Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes

Article abstract of DOI:10.1021/acs.joc.8b01840

A mild, general, and highly efficient catalytic etherification protocol for chloroheteroarenes was developed using the Pd/PTABS catalytic system. The protocol is selective for the etherification of chloroheteroarenes using a large variety of electron-rich and electron-deficient phenol bearing synthons which include inter alia biologically and commercially important estrone, estradiol, tyrosine, and several other molecules. The mildness of the new protocol is expected to be beneficial for the synthesis of complex drugs and drug intermediates offering late-stage modification of bioactive compounds.

Full text of DOI:10.1021/acs.joc.8b01840

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Article
Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes
Shatrughn Bhilare, Siva Sankar Murthy Bandaru, Jagrut Shah, Nicolas
Chrysochos, Carola Schulzke, Yogesh S. Sanghvi, and Anant R. Kapdi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01840 • Publication Date (Web): 08 Oct 2018
Downloaded from http://pubs.acs.org on October 8, 2018
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Pd/PTABS: Low Temperature Etherification of
Chloroheteroarenes
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a
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Shatrughn Bhilare ,Siva Sankar Murthy Bandaru , Jagrut Shah , Nicolas Chrysochos , Carola
b
c
a,*
Schulzke , Yogesh S. Sanghvi, Anant R. Kapdi
aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh road, Matunga,
Mumbai-400019, India.
bInstitut für Biochemie,Ernst-Moritz-Arndt Universität Greifswald,Felix-Hausdorff-Straße 4,D-
1
7487 Greifswald, Germany
c
Rasayan Inc., 2802 Crystal Ridge Road, Encinitas CA 92024-6615, U. S. A.
KEYWORDS Low Temperature, Etherification, Palladium-Catalyzed, ChloroHeteroarenes,
PTABS.
Graphical abstract
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ABSTRACT: A mild, general and highly efficient catalytic etherification protocol for
chloroheteroarenes has been developed using the Pd/PTABS catalytic system. The protocol is
selective for the etherification of chloroheteroarenes using a large variety of electron-rich and
electron-deficient phenol bearing synthons which include inter alia biologically and
commercially important estrone, estradiol, tyrosine and several other molecules. The mildness of
the new protocol is expected to be beneficial for the synthesis of complex drugs and drug
intermediates offering late-stage modification of bioactive compounds.
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1. Introduction
The etherification of heteroarenes is an important synthetic methodology due to the frequent
occurrence of diaryl ether linkages in naturally occurring bioactive molecules and
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pharmaceutical drugs such as Sorafenib , AMG 900 , anti-tumor agent XK469 , herbicide such
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as Bispyribac-Sodium and several others (Scheme 1A). The significance associated with this
methodology has provided researchers with an increased impetus for the development of
efficient metal-mediated routes for accessing these prized structural motifs. Copper-catalyzed
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Ullmann and Chan-Lam-Evans-type diaryl etherification protocols are well known, though,
less attractive commercially due to the employment of stoichiometric amounts of copper as well
as expensive boron reagents. Low to moderate yields associated with these transformations have
further limited their utility and challenged researchers to develop more efficient, e.g. palladium-
catalyzed etherification protocols.
The coupling of aryl halides (I, Br or Cl) with phenols has been explored extensively by
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researchers including Buchwald , Olofsson , Hierso and Beller . Several sterically hindered
and electron-rich phosphines have been used as ligands in combination with common palladium
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precursors to facilitate etherification reactions. The possibility of using aryl silanes or stannanes
as coupling partners has further fueled respective studies and improved their versatility.
However, most of these protocols allow the formation of diaryl ethers (via coupling of Ar-X and
phenols) while only a handful procedures are known which allow heteroaryl halides to be
employed as coupling partners (Scheme 1B).7a-b, 9 The importance of using the latter, though, is
evident from their occurrence in a variety of naturally occurring bio-active molecules and
pharmaceutical drugs. Recently, Yamaguchi and co-workers have reported the decarbonylative
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diaryl ether formation under Pd or Ni catalytic conditions. Besides providing the desired diaryl
ethers most of these protocols suffer from various process limitations such as high reaction
temperature requirements, limited substrate scope and employment of expensive ligands often
accompanied by only moderate yields. Difficulties in overcoming such challenges have impeded
wider application of these protocols.
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Scheme 1: A) Drugs containing ether linkages B) Previous reports C) This work: Etherification of
chloroheteroarenes.
To address and overcome the above described limitations, we provide herein a sustainable
catalytic solution with a low temperature etherification protocol for chloroheteroarenes utilizing
a simple phosphatriazene ligand (PTABS- Phosphatriazene butane sulfonate). The method
exhibits a large substrate scope (utility of the protocol demonstrated with >50 examples),
providing the possibility of post-synthetic modifications of bioactive compounds and facilitates
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the synthesis of an anti-tumor agent, XK469 (Scheme 1C). The developed protocol is superior to
the existing etherification procedures available in literature and makes use of a bench stable Pd
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catalyst system which is easy to synthesize. The inspiration for the current work came from our
previous results in the employment of the PTA based complexes14a-e and Pd/PTABS catalytic
system14f for the coupling of nucleosides under aqueous conditions and the room temperature
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amination of chloroheteroarenes .
2. Results and Discussion
First, the coupling of, 2-chloropyrazine (1a) with 4-methoxyphenol (2a) was attempted using
Pd/PTABS [Pd(OAc)
2
1.0 mol%, PTABS 2.0 mol%] in DMF with Et N employed as the base at
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o
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0 C providing <5% of the desired ether (Table 1, Entry 1). To assess the effect of the added
base, the catalytic etherification reactions were performed with stronger inorganic bases such as
NaOH, K CO and K PO . The reaction solvent was also found to play an important role as polar
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aprotic solvents such as DMF or Acetonitrile (MeCN) provided higher yields of the product
while non polar solvents such as toluene gave poor yields (Table 1, Entries 5-7). Only <5% of
the coupled product could be obtained with water as the sole reaction solvent most likely due to
the poor solubility of the starting material in this medium.
The temperature was also found to affect the outcome of the catalytic reaction. Although
o
identical reactivity was observed at 80 C (Table 1, Entry 8), performing the catalytic reaction at
o
more ambient temperature (30 C) led to lower catalytic activity and yield. The optimum
concentration of catalyst components resulting in maximum yield was found to be 1.0 mol% Pd
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and 2.0 mol% PTABS. Although as a comparison to the previous reported etherification
methods, Pd/PTABS system at lower catalytic concentration was assessed at slightly elevated
o
temperature of 100 C. It was found that at such elevated temperatures the catalytic activity of
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our system was high allowing the reduction of catalyst concentration to 0.1 mol% (better than
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.2 mol% achieved by Hierso and co-workers ). The extent of the reactivity enhancement of
PTABS for the etherification of chloroheteroarenes versus other known and commonly used
ligand systems was evaluated comparing the yields under otherwise identical conditions.
