Modular copper-catalyzed synthesis of chromeno[4,3-b]quinolines with the utilization of diaryliodonium salts

Article abstract of DOI:10.1021/acs.joc.5b02490

A novel, highly modular synthetic method with high functional group tolerance was developed for the construction of chromenoquinoline derivatives from arylpropynyloxy-benzonitriles and diaryliodonium triflates via an oxidative arylation-cyclization path. The copper(I) chloride catalyzed reaction is presumed to involve the formation of highly active arylcopper(III) species.

Full text of DOI:10.1021/acs.joc.5b02490

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Article
Modular Copper-Catalyzed Synthesis of Chromeno[4,3-
b]quinolines with the Utilization of Diaryliodonium Salts
Klára Aradi, Petra Bombicz, and Zoltán Novák
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02490 • Publication Date (Web): 21 Dec 2015
Downloaded from http://pubs.acs.org on December 28, 2015
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Modular Copper-Catalyzed Synthesis of Chromeno[4,3-b]quinolines with the Utilization
of Diaryliodonium Salts
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Klára Aradi,a Petra Bombicz,b Zoltán Novák*a
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aMTAꢀELTE „Lendület” Catalysis and Organic Synthesis Research Group, Institute of
Chemistry, Eötvös University, Pázmány Péter stny. 1/a Hꢀ1117 Budapest, Hungary
b
Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar
Tudósok körútja 2. Hꢀ1117 Budapest, Hungary
novakz@elte.hu
ABSTRACT: A novel, highly modular synthetic method with high functional group
tolerance was developed for the construction of chromenoquinoline derivatives from
arylpropynyloxyꢀbenzonitriles and diaryliodonium triflates via oxidative arylationꢀcyclization
path. The copper(I) chlorideꢀcatalyzed reaction is presumed to involve the formation of highly
active arylcopper(III) species.
INTRODUCTION
Copperꢀcatalyzed syntheses of aromatic and heteroaromatic systems are intensively
studied areas of current organic chemistry.1 In the last few years, triple bond activation via the
intermediacy of Cu(III) species2,3 using diaryliodonium salts4 as arylating agents has become
an efficient method for the construction of diverse heterocyclic skeletons. The highly
electrophilic arylcopper(III) intermediates can activate triple bonds or generate carbocationic
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species from alkynes and nitriles. These copper complexes and the carbocationic
intermediates can easily undergo ring closure when in the close proximity of nucleophilic
functional groups. For example, Gaunt and coworkers2b developed several copper catalyzed
transformations for the synthesis of dihydronaphthalene, chromene and dihydroquinoline
derivatives from functionalized electron rich alkynes and diaryliodonium salts via vinyl cation
intermediates. Besides the transformation of alkynes, the activation of a nitrile group with
copper catalysts and iodonium salts is also possible, and the construction of heterocyclic
skeletons such as quinolines3a,3c, quinazolines3b and tetrahydroacridines3a through the
formation of iminium cations were described by Chen et al. Utilizing the strategy of triple
bond activation with the aid of Cu(III) species, our research group also developed novel
copperꢀcatalyzed cyclizations for the synthesis of benzoxazine5a, iminobenzoxazine5b and
dihydrooxazole5c derivatives (Scheme 1). Considering the activation ability of Cu(III)ꢀaryl
species toward triple bonds, we aimed to develop a novel, highly modular catalytic strategy
for the construction of complex heterocyclic systems from substrates equipped both with
nitrile and alkyne functional groups.
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Scheme 1. Utilization of arylation-ring closure strategy
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RESULT AND DISCUSSION
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To realize the concept, we synthesized arylpropynyloxyꢀbenzonitriles as model
substrates from the appropriate 2ꢀhydroxybenzonitrile derivatives. In the presence of a C≡C
triple bond ortho to the nitrile moiety, a ring closure reaction can occur which should provide
chromeno[4,3ꢀb]quinolines6aꢀ6c through two sequential cyclization paths (Scheme 2).
Scheme 2. Highly modular synthesis of chromenoquinolines via arylation-ring closure
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Beyond the importance of the conceptual aspects of this transformation, the realization
of this chemical approach would provide a new synthetic route to chromenoquinolines, an
important and synthetically useful class of heterocyclic compounds.
