to 80 °C for 18 h to give 60 mg (33%) of a yellow solid. H NMR (500
MHz, DMSOꢀd ) δ 8.40 (t, J = 1.9 Hz, 1H), 8.20 (dt, J = 1.4, 7.9 Hz, 1H), 7.76 (s, 2H), 7.56 (dt, J = 1.5, 8.1 Hz, 1H), 7.45 (t,
6
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13
J = 7.9 Hz, 1H), 3.18 (s, 6H). C NMR (101 MHz, DMSOꢀd ) δ 166.8, 161.0, 133.1, 132.8, 131.3, 131.0, 130.9, 127.5,
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
24.5, 124.3, 122.1, 37.6, 36.1. HRMS (ESI) [M+H] calc. C H BrN OS 366.0024, found: 366.0019.
13
13
5
5
ꢀ(3ꢀbromophenyl)ꢀNꢀmethoxyꢀNꢀmethylimidazo[5,1ꢀb]thiazoleꢀ7ꢀcarboxamide (4h). NꢀmethoxyꢀNꢀmethylꢀ2ꢀthiazolꢀ2ꢀylꢀ
acetamide 1h (80 mg, 0.43 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A
1
but instead of room temperature was heated to 80 °C for 18 h to afford 85 mg (54%) of an offꢀwhite amorphous solid. H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (400 MHz, CDCl ) δ 8.03 – 7.98 (m, 1H), 7.80 (d, J = 4.3 Hz, 1H), 7.78 – 7.74 (m, 1H), 7.57 – 7.52 (m, 1H), 7.40 –
3
13
7
.33 (m, 1H), 7.10 (d, J = 4.2 Hz, 1H), 3.91 (s, 3H), 3.62 (s, 3H). C NMR (101 MHz, CDCl ) δ 162.6, 141.2, 136.3, 132.1,
3
+
1
32.0, 130.6, 129.7, 125.1, 124.2, 123.3, 120.0, 118.0, 61.9, 35.1. HRMS (ESI) [M+H] calc. C H BrN O S 365.9912,
14
13
3
2
found: 365.9908.
Ethyl 5ꢀ(3ꢀbromophenyl)ꢀ1ꢀmethylꢀ1Hꢀimidazo[1,5ꢀa]imidazoleꢀ7ꢀcarboxylate (4i). Methyl 2ꢀ(1ꢀmethylimidazolꢀ2ꢀ
yl)acetate hydrochloride 1i (0.45 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general proceꢀ
1
dure A to give 54 mg (34%) of an orange solid. H NMR (400 MHz, DMSOꢀd ) δ 8.05 – 8.01 (m, 2H), 7.91 – 7.87 (m, 1H),
6
7
3
5
.56 – 7.52 (m, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.47 – 7.41 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 1.32 (t, J = 7.1 Hz,
13
H). C NMR (101 MHz, DMSOꢀd ) δ 161.9, 142.4, 132.0, 131.1, 130.1, 127.8, 127.2, 126.9, 123.1, 122.3, 106.4, 104.6,
6
+
9.0, 35.1, 14.5. HRMS (ESI) [M+H] calc. C H BrN O 348.0348, found: 348.0342.
15
15
3
2
Ethyl 5ꢀ(3ꢀbromophenyl)ꢀ1Hꢀimidazo[5,1ꢀc][1,2,4]triazoleꢀ7ꢀcarboxylate (4j). Ethyl 2ꢀ(4Hꢀ1,2,4ꢀtriazolꢀ3ꢀyl)acetate 1j
(
0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (1.1 equiv) according to general procedure A to give 67 mg (40%) of a
1
yellow solid. H NMR (400 MHz, DMSOꢀd ) δ 8.74 (s, 1H), 8.41 – 8.35 (m, 1H), 8.25 – 8.17 (m, 1H), 7.59 – 7.52 (m, 1H),
6
13
7
.52 – 7.43 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 161.4, 147.3,
6
+
1
31.3, 131.1, 130.3, 127.2, 126.6, 123.2, 122.1, 102.7, 59.1, 14.6. HRMS (ESI) [M+H] calc. C H BrN O 335.0144,
13
12
4
2
found: 335.0138.