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Commercially available phosphine ligands such as PPh
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, P(o-Tol) , X-Phos, S-Phos as well as N-
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heterocyclic carbene ligands like IMes.HCl and IPr.HCl were tested (Table 1, Entries 17-22). In
all cases including the highly electron-rich phosphines and N-heterocyclic carbenes, only minor
amount of the desired product could be observed reaffirming the versatility and exceptional
capability of the PTABS ligand system in catalyzing the transformation.
Table 1: Optimization of the Reaction Conditions.
Catalyst loading
o
a
Entry
Ligand
(mol%)
Pd:Ligand)
1.0:2.0
Base (equiv.)
Solvent
Temp. ( C)
Yield (%)
(
1
2
PTABS
PTABS
NEt
NaOH
CO
PO
3
DMF
DMF
60
<5%
<5%
1.0:2.0
60
3
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7
8
9
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
0.1:0.2
0.5:1.0
0.5:1.0
0.2:0.4
0.1:0.2
0.01:0.02
K
2
3
DMF
DMF
MeCN
toluene
60
60
60
60
60
80
30
60
60
100
100
100
100
20
90
75
<5%
<5%
90
65
20
45
98
K
3
4
K
K
K
K
K
K
K
K
K
K
K
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
H
2
O
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1
1
1
1
0
1
2
3
97
99
72
14
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PTABS
PPh
P(o-Tolyl)
XPhos
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
1.0:2.0
K
K
K
K
K
K
K
K
K
3
3
3
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
4
4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
60
60
60
60
60
60
60
60
60
85
<5%
25
<5%
<5%
38
41
66
81
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SPhos
1
2
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4
IMes.HCl
IPr.HCl
PTA
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PTAMeI
Reaction conditions: 1.0 mmol of 1a, 1.5 mmol of 2a, 1.0 mol% of Pd(OAc)
2
and PTABS 2.0
a
mol%,3.0 mL of solvent, reaction time 2 hours under N
2
atmosphere unless stated otherwise,
isolated yields.
The employment of the parent PTA as well as methyl substituted PTA (PTAMeI) failed to
provide comparable yields to that of PTABS (Table 1, entries 22,23). A rationale for the
enhanced activity of PTABS compared to other PTA analogues points towards the activating
influence of the substitution on the nitrogen atom of the parent PTA as well as the chain length
and anionic counterpart. Further studies will be needed to ascertain the given assumption with
DFT playing a crucial role in determining the exact influence of substituent’s and electronics on
the donation capacity of phosphorus atom in different PTA ligands, which will be reported at a
later stage as it falls outside the purview of this manuscript.
With such a highly active catalytic system in hand, the substrate scope for the palladium-
catalyzed diaryl ether synthesis was investigated (Scheme 2). It was decided to test the catalytic
system for 5 different chloroheteroarenes: 2-chloropyrazine, 2-chloro benzothiazole, 2-chloro
benzoxazole, 2-chloroquinoxaline and 7-chloro-4-(pentyloxy)pteridin-2-amine for ascertaining
the extent of the utility. Initially, simple aromatic phenols such as 4-methoxyphenol, 4-tert-
butylphenol and few others were employed as the nucleophilic coupling partners.
As a general trend, it could be observed that the employment of electronically activated phenols
(
OMe or tBu as electron-releasing substituents) provided good to excellent yields of the
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etherification product irrespective of the chloroheteroarene (Scheme 2). Even sterically
demanding 2,4,6-trimethylphenol as substrate was well tolerated without any loss in reactivity
(Scheme 2, 3l). Electronically neutral phenol as well as several electronically deactivated
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phenols (3-NO
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, 2-CHO, 4-F, 4-CO Me) were also well tolerated, furnishing good to excellent
2
yields of the etherified product. Pentafluoro phenol is an essential pharmacophore of high
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biological relevance and therefore a desirable coupling partner. The reactivity of this phenol as
synthon, though, was found to be comparably lower due to the deactivating nature of the fluoro
substituents (Scheme 2, 3r).
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Scheme 2: Substrate scope for palladium-catalyzed etherification of chloroheteroarenes with
diverse substituted arylphenols.
The catalytic efficiency and the mild nature of Pd/PTABS were further demonstrated by
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performing a chemoselective etherification procedure using 1-bromo-2-naphthol as coupling
partner (Scheme 2, 3u & 3v) which did not lead to bromine induced homocoupling. This
selectivity for the activation of the C–Cl over the C–Br bond by the catalytic system provides a
useful handle for further functionalization. The selectivity towards chloro functionality has been
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attributed to the possible coordination of the Pd-PTABS system to the nitrogen atom next to the
chlorine atom directing it activation of C-Cl bond which is also more active due to the
electronics on the heteroaromatic ring systems. It has also been observed that activation of C-Cl
in 3rd position with regards to N atom does not occur. Some of the compounds synthesized were
crystallized using suitable solvent to obtain single crystals allowing their characterization via x-
ray analysis (3j, 3k, 3l, 3n and 3r).
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Given the success of the Pd/PTABS system with relatively simple phenols, we further explored
the possibility of using benzylic alcohols as well as heteroaromatic phenols as coupling partners
(Scheme 3A, 4a-g). Good to excellent yields of the coupled products were obtained despite of a
free-NH function in the case carbazole (4g).
With such a large substrate scope, efficiently allowing aromatic and heteroaromatic phenols to be
readily coupled under the optimized conditions at relatively lower temperature, the Pd/PTABS
etherification protocol was further envisioned to be beneficial for molecules bearing temperature
sensitive functional groups and having commercial or pharmaceutical relevance. Eugenol with its
1
8
extensive usage as an essential oil, in perfumery applications as well as a local anesthetic was
first chosen as a challenging candidate synthon for trying the etherification methodology. The
etherification of eugenol was performed with three different chloroheteroarenes namely, 2-
chlorobenzothiazole, 2-chloropyrazine and 2-chloro quinoxaline furnishing the respective
products in excellent yields (Scheme 3B, 5a-c). The lability of the allyl functional group under
1
9
typical metal-mediated conditions is well known; the mild nature of the new protocol, however,
allowed the allyl group to be left unaffected. Another molecule of importance is the most
commonly used pain reliever, paracetamol (acetaminophen) which was next to be coupled with
four different chloroheteroarenes resulting in good to excellent yields (Scheme 3B, 5d-g).