Chromenoquinolines are significant due to their biological activity and their
applications in medical chemistry. For example, 6Hꢀchromeno[4,3ꢀb]quinolines act as
estrogen receptor β–selective ligands,7a and they can be used also for bioimaging due to their
fluorescent properties.7b,7c Moreover, the spiro analogues of benzothiazolylchromeno
derivatives have shown cytotoxic activity against MCFꢀ7 (breast cancer) and HeLa (cervical
cancer) cell lines.7d
To optimize the reaction conditions, we chose 2ꢀ((3ꢀphenylpropꢀ2ꢀynꢀ1ꢀ
yl)oxy)benzonitrile (1a) as a substrate and phenylmesityliodonium triflate (2a) as the
arylating agent, while the oxidative coupling was performed at 75 °C for 1 h.8 Examination of
the solvent effect on the conversion showed that the reaction is slow in DMF, CH2Cl2, THF,
PhMe and DCE, and no reaction occurs in MeOH (Table 1, entries 1ꢀ6). In contrast, full
conversion was reached in 1 h when the reaction was conducted in EtOAc (entry 7).
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Comparison of the activity of different copper catalysts showed that CuCl and CuBr are
suitable for the transformation (entries 7ꢀ8). In the case of CuI or CuO, no reaction occurs in 1
h (entries 9ꢀ10), while the reaction was slow when Cu(OTf)2, CuSO4, Cu(acac)2 or
(MeCN)4Cu(OTf) were used (entries 11ꢀ14). No reaction was observed in the absence of
catalyst (entry 15).
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Table 1. Optimization studiesa
entry
1
catalyst
CuCl
solvent
MeOH
DMF
conversionb (%)
0
5
2
CuCl
3
CuCl
CH2Cl2
THF
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29
35
41
100
100
0
4
CuCl
5
CuCl
PhMe
6
CuCl
DCE
7
CuCl
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
8
CuBr
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CuI
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CuO
0
Cu(OTf)2
CuSO4
Cu(acac)2
(MeCN)4Cu(OTf)
ꢀ
3
10
12
40
0
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2ꢀ((3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)oxy)benzonitrile (0.125 mmol), mesitylphenyliodonium triflate
(0.150 mmol, 1.20 equiv.), copper catalyst (0.013 mmol, 0.10 equiv.); solvent (250 ꢁL), Ar,
b
75 °C, 1 h.; Conversion of the starting material to desired product was determined by
GCFID analysis.
With optimal conditions in hand, we aimed to explore the scope and limitations of the
method. First, we reacted 2ꢀ((3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)oxy)benzonitrile (1a) with
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phenylmesityliodonium triflate (2a) using 10 mol % of CuCl in EtOAc at 75 °C, and 3aa was
obtained in 78% yield (Scheme 3). When a methyl substituent was present in the ortho
position of the phenyl group of the iodonium salt, the reaction was slower (5 h reaction time
was needed) and the desired product (3ab) was isolated in 32% yield. In contrast, when the
methyl group was meta or para to the iodonium salt, the reaction was fast, and the desired
compounds (3ac and 3ad) were obtained in 65% and 50% yields, respectively. When the aryl
part of the iodonium salt contained a halogen atom (F, Cl or Br) ortho to the iodine, the ring
closure reaction was retarded and the desired compounds were detected only with GCꢀMS (5ꢀ
8% GCꢀMS conversion, not shown). When the reaction was attempted with diaryliodonium
salts containing halogens in the meta or para positions, 1a was transformed to the appropriate
chromenoquinoline derivatives (3afꢀ3al) in 47ꢀ65% yield. Diaryliodonium salt bearing a para
COOEt group provided the desired product (3am) in 70% yield. In the case of meta
substituted iodonium salts, chromenoquinolines 3ac, 3ah and 3ak were obtained as 1:1
mixtures of possible regioisomers originated from the aromatic electrophilic substitution step
of the transformation (for mechanism see Scheme 6.)