Ethyl 5ꢀ(3ꢀbromophenyl)imidazo[5,1ꢀb]benzo[d]thiazoleꢀ7ꢀcarboxylate (4k). Methyl 2ꢀ(benzo[d]thiazolꢀ2ꢀyl)acetate 1k
(
0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure B to give 130 mg (65%) of
1
a white solid. H NMR (400 MHz, DMSOꢀd ) δ 8.08 – 8.04 (m, 1H), 8.00 – 7.97 (m, 1H), 7.85 – 7.79 (m, 2H), 7.62 – 7.56
6
13
(
m, 1H), 7.51 – 7.41 (m, 2H), 7.39 – 7.35 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). C NMR (101 MHz,
DMSOꢀd ) δ 161.4, 139.3, 138.5, 133.0, 132.7, 132.0, 131.7, 131.5, 130.7, 128.1, 126.3, 126.1, 121.7, 121.2, 114.1, 59.9,
6
+
1
4.2. HRMS (ESI) [M+H] calc. C H BrN O S 400.9959, found: 400.9960.
18
14
2
2
Ethyl
5ꢀ(3ꢀbromophenyl)ꢀ1ꢀmethylꢀ1Hꢀbenzo[d]imidazole[1,5ꢀa]imidazoleꢀ7ꢀcarboxylate
(4l).
Ethyl
2ꢀ(1ꢀ
methylbenzimidazolꢀ2ꢀyl)acetate 1l was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A
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The Journal of Organic Chemistry
1
to give 108 mg (54%) of a white solid. H NMR (400 MHz, DMSOꢀd ) δ 8.00 – 7.97 (m, 1H), 7.88 – 7.84 (m, 1H), 7.74 –
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
4
.71 (m, 1H), 7.65 – 7.60 (m, 2H), 7.59 – 7.54 (m, 1H), 7.52 – 7.47 (m, 1H), 7.28 – 7.23 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H),
13
.12 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, DMSOꢀd ) δ 162.1, 144.3, 139.0, 132.2, 131.6, 131.0, 130.8,
6
+
130.1, 126.3, 125.3, 123.1, 121.8, 120.6, 112.1, 110.9, 104.9, 59.1, 31.4, 14.3. HRMS (ESI) [M+H] calc. C H BrN O
19
17
3
2
398.0504, found: 398.0499
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Methyl 1ꢀ(3ꢀbromophenyl)benzo[d]imidazo[5,1ꢀb]oxazoleꢀ3ꢀcarboxylate (4m). Methyl 2ꢀ(benzo[d]oxazolꢀ2ꢀyl)acetate 1m
(
1.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A to give 75 mg (13%) of a
1
white solid following reverse phase HPLC purification. H NMR (400 MHz, DMSOꢀd ) δ 8.05 – 8.02 (m, 1H), 7.94 – 7.88
6
13
(
m, 2H), 7.81 – 7.75 (m, 1H), 7.75 – 7.70 (m, 1H), 7.63 – 7.53 (m, 2H), 7.51 – 7.45 (m, 1H), 3.86 (s, 3H). C NMR (101
MHz, DMSOꢀd ) δ 161.1, 153.7, 152.5, 132.4, 131.9, 131.4, 131.3, 130.0, 126.7, 126.3, 126.3, 125.0, 124.8, 122.2, 113.4,
6
+
1
13.3, 104.8, 51.2. HRMS (ESI) [M+H] calc. C H BrN O 371.0031, found: 371.0026.