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20
Tyrosine as particularly challenging substrate with high biological relevance is a non-essential
amino acid involved in protein synthesis. It was selected for etherification testing with 2-
chlorobenzoxazole. The present free NH group as part of the tyrosine structure has similar
2
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reactivity to the phenolic-OH and therefore rather than obtaining the selectively etherified
product, the bis-arylation product of tyrosine was observed as the major component (the
etherification product was obtained in significantly lower quantity of <5%; Scheme 3B, 5h).
With a unique structural feature involving four fused carbocyclic rings, steroids are perhaps
amongst the most widely applicable drugs for anesthetic usage besides their significance as
2
1
hormones. Estrone and estradiol are two such hormones with useful biological properties and
several stereogenic centers that were next selected for coupling with different
chloroheteroarenes. Even in these cases, the Pd/PTABS catalytic system was successful in
providing very high yields of the coupled products (Scheme 3B, estrone: 5i-k, estradiol: 5l). A
similar success was accomplished for δ-tocopherol as synthon, which represents the orally
available δ form of essential vitamin E as well as possessing promising anti-oxidant properties.
The palladium/PTABS-catalyzed etherification of 5-chlorobenzoxazole with δ-tocopherol
proceeded smoothly providing the coupled product in good yield (Scheme 3B, 5m).
All results described above point towards the mild yet powerful nature of the novel catalytic
system which not only allows the coupling to take place at significantly lower reaction
temperature than the ones currently reported in literature but also provides ideal conditions for
the late-stage modification of commercially and pharmaceutically useful compounds generating
new leads for drug discovery.
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Scheme 3: Substrate scope for palladium-catalyzed etherification of chloroheteroarenes with
diverse substituted heteroarylphenols (A) and pharmaceutically relevant phenols (B).
Regioselectivity in catalytic processes is an important and sought-after synthetic trait for the
selective functionalization, i.e. tailored modification of substrates. The selective
functionalization of polyhalogenated heteroarenes is therefore advantageous and in recent years
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has been more extensively accomplished using palladium-catalyzed cross-coupling reactions.22
To investigate whether the described Pd/PTABS catalyst system would foster selectivity, the
mono-etherification of 2,4-dichloropyrimidine was tested with four different phenols being 4-
tert-butylphenol, 4-methoxyphenol, 8-hydroxyquinoline, thymol and estrone (Scheme 4, 7a-e).
Some of the compounds synthesized were crystallized using suitable solvent to obtain single
crystals allowing their characterization via x-ray analysis (7b-d).
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Scheme 4: Mono-selective etherification
In each investigated case, the mono-etherification (selective towards the activation of the 4-Cl
position) gave the major mono-ether product in good to excellent yield with a limited amount of
di-etherification side product. To promote di-etherification specifically, an excess of the phenol
synthons (4-methoxyphenol and estrone) resulted in excellent yield for 4-methoxyphenol while
most likely steric effects reduced the product yield for estrone to 56% (Scheme 4, 8a-b).
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Nucleosides comprise another example of biologically important molecules with a variety of
23a-c
applications. The four naturally occurring bases in the the 2ꞌ-deoxynucleosides exhibit only low
fluorescence quantum yields and therefore, to enhance their applicability as fluorescent DNA
probes, palladium-catalyzed coupling processes to attach or generate fluorophores have been
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23d
extensively studied. 6-Chloro-9-β-D-ribofuranosyl-purine (9) for instance is one such substrate
that has attracted a lot of attention in the respective synthetic community.
Scheme 5: Synthesis of 6-alkoxy functionalized purine
The mild and efficient nature of the developed Pd/PTABS catalytic system allows the coupling
of the ribose nucleoside without the requirement of any form of protection of the sugar hydroxyl
groups, providing the 6-phenoxy-9-β-D-ribofuranosyl-purine products with four different
phenols in appreciable yields (Scheme 5, 10-d).
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Scheme 6: Tandem catalytic processes using the Pd/TPABS system
Improving sustainability in synthesis is an important trait with which various environmental
problems including waste generation and management are addressed. Tandem catalytic processes
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involving the combination of two or several catalytic reactions (either with a single catalyst or
multi-catalyst systems) in a single pot procedure without the isolation of the intermediates has
24
come forth as a sustainable solution for waste reduction. It provides multiple advantages over
multi-step synthesis such as lower solvent usage for synthesis and purification, probable
reduction in by-product formation and overall better efficiency. The Pd/PTABS catalytic system
was, hence, tested for tolerating the combination of the etherification procedure with other
catalytic processes giving access to functionalized molecules with improved synthetic
applicability (Scheme 6).
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A double tandem strategy was applied starting with the Pd/PTABS catalyzed etherification of 2-
chlorobenzothiazole with 4-bromophenol activating chemoselectively the C–Cl bond and
yielding 2-(4-bromophenoxy)benzothiazole (not isolated) bearing a handle for further
functionalization.
The
Sonogashira
alkynylation
of
the
resultant
2-(4-
bromophenoxy)benzothiazole with three different alkynes was enabled by introducing the Pd/X-
Phos catalytic system providing highly functionalized 2-(4-(arylethynyl)phenoxy)benzothiazoles
in good yields (Scheme 6A, 11a-d). The success achieved with this double tandem procedure
demonstrates the excellent compatibility of the Pd/PTABS catalytic system, which can readily be
coupled with other catalysts (in this case Pd/X-Phos) with no interference. The next accepted
challenge was to incorporate another catalytic system utilizing a different metal as part of the
one-pot reaction sequence. This was achieved while changing the alkyne synthon from simple
arylacetylenes to 5-ethynyl-2ꞌ-deoxyuridine, which itself is a useful 2ꞌ-deoxyuridine analog for
25
Click chemistry. First, the procedure applied to the installation of the alkyne was identical to
the double tandem procedure discussed vide supra. This was followed by a copper-mediated
cyclization strategy involving coordination of copper to the alkyne and the subsequent
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isomerization of the amide to an imino-alcohol. Finally the nucleophilic attack of the alcohol on
the electron-deficient alkyne furnished the cyclized product as a highly fluorescent furo-
2
6
pyrimidine analog in good yield (Scheme 6B, 13).
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Scheme 7: Palladium-catalyzed etherification for the synthesis of XK469 (anti-tumor agent).