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Scheme 3. Synthesis of chromeno[4,3-b]quinolines 1.a
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a
2ꢀ((3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)oxy)benzonitrile (0.5 mmol, 1.0 equiv), arylmesityliodonium
triflate (0.6 mmol, 1.2 equiv), CuCl (0.05 mmol, 0.10 equiv), EtOAc (1.0 mL), Ar, 75 °C, %
isolated yield. b isolated as 1:1 mixture of regioisomers
Next, we investigated the scope of this transformation by studying the reactivity of
different nitriles in the ring closure reaction (Scheme 4). Nitriles 1bꢀ1l bearing different aryl
groups on the alkyne moiety were reacted with phenylmesityliodonium triflate (2a) to prepare
the desired chromenoquinoline derivatives (3baꢀ3la). Two more examples (3im and 3lm) are
given where the applicability of the ring closure reaction is demonstrated with 4ꢀ
ethoxycarbonylꢀphenylmesityliodonium triflate (2m). When the arylpropynyloxybenzonitrile
contained a thiophenyl group (1b), the appropriate product (3ba) was isolated in 48% yield,
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respectively. When the reaction was performed with nitrile derivatives bearing electronꢀ
donating groups (1c and 1d) in the para position, the desired compounds (3ca and 3da) were
obtained in 71% and 34% yields. The presence of halogens (1eꢀ1i) on the aromatic ring of the
nitrile was wellꢀtolerated in the ortho, meta and para positions, and the appropriate products
(3eaꢀ3ia) were isolated in 60ꢀ75% yield. Reaction with nitriles bearing electronꢀwithdrawing
groups (1j and 1k) in the para position afforded the desired chromenoquinoline derivatives
(3ja and 3ka) in 72% and 48% yields. In the presence of an ester group on the aromatic ring
of the arylpropynyloxybenzonitrile derivative (1l), we could isolate product 3la with good
yield (80%). The reaction of substrate 1i and 1l with the paraꢀester derivative (2m) of the
iodonium salt led to the appropriate products (3im and 3lm) in 51% and 67% yields.
Finally, the cyclization was performed with substrates bearing halogen and phenyl
substituents (1mꢀ1p) on the hydroxybenzonitrile moiety. The presence of halogens (1m, 1n
and 1o) on the aromatic ring of the nitrile was wellꢀtolerated and the desired chloro (3ma) and
bromo (3na and 3oa) substituated chromenoquinolines were isolated with 78%, 80% and 67%
yields, respectively. The phenyl substituated derivative (1p) of the nitrile was also active in
the ring closure reaction and afforded the appropriate product (3pa) in 70% yield.
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Scheme 4. Synthesis of chromeno[4,3-b]quinolines 2.a
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a
2ꢀ((3ꢀphenylpropꢀ2ꢀynꢀ1ꢀyl)oxy)benzonitrile (0.5 mmol, 1.0 equiv), arylmesityliodonium
triflate (0.6 mmol, 1.2 equiv), CuCl (0.05 mmol, 0.10 equiv), EtOAc (1.0 mL), Ar, 75 °C, %
isolated yield
The reactivity of substrate 1q was conceptually important in establishing the
preferential site of activation and comparing the reactivity of the acetylene and the nitrile
groups toward the highly electrophilic arylcopper species (Scheme 5). The ortho ethynyl
anilide motif could undergo cylization in which the amide moiety is involved, providing
benzoxazines through acetylene activation as we demonstrated earlier.5a The Nꢀaryliminium
ion formation via the activation of nitrile could provide quinolines or condensed
benzoxazines. The reaction of 1q with phenylmesityliodonium triflate afforded the
appropriate chromenoquinoline product (3qa) in 46% yield. While we were not able to detect
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the formation of any other byproducts, we can conclude that the nitrile function has
preferential reactivity over the alkyne moiety, and that electrophilic substitution of the
presumed vinyl cation intermediateby the aromatic ring is preferable to attack by the amide
part.
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Scheme 5. Ring closure of trifunctional substrate
The geometry of the chromenoquinoline frame was established by single crystal Xꢀray
diffraction analysis in the case of compound 3aa (Figure 1).
Figure 1. Molecular structure ORTEP representation of compound 3aa.8,9 Displacement
ellipsoids are drawn at the 50% probability level.
Regarding a possible mechanism for the transformation, on the basis of the literature
reports2,3,5 we suppose that diaryliodonium salts (1) generate highly electrophilic
arylcopper(III) species 4 in the presence of the copper catalyst (Scheme 6). This copper(III)ꢀ
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intermediate interacts with the nitrile function (2) and forms a cationic species (5) and Cu(I).