17
12
2
3
Methyl 6ꢀ(3ꢀbromophenyl)imidazo[1,5ꢀa]pyrimidineꢀ8ꢀcarboxylate (4n). Methyl 2ꢀ(2ꢀpyrimidyl)acetate 1n (0.5 mmol)
was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A to give 70 mg (42%) of a light yelꢀ
1
low solid. H NMR (400 MHz, DMSOꢀd ) δ 8.96 (dd, J = 7.3, 1.8 Hz, 1H), 8.65 – 8.59 (m, 1H), 8.07 – 8.01 (m, 1H), 7.95 –
6
13
7
.84 (m, 1H), 7.78 – 7.70 (m, 1H), 7.59 – 7.50 (m, 1H), 7.07 (dd, J = 7.3, 3.8 Hz, 1H), 3.87 (s, 3H). C NMR (101 MHz,
DMSOꢀd ) δ 162.0, 151.4, 140.8, 134.0, 132.1, 131.5, 130.9, 130.6, 130.5, 126.9, 122.0, 119.1, 110.3, 50.8. HRMS (ESI)
6
+
[
M+H] calc. C H BrN O : 332.0035, found: 332.0029.
14
11
3
2
Methyl 3ꢀ(3ꢀbromophenyl)imidazo[1,5ꢀa]pyrazineꢀ1ꢀcarboxylate (4o). Methyl 2ꢀpyrazineacetate 1o (0.5 mmol) was reactꢀ
1
ed with 3ꢀbromobenzylamine 2a (1.1 equiv) according to general procedure B to give 120 mg (72%) of a white solid. H
NMR (400 MHz, DMSOꢀd ) δ 9.52 (d, J = 1.7 Hz, 1H), 8.59 (dd, J = 5.0, 1.6 Hz, 1H), 8.07 – 8.05 (m, 1H), 7.95 – 7.91 (m,
6
13
1
1
H), 7.90 (d, J = 5.0 Hz, 1H), 7.81 – 7.77 (m, 1H), 7.60 – 7.55 (m, 1H), 3.95 (s, 3H). C NMR (101 MHz, DMSOꢀd ) δ
6
+
62.1, 146.0, 138.0, 132.7, 131.2, 130.9, 130.6, 130.2, 128.7, 127.3, 124.5, 122.2, 116.3, 51.7. HRMS (ESI) [M+H] calc.
C H BrN O : 332.0035, found: 332.0030.
1
4
11
3
2
Methyl 3ꢀ(3ꢀbromophenyl)ꢀ5ꢀmethoxyimidazo[1,5ꢀc]pyrimidineꢀ1ꢀcarboxylate (4p). Methyl 2ꢀ(2ꢀmethoxypyrimidinꢀ4ꢀ
yl)acetate 1p (0.27 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A to give 80
1
mg (81%) of a light yellow solid. H NMR (400 MHz, DMSOꢀd ) δ 7.94 – 7.90 (m, 1H), 7.74 – 7.68 (m, 2H), 7.65 (d, J =
6
13
6
1
.4 Hz, 1H), 7.60 (d, J = 6.4 Hz, 1H), 7.47 – 7.40 (m, 1H), 3.96 (s, 3H), 3.87 (s, 3H). C NMR (101 MHz, DMSOꢀd ) δ
6
+
62.7, 147.8, 138.5, 137.6, 137.2, 133.3, 133.1, 131.6, 129.5, 129.3, 120.9, 120.3, 106.5, 55.6, 51.3. HRMS (ESI) [M+H]
calc. C H BrN O 362.0140, found: 362.0135.