To demonstrate the synthetic potential of the new catalytic system for the preparation of
molecules of commercial relevance, the synthesis of an anti-tumor agent (XK469) was
attempted. The XK469 is a quinoxaline phenoxypropionic acid derivative the R enantiomer of
which is capable of inducing reversible DNA crosslinks in mammalian cells, inhibiting the
3
topoisomerase II as well as performing several other biological functions. The synthetic strategy
employed for XK469 involves the coupling of 2,7-dichloro quinoxaline with (R)-ethyl 2-(4-
hydroxyphenoxy)propanoate under the palladium-catalyzed etherification conditions providing a
good yield of the ethyl ester of the anti-tumor agent (Scheme 7, 15). A similar result was
obtained when 2,7-dichloro quinoxaline was replaced by 2-chlorobenzothiazole to give the
coupled product in very good yield (Scheme 7, 16).
3
. Conclusion: In conclusion, the Pd/PTABS catalyst system was demonstrated to efficiently
catalyze the etherification of chloroheteroarenes at relatively lower temperature (also works at
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lower catalyst loading of 0.1 mol% at 100 C), with a large substrate scope (electronically
activated as well as deactivated phenols well-tolerated) and allowing the post synthetic
functionalization of commercially important bio-active molecules such as estrones, estradiols,
tryptophans, and δ-tocopherol for instance. The mild synthetic potential of the catalytic system
was further explored for regioselectivity, ribonucleoside modification as well as the development
of unique double and triple tandem protocols without inhibiting the reactivity of other reagents.
Finally, the synthesis of the anti-tumor agent XK469 was realized through the direct
etherification of 2,7-dichloroquinoxaline and (R)-ethyl 2-(4-hydroxyphenoxy)propanoate in good
yield. In summary, a mild catalytic system with the potential for generating a library of ethers for
drug discovery efforts has been disclosed.
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4
. EXPERIMENTAL SECTION
4
.1 General:
All the reactions were performed under nitrogen atmosphere using oven dried standard schlenk
glassware. The completely dried N,N Dimethylformamide (DMF, 99.8%, extra dry, stored over
molecular sieves) was purchased from Acros organics was used as received for all air or
1
13
moisture sensitive reactions. H NMR (300 MHz) and C NMR (75 MHz) spectra were recorded
either on NMR EMAU Avance II-300 spectrometer or Agilent-400 MHz spectrometer. Chemical
1
13
shifts δ are given in ppm and the solvent residual peak (CDCl : H, δ = 7.27; C, δ = 77.0 and
3
1
13
DMSO-d6: H, δ = 2.50; C, δ = 40) was used as an internal standard. Peak multiplicities are
specified as followed: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. APCI-
MS (m/z) spectra were recorded on a Advion MS. Mechenary-Nagel silica gel 60 F254 plates
were used for thin layer chromatography (TLC) and detection was achieved by UV light.
Column chromatography was performed on silica gel 60 (40-63 μm) or on Acros Organics silica
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gel 60 (35-70 μm). The X-ray single crystal structure experiments conducted by using “STOE
IPDS2T” and diffraction source with fine- focus sealed molybdenum tube. “Elementar Vario
MICRO cube” was used for the experimental determination of elemental configurations of final
pure products.
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.1 General procedure (GP):
A 25 mL of oven dried schlenk tube was given with 1 mol% of Pd(OAc)
ligand, Phosphoadamantinebutylsaltone) and 1 mmol of chloroheterocyclic derivative under N
atmosphere and the resultant mixture dissolved in 3 mL of dry DMF. The reaction mixture
2
, 2 mol% of PTABS
(
2
stirred for 5 minutes and added by 1.2 eq. of corresponding phenol, 2.0 eq. of K
3
PO followed by
4
0
stirring at 60 C for 1-2hrs. After consumption of starting material (monitored by TLC / TLC-
MS), the solvent was removed in vacuum and the resultant residue obtained was purified by
column chromatography in Hexane: Ethyl Acetate (10% to 50%) solvent system to afford the
desired product. In the case of riboside derivatives and purine substrate (10a-10C) CHCl
9:1) was used as a mobile phase for column chromatography.
.2 General procedure for Double Tandem Reactions (GPT):
A 25 mL of oven dried schlenk tube was charged with 1 mol % of Pd(OAc)
ligand) and 0.5 mmol of 2-Chlorobenzthiazole under N atmosphere and the resultant mixture
3
:MeOH
(
1
2
, 2 mol % of PTABS
(
2
dissolved in 1.5 mL of dry DMF. The reaction mixture stirred for 5 minutes and was added 2.5
equiv. of Potassium phosphate, 1.2 equiv. of 4-Bromo phenol and 1.5 ml dry DMF. The resultant
o
mixture was stirred at 60 C for 2 h. After consumption of starting material (monitored by TLC /
TLC-MS), in the reaction mixture was added 1 mol % of Pd(OAc)2, 2 mol% of XPhos, 1.5 equiv.
of terminal alkyne, 0.5 mol % of Copper iodide and lastly 2.1 equiv. of triethyl amine and was
o
stirred at 80 C for 24 h. Then the solvent was removed in vacuum and the resultant residue
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obtained was purified by column chromatography in hexane: ethyl acetate (2.0% to 3.0%)
solvent system to afford the desired product.
2
.1 Substrate scope for palladium-catalyzed etherification of chloroheteroarenes with diverse
substituted phenols
-(4-Methoxyphenoxy)pyrazine (3a):
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General Procedure (GP) was followed by using 2-chloropyrazine (1 mmol, 1 equiv.) and 4-
methoxy phenol (1.1 mmol, 1.1 eq.) yielded a desired product (182 mg, 90%) as a white
o
1
solid.Mp: 78-80 C, H NMR (400 MHz, CDCl ) δ: 8.38 (d, J = 1.0 Hz, 1H), 8.21 (d, J = 2.5 Hz,
3
1
3
1
H), 8.09 – 8.05 (m, 1H), 7.07 (dd, J = 6.8, 2.2 Hz, 2H), 6.95 – 6.91 (m, 2H), 3.80 (s, 3H). C
NMR (101 MHz, CDCl
3
) δ 160.5 (s), 157.0 (s), 146.2 (s), 141.0 (s), 138.1 (s), 135.6 (s), 122.2
: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.23;
(
s), 114.8 (s), 55.5 (s). Anal.Calcd.for C11
H, 4.94; N, 13.87.