The arylnitrilium intermediate 5 can be readily attacked in an intramolecular fashion by the
acetylene moiety resulting the formation of the chromene ring with exo vinyl cation. (6). The
resulting intermediate 6 can undergo an intramolecular cyclization via electrophilic aromatic
substitution, providing the chromenoquinoline product (3).
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Scheme 6. Plausible mechanism for the arylation-cyclization reaction.
CONCLUSION
In conclusion, we have demonstrated in a novel reaction that the ring closing strategy
based on electrophilic ArꢀCu(III) activation can be extended to substrates containing both
nitrile and acetylene functional groups. Herein, we report the development of a new copperꢀ
catalyzed oxidative transformation for the construction of chromenoquinoline derivatives
from arylpropynyloxybenzonitriles and diaryliodonium salts. The overall transformation
includes two sequential cyclizations which are accompanied by the formation of new CꢀC and
CꢀN bonds. The developed method enables the synthesis of chromenoquinoline derivatives
with high modularity due to the ease with which variable functional groups can be built into
the reaction. Further applications of the oxidative ring closureꢀarylation concept for the
construction of novel heterocyclic systems are in progress in our laboratory.
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EXPERIMENTAL SECTION
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General methods
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Ring closure reaction of substrates 1aꢀ1q with the appropriate iodonium salt (2aꢀ2m) were
performed under argon atmosphere. All solvents used were distilled using standard methods.
Ethyl acetate was distilled from calcium hydride. mCPBA was dried under high vacuum at
room temperature and was stored under argon. Unless otherwise noted, all reagents were
ordered and used without further purification. 1HꢀNMR and 13CꢀNMR spectras were recorded
at 250 MHz and 62.5 MHz using CDCl3 or DMSOꢀd6 as solvent. Chemical shifts are given in
ppm relative to TMS for CDCl3, or the residual solvent peak of DMSO as internal standards.
Coupling constants (J) are reported in Hertz (Hz). Infrared spectras were recorded on a singleꢀ
reflection diamond ATR spectrometer as solids or thin films. In the IR spectras only the
strongest/structurally most important peaks (n, cmꢀ1) are listed. HRMS data for new
compounds were obtained using a QꢀTQF high resolution mass spectrometer equipped with
an electrospray ion source. The measured melting points are uncorrected.
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General Procedure 1 for the synthesis of 2-(prop-2-yn-1-yloxy)benzonitriles
2ꢀ(Propꢀ2ꢀynꢀ1ꢀyloxy)benzonitriles were synthesized from the appropriate 2ꢀ
hydroxybenzonitrile derivatives and propargyl bromide according to the procedure of
Lingam10. 2ꢀhydroxybenzonitrile (1.12 g; 10.0 mmol) and potassium carbonate (2.76 g; 20.0
mmol) were added to a 100 ml round botton flask fitted with a rubber septum then the system
was charged with argon. Dimethyl formamide (60 ml) was added under argon atmosphere
then propargyl bromide (80% toluene solution) (1.93 g; 13.0 mmol; 1.45 ml) was added
dropwise. After that the mixture was stirred at 50 °C for 16 h. Dichloromethane (50 ml) and
distilled water (50 ml) were added to the reaction mixture, the aqueous phase was extracted
with dichloromethane (3 x 50 ml), the combined organics were washed with saturated LiCl
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solution (5 x 50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The
crude residue was purified by column chromatography.
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2-(Prop-2-yn-1-yloxy)benzonitrile (1a’)10
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Prepared according to the general procedure from 2ꢀhydroxybenzonitrile. Purification of the
crude product by column chromatography on silica gel afforded the product as a white
crystalline solid (1.48 g, 9.42 mmol, 94%). M. p. 77ꢀ78 °C; Rf = 0.35 (hexaneꢀethyl acetate,
5:1). 1H NMR (250 MHz, CDCl3): δ= 7.49 (dd, J = 10.1, 4.0 Hz, 2H), 7.07 (d, J = 8.9 Hz,
1H), 6.98 (t, J = 7.6 Hz, 1H), 4.75 (d, J = 2.3 Hz, 1H), 2.50 (t, J = 2.2 Hz, 1H); 13C NMR
(62.5 MHz, CDCl3): δ= 159.4, 134.6, 134.3, 122.1, 116.6, 113.4, 102.9, 78.0, 77.6, 56.9; IR
νmax/cmꢀ1 (solid): 2941, 2573, 2237, 1600, 1490, 1454, 1290, 1233, 1017, 740.