15
13
3
3
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Methyl 3ꢀ(3ꢀbromophenyl)ꢀ6ꢀchloroimidazo[1,5ꢀa]pyrazineꢀ1ꢀcarboxylate (4q). Methyl 2ꢀ(5ꢀchloropyrazinꢀ2ꢀyl)acetate 1q
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (1.1 equiv) according to general procedure B to give 120 mg (65%) of
1
a white solid. H NMR (400 MHz, DMSOꢀd ) δ 9.51 (s, 1H), 8.02 (s, 1H), 7.91 – 7.89 (m, 1H), 7.80 – 7.76 (m, 1H), 7.71 –
6
13
7.67 (m, 1H), 7.50 – 7.45 (m, 1H), 3.95 (s, 3H). C NMR (101 MHz, DMSO) δ 161.8, 144.5, 139.0, 133.7, 132.7, 132.6,
+
130.8, 130.3, 130.0, 129.4, 124.6, 121.8, 120.4, 51.9. HRMS (ESI) [M+H] calc. C H BrClN O 365.9645, found:
14
10
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
365.9639.
ꢀ(tertꢀbutyl) 7ꢀmethyl 9ꢀ(3ꢀbromophenyl)ꢀ3,4ꢀdihydroimidazo[1,5ꢀa][1,8]naphthyridineꢀ1,7(2H)ꢀdicarboxylate (4r). (8ꢀ
1
Bocꢀ5,6,7,8ꢀtetrahydroꢀ[1,8]naphthyridinꢀ2ꢀyl)ꢀacetic acid methyl ester 1r (0.5 mmol) was reacted with 3ꢀbromobenzylamine
1
2
8
1
a (2.0 equiv) according to general procedure B to give 170 mg (70%) of a white solid. H NMR (400 MHz, DMSOꢀd ) δ
6
.01 (d, J = 9.0 Hz, 1H), 7.72 (s, 1H), 7.61 – 7.53 (m, 2H), 7.38 – 7.31 (m, 1H), 7.19 (d, J = 9.1 Hz, 1H), 4.16 – 4.05 (m,
13
H), 3.87 (s, 3H), 3.49 – 3.36 (m, 1H), 2.93 – 2.84 (m, 1H), 2.81 – 2.70 (m, 1H), 2.06 – 1.85 (m, 2H), 1.02 (s, 9H). C NMR
(
101 MHz, DMSOꢀd ) δ 163.6, 152.2, 138.5, 136.7, 133.8, 132.8, 132.1, 131.2, 129.2, 128.2, 121.0, 120.6, 118.7, 115.8,
6
+
81.8, 51.3, 45.0, 27.8, 24.9, 23.0. HRMS (ESI) [M+H] calc. C H BrN O 486.1028, found: 486.1010.
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3
4
Methyl 7ꢀ(3ꢀbromophenyl)imidazo[1,5ꢀb]pyridazineꢀ5ꢀcarboxylate (4t). Methyl pyridazinꢀ3ꢀylꢀacetate 1t (0.5 mmol) was
1
reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure B to give 130 mg (78%) of a white solid. H
NMR (400 MHz, DMSOꢀd ) δ 8.68 (d, J = 4.2 Hz, 1H), 8.61 – 8.50 (m, 2H), 8.41 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.9 Hz,
6
13
1
1
3
H), 7.57 – 7.48 (m, 1H), 7.27 (dd, J = 9.3, 4.4 Hz, 1H), 3.92 (s, 3H). C NMR (101 MHz, DMSOꢀd ) δ 162.3, 146.5, 137.9,
6
+
31.9, 130.8, 130.6, 129.9, 129.7, 128.0, 126.4, 121.7, 120.8, 117.7, 51.5. HRMS (ESI) [M+H] calc. C H BrN O :
14
11
3
2
32.0035, found: 332.0029. Intermediate 4t was previously synthesized and claimed in a patent (reference 1d) but no characꢀ
terization data was reported.