2-(4-(tert-Butyl)phenoxy)pyrazine (3b):
H
10
N
2
O
2
General Procedure (GP) was followed by using 2-chloropyrazine (1 mmol, 1 equiv.) and 4-tert
butyl phenol (1.1 mmol, 1.1 eq.) yielded a desired product (184 mg, 81%) as a white solid.Mp:
1
N.R, H NMR (400 MHz, CDCl
3
) δ 8.33 (s, 1H), 8.17 (d, J = 2.5 Hz, 1H), 8.04 (s, 1H), 7.36 (d, J
1
3
=
8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 1.27 (s, 9H). C NMR (101 MHz, CDCl
49.5 (s), 147.1 (s), 140.0 (s), 137.2 (s), 134.8 (s), 125.7 (s), 119.4 (s), 33.4 (s), 30.4 (s).
Anal.Calcd. For C14 O : C, 73.66; H, 7.06; N, 12.27. Found: C, 74.01; H, 7.21; N, 12.21.
3
) δ 159.3 (s),
1
H
16
N
2
2
-(Naphthalen-2-yloxy)pyrazine (3c):
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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
General Procedure (GP) was followed by using 2-chloropyrazine (1 mmol, 1 equiv.) and 2-
naphthol (1.1 mmol, 1.1 eq.) yielded a desired product (195 mg, 88%) as a white solid. Mp:116-
o
1
118 C, H NMR (400 MHz, CDCl
3
) δ 8.48 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.88 (dd, J = 16.7,
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
8
.2 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.52 – 7.44 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H).
13C NMR (101 MHz, CDCl
) δ 160.3 (s), 150.6 (s), 141.1 (s), 138.5 (s), 135.9 (s), 134.0 (s),
3
131.2 (s), 129.8 (s), 127.8 (s), 127.5 (s), 126.6 (s), 125.5 (s), 120.9 (s), 117.8 (s).Anal.Calcd. For
O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.56; H, 4.56; N, 12.42.
C
14
H
10
N
2
2
-(Naphthalen-1-yloxy)pyrazine (3d) :
General Procedure (GP) was followed by using 2-chloropyrazine (1 mmol, 1 equiv.) and 1-
naphthol (1.1 mmol, 1.1 eq.) yielded a desired product (177 mg, 80%) as a white solid. Mp: 100-
o
1
1
02 C, H NMR (400 MHz, CDCl
3
) δ 8.53 (d, J = 2.9 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.07 (d,
J = 1.3 Hz, 1H), 7.92 (dd, J = 5.2, 1.8 Hz, 2H), 7.82 – 7.75 (m, 1H), 7.56 – 7.44 (m, 3H), 7.30 –
1
3
7.23 (m, 1H). C NMR (101 MHz, CDCl
3
) δ 148.9 (s), 141.3 (s), 138.5 (s), 135.3 (s), 134.9 (s),
28.1 (s), 127.1 (s), 126.5 (d), 125.68 (d), 121.5 (s), 117.3 (s). Anal.Calcd. For C14 O: C,
5.66; H, 4.54; N, 12.60. Found: C, 75.44; H, 4.70; N, 12.34.
1
7
H
10
N
2
2-(Naphthalen-2-yloxy)benzo[d]thiazole (3e):
General Procedure (GP) was followed by using 2-chlorobenzothiazole (1 mmol, 1 equiv.) and 2-
naphthol (1.1 mmol, 1.1 eq.) yielded a desired product (235 mg, 85%) as a white solid.Mp:68-70
o
1
C, H NMR (400 MHz, CDCl
.9, 5.4 Hz, 3H), 7.41 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H). C NMR (101 MHz, CDCl
δ 172.0 (s), 152.3 (s), 149.1 (s), 133.9 (s), 132.4 (s), 131.6 (s), 130.1 (s), 127.8 (d), 126.8 (s),
26.3 (s), 126.0 (s), 124.1 (s), 121.8 (s), 121.3 (s), 120.1 (s), 117.5 (s). Anal.Calcd. For
3
) δ 7.96 – 7.76 (m, 5H), 7.68 (d, J = 7.9 Hz, 1H), 7.51 (dd, J =
1
3
8
3
)
1
C
17
H
11NOS: C, 73.62; H, 4.0; N, 5.05; S, 11.56. Found: C, 74.02; H, 4.04; N, 5.12; S, 11.77.
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-(Naphthalen-1-yloxy)benzo[d]thiazole (3f) :
General Procedure (GP) was followed by using 2-chlorobenzothiazole (1 mmol, 1 equiv.) and 1-
naphthol (1.1 mmol, 1.1 eq.) yielded a desired product (227 mg, 82%) as a white solid.Mp: 100-
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
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
o
1
1
02 C, H NMR (400 MHz, CDCl
3
) δ 8.10 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 6.7 Hz, 1H), 7.82 (d,
J = 6.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.57 – 7.48 (m, 4H), 7.38 (t, J
1
3
=
7.7 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H). C NMR (101 MHz, CDCl
s), 134.9 (s), 132.3 (s), 128.0 (s), 127.0 – 126.5 (m), 126.3 (d), 125.5 (s), 124.0 (s), 121.7 (s),
21.3 (d), 117.1 (s). Anal.Calcd. For C17 11NOS: C, 73.62; H, 4.0; N, 5.05; S, 11.56. Found: C,
74.01; H, 4.14; N, 5.06; S, 12.00.
3
) δ 172.6 (s), 150.7 (s), 149.1
(
1
H
2-(4-Methoxyphenoxy)benzo[d]thiazole (3g) :30
General Procedure (GP) was followed by using 2-chlorobenzothiazole (1 mmol, 1 equiv.) and 4-
methoxy phenol (1.1 mmol, 1.1 eq.) yielded a desired product (218 mg, 85%) as a white solid.
1H NMR (400 MHz, CDCl
) δ 7.72 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.39 – 7.32 (m,
3
1
3
1
H), 7.29 – 7.22 (m, 3H), 6.98 – 6.90 (m, 2H), 3.82 (s, 3H). C NMR (101 MHz, CDCl
72.9 (s), 157.6 (s), 149.2 (s), 148.3 (s), 132.2 (s), 126.1 (s), 123.8 (s), 121.8 (s), 121.6 (s), 121.2
S: C, 65.35; H, 4.31; N, 5.44; S, 12.46.