5-Chloro-2-(prop-2-yn-1-yloxy)benzonitrile (1b’)
Prepared according to the general procedure from 5ꢀchloroꢀ2ꢀhydroxybenzonitrile (500 mg,
3.27 mmol). Purification of the crude product by column chromatography on silica gel
afforded the product as a white crystalline solid (488 mg, 2.56 mmol, 78%). M. p. 125ꢀ126
°C; Rf = 0.60 (hexaneꢀethyl acetate, 4:1). 1H NMR (250 MHz, CDCl3) δ 7.51 (d, J = 8.1 Hz,
2H), 7.10 (d, J = 8.8 Hz, 1H), 4.82 (d, J = 1.9 Hz, 2H), 2.59 (s, 1H); 13C NMR (62.5 MHz,
CDCl3) δ 158.1, 134.6, 133.5, 127.0, 115.2, 114.8, 104.3, 77.7, 77.1, 57.3; IR νmax/cmꢀ1
(solid): 2930, 1488, 1285, 1266, 1234, 1135, 1018; HRMS m/z [MꢀH] Calculated for
C10H5NOCl: 190.0060; found 190.0069.
5-Bromo-2-(prop-2-yn-1-yloxy)benzonitrile (1c’)
Prepared according to the general procedure from 5ꢀbromoꢀ2ꢀhydroxybenzonitrile (1.00 g,
5.05 mmol). Purification of the crude product by column chromatography on silica gel
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afforded the product as a white crystalline solid (1.13 g, 4.81 mmol, 95%). M. p. 128ꢀ129 °C;
Rf = 0.32 (hexaneꢀethyl acetate, 5:1). 1H NMR (250 MHz, CDCl3) δ 7.66 – 7.52 (m, 2H), 6.98
(d, J = 8.7 Hz, 1H), 4.76 (d, J = 2.4 Hz, 2H), 2.52 (t, J = 2.3 Hz, 1H); 13C NMR (62.5 MHz,
CDCl3) δ 158.5, 137.4, 136.4, 115.10, 115.07, 113.7, 104.7, 77.8, 77.1, 57.2; IR νmax/cmꢀ1
(solid): 2957, 1486, 1286, 1235, 1132, 1016; HRMS m/z [MꢀH] Calculated for C10H5NOBr:
233.9554; found 233.9565.
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General procedure 2 for the synthesis of arylpropynyloxy-benzonitriles
Arylpropynyloxyꢀbenzonitriles were synthesized by Sonogashira reaction from the
appropriate 2ꢀ(propꢀ2ꢀynꢀ1ꢀyloxy)benzonitrile derivative and aryl iodide according to the
modified procedure of Kotschy11. 2ꢀ(propꢀ2ꢀynyloxy)benzonitrile (390 mg, 2.48 mmol),
PdCl2(PPh3)2 (43.5 mg, 0.060 mmol, 3 mol%) and copper(I)iodide (11.8 mg, 0.060 mmol, 3
mol%) were added to a 50 ml round bottom flask fitted with a rubber septum then the system
was charged with argon. DIPA (20 ml) was added under argon atmosphere then the
iodobenzene (422 mg, 2.07 mmol, 231 µl) was added dropwise. If the iodoarene was solid, it
was added with the copper and palladium sources before the addition of DIPA. The resulted
mixture was stirred at 30ꢀ45 °C for the appropriate time. The reaction mixure was diluted with
dichloromethane (20 ml) and distilled water (20 ml), neutralized with 2 M HCl solution,
extracted with dichloromethane (4 x 20 ml). The combined organics were washed with
distilled water (1 x 50 ml), with brine (1 x 50 ml), dried over anhydrous magnesium sulfate,
filtered and evaporated. The crude residue was purified by column chromatography.