Ethyl 2ꢀ(((1ꢀmethylꢀ1Hꢀpyrazolꢀ4ꢀyl)methyl)imino)ꢀ2ꢀ(thiazolꢀ2ꢀyl)acetate (5). Ethyl 2ꢀ(thiazolꢀ2ꢀyl)acetate 1a (0.5 mmol,
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0 mg) was reacted with (1ꢀmethylpyrazolꢀ4ꢀyl)methanamine 2k (2.0 equiv, 110 mg) according to general procedure A to
1
give 70 mg (51% yield) of a white solid (E/Z geometry was not determined). H NMR (400 MHz, CDCl ) δ 7.93 (d, J = 3.2
3
Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.37 (s, 1H), 4.66 (s, 2H), 4.51 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.42 (t, J =
13
7
.1 Hz, 3H). C NMR (101 MHz, CDCl ) δ 165.5, 163.4, 155.6, 144.3, 138.7, 129.3, 122.4, 117.9, 62.3, 49.2, 39.0, 14.3.
3
+
HRMS (ESI) [M+H] calc. (C H N O S): 279.0916, found: 279.0919.
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4
2
2
ꢀ(5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀyl)ꢀ2ꢀ((3ꢀbromobenzyl)amino)ꢀN,Nꢀdimethylacetamide (6). 2ꢀ(5ꢀaminoꢀ1,3,4ꢀthiadiazolꢀ2ꢀ
yl)ꢀN,Nꢀdimethylacetamide 1g (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general proceꢀ
1
dure A to give 80 mg (43%) of an offꢀwhite solid. H NMR (400 MHz, DMSOꢀd ) δ 7.57 – 7.52 (m, 1H), 7.46 – 7.41 (m,
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H), 7.34 – 7.24 (m, 2H), 7.11 (s, 2H), 4.88 (d, J = 9.1 Hz, 1H), 3.70 – 3.64 (m, 2H), 3.21 – 3.11 (m, 1H), 2.98 (s, 3H), 2.85
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(
s, 3H). C NMR (101 MHz, DMSOꢀd ) δ 169.2, 169.0, 159.1, 143.0, 130.6, 130.3, 129.6, 127.0, 121.6, 57.0, 50.0, 36.5,
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+
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5.4. HRMS (ESI) [M+H] calc. C H BrN OS 370.0337, found 370.0334.
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5
(1ꢀ(3ꢀBromophenyl)ꢀ4ꢀmethylꢀ4Hꢀbenzo[d]imidazo[1,5ꢀa]imidazolꢀ3ꢀyl)(phenyl)methanone (4u) and 2ꢀ(3ꢀbromophenyl)ꢀ
4ꢀ(1ꢀmethylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ5ꢀphenyloxazole (7). 2ꢀ(1ꢀMethylbenzimidazolꢀ2ꢀyl)ꢀ1ꢀphenylꢀethanone 1u (0.46
mmol) was reacted with 3ꢀbromobenzylamine 2a (2.0 equiv) according to general procedure A, followed by trituration from
a mixture of MeOH/DCM for the ketone product, to give 4u, 43 mg (22%) of a yellow solid, and 7, 88 mg (44%) of a white
solid.
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Data for (4u):
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H NMR (500 MHz, DMSOꢀd ) δ 8.28 – 8.23 (m, 2H), 8.05 (t, J = 1.9 Hz, 1H), 7.93 (dt, J = 1.3, 7.8 Hz, 1H), 7.77 (ddd, J =
6
0
.9, 2.1, 7.9 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.62 – 7.50 (m, 5H), 7.34 (ddd, J = 1.1, 7.4, 8.4 Hz,
13
1
H), 4.33 (s, 3H). C NMR (101 MHz, DMSO) δ 184.0, 146.0, 139.0, 138.8, 132.1, 132.0, 131.1, 131.0, 131.0, 130.3, 130.0,
+
1
27.7, 126.8, 125.6, 123.1, 122.0, 121.4, 115.5, 112.4, 111.6, 32.2. HRMS (ESI) [M+H] calc. C H ON Br: 430.0550,
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3
found: 430.0541.