3
) δ
1
(s), 114.8 (s), 55.6 (s). Anal.Calcd. For C14
H11NO
2
1
13
Found: C, 65.05; H, 4.36; N, 5.17; S, 12.33.The compound exhibited identical H and C NMR
data to previous reports.30
2
-(4-(tert-Butyl)phenoxy)benzo[d]thiazole (3h):
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General Procedure (GP) was followed by using 2-chlorobenzothiazole (1 mmol, 1 equiv.) and 4-
tert butyl phenol (1.1 mmol, 1.1 eq.) yielded a desired product (240 mg, 85%) as a white
o
1
solid.Mp: 108-110 C, H NMR (400 MHz, CDCl
3
) δ 7.73 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.5
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
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.31 – 7.23 (m, 3H), 1.34 (s, 9H). C
NMR (101 MHz, CDCl
3
) δ 172.2 (s), 152.4 (s), 149.2 (s), 132.2 (s), 126.8 (s), 126.1 (s), 123.9
17NOS: C, 72.05; H,
(s), 121.6 (s), 121.2 (s), 119.9 (s), 34.5 (s), 31.4 (s). Anal.Calcd. For C17
H
6
.05; N, 4.94; S, 11.31. Found: C, 72.42; H, 6.24; N, 4.66; S, 11.10.
2
-(4-Methoxyphenoxy)benzo[d]oxazole (3i):
General Procedure (GP) was followed by using 2-chlorobenzo[d]oxazole (0.116 mL,1 mmol)
and 4-methoxy phenol (149 mg, 1.2 mmol, 1.2 eq.) provided desired 2-(4-
1
methoxyphenoxy)benzo[d]oxazole (224 mg, 0.93 mmol, 93%) as a colorless liquid. H NMR
(
300 MHz, CDCl
H), 7.37 - 7.43 (m, 1 H), 7.47 - 7.53 (m, 1 H); C NMR (75 MHz, CDCl
s, 1 C), 114.8 (s, 1 C), 118.6 (s, 1 C), 121.2 (s, 1 C), 123.2 (s, 1 C), 124.4 (s, 1 C), 140.8 (s, 1
C), 146.3 (s, 1 C), 148.4 (s, 1 C), 157.6 (s, 1 C), 162.8 (s, 1 C); (+ve)APCI-MS m/z = 241.07 m/z
calcd. for C14 [M]; found : 242.21[M+H].Anal.Calcd. For C14 :C, 69.70; H, 4.60;
N, 5.81; Found: C, 69.52; H, 4.44; N, 5.79.
-(4-tert-Butylphenoxy)quinoxaline (3j):
3
) δ: 3.82 (s, 3 H), 6.92 - 6.99 (m, 2 H), 7.18 - 7.28 (m, 2 H), 7.28 - 7.35 (m, 2
1
3
3
) δ: 55.6 (s, 1 C), 109.8
(
H
11NO
3
H11NO
3
2
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg,1 mmol) and 1-
tert-butyl-4-methoxybenzene (180 mg, 1.2 mmol, 1.2 eq.) provided a desired 2-(4-tert-
o
butylphenoxy)quinoxaline (265 mg, 0.949 mmol, 95%) as a colorless crystals. Mp: 66.7-68.7 C,
1H NMR (300 MHz, CDCl
) δ : 1.37 (s, 9 H), 7.21 - 7.27 (m, 2 H), 7.43 - 7.51 (m, 2 H), 7.57 -
3
13
7
.70 (m, 2 H), 7.76 - 7.83 (m, 1 H), 8.06 (dd, J=8.07, 1.56 Hz, 1 H), 8.68 (s, 1 H); C NMR (75
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MHz, CDCl
3
) δ: 31.8 (s, 1 C), 31.9 (s, 1 C), 34.9 (s, 1 C), 121.0 (s, 1 C), 126.8 (s, 1 C), 126.9 (s,
1
C), 127.7 (s, 1 C), 128.1 (s, 1 C), 129.2 (s, 1 C), 130.7 (s, 1 C), 139.6 (s, 1 C), 139.9 (s, 1 C),
148.6 (s, 1 C), 150.8 (s, 1 C), 157.4 (s, 1 C); (+ve)APCI-MS m/z = 278.35 calcd. for
O[M], found : 279.4[M+H]. Anal.Calcd. For C18 O:C, 77.67; H, 6.52; N, 10.06;
Found: C, 77.59; H, 6.48; N, 10.17.
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
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
C
18
H
18
N
2
H
18
N
2
2
-(4-Methoxyphenoxy)quinoxaline (3k):
General Procedure (GP) was followed by using 2-Chloroquinoxiline (164 mg, 1 mmol) and 4-
methoxy phenol (149 mg,1.2 mmol, 1.2 eq.) yielded a desired 2-(4-methoxyphenoxy)quinoxaline
o
1
(219 mg, 0.79 mmol, 87%) as a white crystals. Mp: 144.7-146.7 C, H NMR (300 MHz, CDCl )
3
δ: 3.86 (s, 3 H), 6.96 - 7.02 (m, 2 H), 7.19 - 7.25 (m, 2 H), 7.57 - 7.70 (m, 2 H), 7.75 - 7.81 (m, 1
13
H), 8.07 (dd, J=7.98, 1.56 Hz, 1 H), 8.68 (s, 1 H) ; C NMR (75 MHz, CDCl ) δ: 55.6 (s, 1 C),
3
5
5.7 (s, 1 C), 114.6 (s, 1 C), 114.7 (s, 1 C), 116.0 (s, 1 C), 122.3 (s, 1 C), 127.2 (s, 1 C), 127.6 (s,
1 C), 128.8 (s, 1 C), 130.3 (s, 1 C), 139.1 (s, 1 C) 139.4 (s, 1 C), 140.0 (s, 1 C), 146.1 (s, 1 C),
1
2
56.9 (s, 1 C); (+ve)APCI-MS m/z = 252.27 [M]calcd. for C15
H
12
N
2
O
2
[M], found:
53.33[M+H]. Anal.Calcd. For C15 : C, 71.42; H, 4.79; N, 11.10; Found: C, 71.09; H,
H
12
N
2
O
2
4.98; N, 11.07.
2-(Mesityloxy)quinoxaline (3l):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and
2,4,6-trimethylphenol (163 mg, 1.2 mmol, 1.2 eq.) provided desired 2-(mesityloxy)quinoxaline
o
1
(
243.25 mg, 0.92 mmol, 92%) as a shiny white needles; . Mp: 92.3-94.0 C, H NMR (300 MHz,
CDCl ) δ: 2.13 (s, 6 H), 2.36 (s, 3 H), 6.97 (s, 2 H), 7.62 (t , J=7.45, 1.79 Hz, 2 H), 7.71 - 7.81
m, 1 H), 8.04 - 8.12 (m, 1 H), 8.73 (s, 1 H); C NMR (75 MHz, CDCl ) δ: 16.5 (s, 1 C), 20.8 (s,
3
d
1
3
(
3
1
C), 127.0 (s, 1 C), 127.7 (s, 1 C), 128.8 (s, 1 C), 129.3 (s, 1 C), 130.1 (s, 1 C), 130.3 (s, 1 C),
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35.0 (s, 1 C), 138.5 (s, 1 C), 139.4 (s, 1 C), 140.4 (s, 1 C), 147.4 (s, 1 C), 156.3 (s, 1 C);
(+ve)APCI-MS m/z = 264.32 calcd. for C17
H
16
N
2
O [M], found : 265.43 [M+H]. Anal.Calcd. For
C
17
H
16
N
2
O:C, 77.25; H, 6.10; N, 10.60; Found: C, 77.22; H, 6.48; N, 10.43.
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
2-Phenoxyquinoxaline (3m):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and
phenol (119 mg, 1.2 mmol, 1.2 eq.) provided desired 2-phenoxyquinoxaline (182 mg, 0.82
1
mmol, 82%) as a colorless crystals.; H NMR (300 MHz, CHLOROFORM-d) δ:7.19 - 7.33 (m, 3
H), 7.37 - 7.50 (m, 2 H), 7.52 - 7.68 (m, 2 H), 7.68 - 7.79 (m, 1 H), 8.03 (dd, J=7.98, 1.56 Hz, 1
1
3
H), 8.66 (s, 1 H); C NMR (75 MHz, CHLOROFORM-d) δ:, 121.4 (s, 1 C), 125.4 (s, 1 C),
27.4 (s, 1 C), 127.7 (s, 1 C), 128.8 (s, 1 C), 129.6 (s, 1 C), 130.3 (s, 1 C), 139.2 (s, 1 C), 139.6
s, 1 C), 140.0 (s, 1 C), 152.8 (s, 1 C), 156.9 (s, 1 C); (+ve)APCI-MS m/z = 222.24, calcd. for
1
(
1
13
C
14
H
10
N O [M], Found : 223.5 [M+H]. The compound exhibited identical H and C NMR data
2
1
2
to previous reports .
-(3-Nitrophenoxy)quinoxaline (3n):31
2
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and 3-
nitrophenol (208 mg, 1.5 mmol, 1.5 eq.) provided desired 2-(3-nitrophenoxy)quinoxaline(254
1
mg, 0.95 mmol, 95%) as a colorless crystals. H NMR (300 MHz, CDCl
3
) δ: 7.61 - 7.72 (m, 4
H), 7.72 - 7.79 (m, 1 H), 8.07 - 8.15 (m, 1 H), 8.18 (dt, J=6.95, 2.21 Hz, 1 H), 8.23 - 8.28 (m, 1
1
3
H), 8.77 (s, 1 H); C NMR (75 MHz, CDCl
3
) δ: 117.2 (s, 1 C), 120.3 (s, 1 C), 127.6 (s, 1 C),
1
27.9 (s, 1 C), 128.0 (s, 1 C), 129.0 (s, 1 C), 130.1 (s, 1 C), 130.7 (s, 1 C), 138.7 (s, 1 C), 139.4
(s, 1 C), 140.0 (s, 1 C), 149.0 (s, 1 C), 153.0 (s, 1 C), 155.9 (s, 1 C); (+ve)APCI-MS m/z =
1
2
67.24 calcd. for C14
H
9
N
3
O
3
[M], Found : 268.18 [M+H]. The compound exhibited identical H
1
3
and C NMR data to previous reports.
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-(Quinoxalin-2-yloxy)benzaldehyde (3o):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and
Salicylaldehyde (0.13 mL, 1.2 mmol, 1.2 eq.) provided desired 2-(quinoxalin-2-
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
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
yloxy)benzaldehyde (232.8 mg, 0.93 mmol, 93%) as a colorless crystals.; H NMR (300 MHz,
CHLOROFORM-d) δ : 7.32 - 7.41 (m, 1 H), 7.45 (t, J=7.57 Hz, 1 H), 7.57 - 7.76 (m, 4 H), 7.98
1
3
-
(
8.17 (m, 2 H), 8.83 (s, 1 H), 10.26 (s, 1 H) ; C NMR (75 MHz, CHLOROFORM-d) δ : 123.4
s, 1 C), 126.5 (s, 1 C), 128.1 (s, 1 C), 128.3 (s, 1 C), 129.0 (s, 1 C), 129.4 (s, 1 C), 130.0 (s, 1
C), 131.0 (s, 1 C), 135.9 (s, 1 C), 139.0 (s, 1 C), 140.1 (s, 1 C), 140.3 (s, 1 C), 155.0 (s, 1 C),
157.3 (s, 1 C), 189.0 (s, 1 C) ;(+ve)APCI-MS m/z = 250.25 Anal.Calcd for C15 [M],
Found : 251.4 [M+H]. The compound exhibited identical H and C NMR data to previous
H
10
N
2
O
2
1
13
1
2
reports .
2
-(4-Fluorophenoxy)quinoxaline (3p):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and 4-
fluorophenol (146 mg, 1.3 mmol, 1.3 eq.) provided desired 2-(4-fluorophenoxy)quinoxaline
1
(223.4 mg, 0.93 mmol, 93%) as a colorless crystals. H NMR (300 MHz, CHLOROFORM-d) δ
:7.08 - 7.20 (m, 2 H), 7.21 - 7.32 (m, 2 H), 7.56 - 7.70 (m, 2 H), 7.70 - 7.80 (m, 1 H), 8.06 (dd,
13
J=8.02, 1.60 Hz, 1 H), 8.68 (s, 1 H); C NMR (75 MHz, CHLOROFORM-d) δ: 116.1 (s, 1 C),
1
16.4 (s, 1 C), 122.9 (s, 1 C), 123.0 (s, 1 C), 127.5 (s, 1 C), 127.6 (s, 1 C), 128.9 (s, 1 C), 130.4
(s, 1 C), 139.0 (s, 1 C), 139.6 (s, 1 C), 139.8 (s, 1 C), 148.4 (s, 1 C), 148.4 (s, 1 C), 156.8 (s, 1
1
9
C), 158.3 (s, 1 C), 161.6 (s, 1 C); F NMR (282 MHz, CHLOROFORM-d) δ :-117.3 (s, 1
F);(+ve)APCI-MS m/z = 240.23 calcd. for C14
H
9
FN
2
O [M], found : 241.15 [M+H]. The
1
13
32
compound exhibited identical H and C NMR data to previous reports.