Data for (7):
1
H NMR (500 MHz, DMSOꢀd ) δ 8.36 (t, J = 1.9 Hz, 1H), 8.21 (dt, J = 1.3, 7.8 Hz, 1H), 8.19 – 8.15 (m, 2H), 7.90 – 7.80
6
(
m, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.53 – 7.44 (m, 3H), 7.38 (ddd, J = 1.2,
13
7
1
.1, 8.2 Hz, 1H), 7.34 – 7.26 (m, 1H), 3.98 (s, 3H). C NMR (126 MHz, DMSOꢀd ) δ 158.3, 150.8, 145.5, 142.6, 136.4,
6
34.4, 132.0, 130.3, 129.3, 129.2, 128.7, 127.8, 127.3, 127.0, 125.9, 123.6, 122.9, 122.8, 119.9, 111.1, 31.9. HRMS (ESI)
+
[
M+H] calc. C H ON Br: 430.0550, found: 430.0547.
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3
13ꢀ((3ꢀbromobenzyl)amino)benzo[4,5]thiazolo[3,2ꢀa]benzo[4,5]thiazolo[3,2ꢀd]pyrazineꢀ6ꢀcarbonitrile
(8).
2ꢀ(1,3ꢀ
benzothiazolꢀ2ꢀyl)acetonitrile 1v (0.5 mmol) was reacted with 3ꢀbromobenzylamine 2a (1.1 equiv) according to general proꢀ
cedure B to give 100 mg of a yellow solid containing 8 and an inseparable unknown byꢀproduct in a 6.7:1 molar ratio for a
1
4
0% combined yield. H NMR (500 MHz, DMSOꢀd ) δ 11.53 (t, J = 6.4 Hz, 1H), 8.32 (dd, J = 8.0, 1.3 Hz, 1H), 8.26 – 8.22
6
(
m, 1H), 8.12 (dd, J = 8.2, 1.2 Hz, 1H), 7.95 (dd, J = 8.0, 0.9 Hz, 1H), 7.69 (td, J = 8.1, 7.7, 1.4 Hz, 1H), 7.64 (ddd, J = 8.6,
.2, 1.3 Hz, 1H), 7.56 (ddd, J = 8.3, 7.4, 1.4 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.46 – 7.41 (m, 1H), 7.34 – 7.28 (m, 2H), 4.66 (d,
7
13
J = 6.4 Hz, 2H). C NMR (126 MHz, DMSOꢀd ) δ 164.9, 157.2, 155.5, 152.6, 152.1, 140.3, 135.6, 131.9, 130.8, 130.4,
6
+
1
30.0, 127.3, 127.1, 126.8, 126.2, 125.0, 124.1, 123.0, 122.2, 121.8, 121.3, 118.7, 77.3, 48.1. HRMS (ESI) [M+H] calc.
C H BrN S 503.0000, found: 502.9994.
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Typical experimental procedure and characterization for all products. (PDF)
AUTHOR INFORMATION
Corresponding Author
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Email: castanedo.georgette@gene.com
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
The Authors would like to thank Steven T. Staben for helpful chemistry discussions and Baiwei Lin and Kewei Xu for
HRMS data.
REFERENCES
1
(
a) Roberts, L.; Bradley, P.; Bunnage, M.; England, K.; Fairman, D.; Fobian, Y.; Fox, D.; Gymer, G.; Heasley, S.; Molette,
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A.; Narayana, L.; Raje, F.; Pisal, D.; Kadam, P.; Gullapalli, S.; Kumar, H.; More, S.; Bajpai, M.; Sangana, R.; Jadhav, S.;
Gudi, G.; KhairatkarꢀJoshi, N.; Merugu, R.; Voleti, S.; Gharat, L. Bioorg. Med. Chem. Lett. 2013, 23, 6747. (d) Blaquiere, N.;
Burch, J.; Castanedo, G.; Feng, J.; Hu, B.; Staben, S.; Wu, G.; Yuen, P. WO Patent 25025 A1, 2015. (e) Quattropani, A.;
Swinnen, D. US Patent 175628 A1, 2013.
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Mohan, D.C.; Rao, S.N.; Ravi, C.; Adimurthy, S. Org. Biomol. Chem. 2015, 13, 5602.
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(
a) Sycheva, T.; Pankina, Z.; Shchukina, M. Khim. Geterotsikl. Soedin. 1970, 6, 440. (b) Aryuzina, V.; Shchukina, M. Khim.
Geterotsikl. Soedin. 1970, 6, 525. (c) Avidon, V.; Shchukina, M. Khim. Geterotsikl. Soedin. 1968, 4, 719. (d) Qiu, G.; Wu, J.
Chem. Comm. 2012, 48, 6046. (e) Bluhm, M.E.; Ciesielski, M.; Gorls, H. Doring, M. Angew. Chem. Int. Ed. 2002, 41, 2962.
(f) Wang, J.; Li, J.; Zhu, Q. Org. Lett. 2015, 17, 5336.
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With methyl 2ꢀ(pyrazinꢀ2ꢀyl)acetate as a test substrate purity enhancements were seen by LCMS when the order of
addition was changed from adding solvent last to all reagents, to adding catalyst /oxidant last to heteroaromatic
substrate/amine/DMA.
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In cases where isolation and purification by trituration was not possible, compounds were isolated by silica gel column
chromatography.
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No formation of aryl iodide was observed during reaction monitoring by LCMS.
A previous report (ref 8) hypothesized that steric hinderance was why 2ꢀmethoxybenzylamine did not work in the reaction.
Zhao, D.; Wang, T.; Shen, Q.; Li, JꢀX. Chem. Commun. 2014, 50, 4302.
Unless otherwise noted, yields were not optimized.
White, J.; Tunoori, A.; Georg, G. J. Am. Chem. Soc. 2000, 122, 11995.
(
a) Wiley, D.W.; Webster, O.W.; Blanchard, E.P. J. Org. Chem. 1976, 41, 1889. (b) Meguro, K.; Kuwada, Y. Heterocycles
974, 2, 335. (c) Middleton, W.J.; Metzger, D. J. Org. Chem. 1970, 55, 3985. (d) the other possible triazole nitrogen regioiꢀ
somer was observed in very minor amounts but was not isolated.
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Catalan, J.; Elguero, J. J. Het. Chem. 1984, 21, 269.
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Katritzky, A.R.; Pozharski, A.F. Handbook of Heterocyclic Chemistry, 2nd Edition, Pergamon/Elsevier, 2000, pp. 177,
77, 379.
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Tran, T.; Patel, N.; Samas, B.; Schwarz, J. Org. Biomol. Chem. 2009, 7, 5063. Imidazo[5,1ꢀb][1,3,4]oxadiazoles in this
paper and in reference 1e have a Cꢀ2 substituent.
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Imidazo[1,5ꢀa]pyridines and one imidazo[1,5ꢀa]pyrimidine could be accessed with prior oneꢀpot methods (ref 5,6,7,8).
Compounds 5 and 6 were also resubjected to the reaction conditions (heated to 80 °C from the beginning since 3k and 4g
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are not formed at room temp) following isolation, to afford clean conversion to products 3k and 4g.
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Chen, Z.; Li, H.; Dong, W.; Miao, M.; Ren, H. Org. Lett. 2016, 18, 1334.
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Complex fragmentation patterns suggesting possible dimers were observed by LCMS for reactions involving heteroaroꢀ
matic substrates (1i, 1j, 1n, 1o, 1q and 1v). We isolated a dimer in one case (example 8) as 4v was not seen and 8 was the
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major byꢀproduct. In other cases where the product was one of the major peaks by LCMS (4i, 4j, 4n, 4o and 4q), we attribute
reduced yields to these dimers. The reduction of amine equivalents from 2 to 1.1 worked well to reduce dimer formation for
isolation of 4j, 4o and 4q but did not appear to make a difference for 4i and 4n. All attempts to isolate and characterize any
other putative dimers observed by LCMS via silica gel chromatography were unsuccessful.
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