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The Journal of Organic Chemistry
Page 28 of 57
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Ethyl 4-(quinoxalin-2-yloxy)benzoate (3q):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and
ethyl 4-hydroxybenzoate (200 mg, 1.3 mmol, 1.3 eq.) provided desired ethyl 4-(quinoxalin-2-
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yloxy)benzoate (256 mg, 0.87 mmol, 87%) as a colorless crystals. H NMR (300 MHz,
CHLOROFORM-d) δ :1.42 (t, J=7.11 Hz, 3 H), 4.41 (q, J=7.15 Hz, 2 H), 7.34 - 7.44 (m, 2 H)
7.59 - 7.72 (m, 2 H), 7.74 - 7.82 (m, 1 H), 8.09 (dd, J=7.93, 1.70 Hz, 1 H), 8.13 - 8.21 (m, 2 H),
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.72 (s, 1 H); C NMR (75 MHz, CHLOROFORM-d) δ :14.3 (s, 1 C), 61.0 (s, 1 C), 121.0 (s, 1
C), 127.5 (s, 1 C), 127.7 (s, 1 C), 127.8 (s, 1 C), 129.0 (s, 1 C), 130.5 (s, 1 C), 131.3 (s, 1 C),
39.0 (s, 1 C), 139.7 (s, 1 C), 139.8 (s, 1 C), 156.2 (s, 1 C), 156.5 (s, 1 C), 165.9 (s, 1 C);
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(+ve)APCI-MS m/z = 294.3 calcd. for C17
H
14
N
2
O
3
[M], found : 295 [M+H]. The compound
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13
33
exhibited identical H and C NMR data to previous reports.
-(Perfluorophenoxy)quinoxaline (3r):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and
,3,4,5,6-pentafluorophenol (276.1 mg, 1.5 mmol, 1.5 eq.) provided desired 2-
perfluorophenoxy)quinoxaline (187 mg, 0.598 mmol, 60%) as a colorless crystals. . Mp: 83.1-
2
2
(
o
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4.3 C H NMR (300 MHz, CDCl ) δ: 7.61 - 7.85 (m, 4 H), 8.09 - 8.24 (m, 1 H), 8.86 (s, 1 H) ;
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13C NMR (75 MHz, CDCl3) δ: 127.6 (s, 1 C), 128.3 (s, 1 C), 129.1 (s, 1 C), 130.9 (s, 1 C), 137.3
s, 1 C), 139.3 (s, 1 C), 139.7 (s, 1 C), 140.0 (s, 1 C), 140.1 (s, 1 C), 140.4 (s, 1 C), 143.4 (s, 1
(
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C), 143.5 (s, 1 C), 143.5 (s, 1 C), 154.4 (s, 1 C); F NMR (282 MHz, CDCl
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) δ: -162.4 (s, 1 F), -
62.4 (s, 1 F), -162.4 (s, 1 F), -162.3 (s, 1 F), -158.5 (s, 1 F), -158.4 (s, 1 F), -158.3 (s, 1 F), -
52.1 (s, 1 F), -152.1 (s, 1 F), -152.0 (s, 1 F), -152.0 (s, 1 F) ;(+ve)APCI-MS m/z = 312.19 calcd.
O [M], found : 313.22 [M+H]. Anal.Calcd. For C14 N2O:C, 53.86; H, 1.61; N,
.97; Found: C, 53.89; H, 1.58; N, 8.93.
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for C14
H
5
F
5
N
2
H F
5 5
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Page 29 of 57
The Journal of Organic Chemistry
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-(Quinoxalin-2-yloxy)benzenamine (3s):
General Procedure (GP) was followed by using 2-Chloroquinoxaline (164 mg, 1 mmol) and 2-
Aminophenol (121 mg, 1.1 mmol, 1.1 eq.) provided desired 2-(quinoxalin-2-
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yloxy)benzenamine(218 mg, 0.92 mmol, 92%) as a yellow needles. H NMR (300 MHz,
CHLOROFORM-d) δ :3.77 (br. s., 2H), 6.81 - 6.93 (m, 2 H), 7.08 - 7.21 (m, 2 H), 7.57 - 7.71
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(m, 2 H), 7.77 - 7.86 (m, 1 H), 8.03 - 8.13 (m, 1 H), 8.71 (s, 1 H); C NMR (75 MHz,
CHLOROFORM-d) δ : 117.0 (s, 1 C), 118.8 (s, 1 C), 122.2 (s, 1 C), 126.4 (s, 1 C), 127.5 (s, 1
C), 127.8 (s, 1 C), 128.9 (s, 1 C), 130.4 (s, 1 C), 138.5 (s, 1 C), 138.9 (s, 1 C), 139.7 (s, 1 C),
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40.0 (s, 1 C), 140.0 (s, 1 C), 156.4 (s, 1 C); (+ve)APCI-MS m/z = 237.26 calcd. for C14
H
11
N O
3
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[M], found : 238.48 [M+H]. The compound exhibited identical H and C NMR data to previous
reports.34
2
-(3,5-Bis(trifluoromethyl)phenoxy)benzo[d]oxazole (3t):34
General Procedure (GP) was followed by using 2-chlorobenzo[d]oxazole (0.116 mL,1 mmol)
and 3,5-bis(trifluoromethyl)phenol (276 mg, 1.2 mmol, 1.2 eq.) provided desired 2-(3,5-
1
bis(trifluoromethyl)phenoxy)benzo[d]oxazole (191 mg, 0.55 mmol, 55%) as a viscous liquid. H
NMR (300 MHz, CDCl ) δ: 7.20 - 7.34 (m, 2 H), 7.38 - 7.46 (m, 1 H), 7.48 - 7.59 (m, 1 H), 7.81
3
13
(s, 1 H), 8.00 (s, 2 H); C NMR (75 MHz, CDCl ) δ: 110.1 (s, 1 C), 117.2 (s, 1 C), 119.1 (s, 1
3
C), 119.9 (s, 1 C), 119.9 (s, 1 C), 120.0 (s, 1 C), 120.0 (s, 1 C), 120.1 (s, 1 C), 120.7 (s, 1 C),
120.8 (s, 1 C), 124.2 (s, 1 C), 124.4 (s, 1 C), 124.9 (s, 1 C), 128.0 (s, 1 C), 132.7 (s, 1 C), 133.2
(s, 1 C), 133.7 (s, 1 C), 134.1 (s, 1 C), 140.1 (s, 1 C), 148.4 (s, 1 C), 152.9 (s, 1 C), 160.6 (s, 1
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C); F NMR (282 MHz, CDCl
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) δ: -63.0 (s, 1 F); (+ve)APCI-MS m/z = 347.04 m/z calcd. for
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15
H
7
F
6
NO [M]; found : 348.13[M+H].The compound exhibited identical H and C NMR
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data to previous reports.34
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