2-(3-Phenylprop-2-ynyloxy)benzonitrile (1a)12
Prepared according to the general procedure from 2ꢀ(propꢀ2ꢀynꢀ1ꢀyloxy)benzonitrile
and iodobenzene (422 mg, 2.07 mmol, 231 µl) at 40ꢀ45°C for 1 h. Purification of the crude
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product by column chromatography on silica gel afforded the product as a drab solid (327 mg,
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1.40 mmol, 68%). M. p. 64ꢀ65 °C; Rf = 0.42 (hexaneꢀethyl acetate, 5:1). H NMR (250
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MHz,CDCl3) δ 7.65 – 7.51 (m, 2H), 7.48 – 7.39 (m, 2H), 7.37 – 7.26 (m, 3H), 7.26 – 7.18 (m,
1H), 7.05 (t, J = 7.5 Hz, 1H), 5.06 (s, 2H);13C NMR (62.5 MHz, CDCl3) δ 159.7, 134.6,
134.3, 132.2, 129.4, 128.8, 122.2, 121.9, 116.8, 113.5, 102.9, 88.7, 82.9, 57.8; IR νmax/cmꢀ1
(solid): 2973, 2232, 1597, 1492, 1454, 1289, 1231, 1015, 758, 737, 694.
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2-((3-(Thiophen-2-yl)prop-2-yn-1-yl)oxy)benzonitrile (1b)10
Prepared according to the general procedure from 2ꢀ(propꢀ2ꢀynyloxy)benzonitrile and
2ꢀiodothiophene (434 mg, 228 µl, 2.07 mmol) for 40 min at 30ꢀ35°C. Purification of the crude
product by column chromatography on silica gel afforded the product as a browny solid (465
mg, 1.95 mmol, 94%). M. p. 79ꢀ80 °C; Rf = 0.45 (hexaneꢀethyl acetate, 4:1). 1H NMR (250
MHz, CDCl3) δ 7.56 – 7.42 (m, 2H), 7.19 (d, J = 5.2 Hz, 1H), 7.17 – 7.06 (m, 1H), 6.97 (t, J =
7.6 Hz, 1H), 6.88 (dd, J = 5.0, 3.8 Hz, 1H), 4.97 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δ
159.6, 134.6, 134.3, 133.6, 128.5, 127.5, 122.0, 116.7, 113.4, 102.9, 86.9, 82.1, 57.8; IR
νmax/cmꢀ1 (solid): 2234, 1597, 1491, 1455, 1290, 1231, 1196, 1167, 1113, 1004, 849, 701.
2-((3-(p-Tolyl)prop-2-yn-1-yl)oxy)benzonitrile (1c)10
Prepared in a oneꢀpot synthesis. 2ꢀhydroxybenzonitrile (834 mg; 7.00 mmol) and
potassium carbonate (1.94 g; 14.0 mmol) were added to a 100 ml round botton flask fitted
with a rubber septum then the system was charged with argon. Dimethyl formamide (35 ml)
was added under argon atmosphere then propargyl bromide (80% toluene solution) (1.35 g;
9.10 mmol; 1.02 ml) was added dropwise then the mixture was stirred at 50 °C for 16 h. After
that PdCl2(PPh3)2 (123 mg; 0.175 mmol; 3 mol%) and copper(I)iodide (33.3 mg; 0.175 mmol;
3 mol%) dissolved in diisopropylamine (3 ml) were added under argom atmosphere to the
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reaction mixture then 4ꢀiodotoluene (1.27 g; 5.83 mmol) dissolved in diisopropylamine (1.5
ml) was added dropwise under argom atmosphere. The resulted mixture was stirred at 40ꢀ45
°C for 3 h. The workup is according to the steps written in the general procedure. Purification
of the crude product by column chromatography on silica gel afforded the product as a light
brown solid (637 mg, 2.58 mmol, 44% for the two steps). M. p. 37ꢀ38 °C; Rf = 0.32 (hexaneꢀ
ethyl acetate, 7:1). 1H NMR (250 MHz, CDCl3) δ 7.64 – 7.51 (m, 2H), 7.31 (d, J = 8.1 Hz,
2H), 7.22 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.6 Hz, 1H), 5.03 (s, 2H),
2.33 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 159.8, 139.6, 134.6, 134.2, 132.1, 129.5, 121.8,
119.1, 116.8, 113.5, 102.8, 88.9, 82.3, 57.8, 21.9; IR νmax/cmꢀ1 (solid): 2231, 1597, 1508,
1492, 1453, 1371, 1291, 1230, 1169, 1110, 1011, 820.
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2-((3-(4-Methoxyphenyl)prop-2-yn-1-yl)oxy)benzonitrile (1d)
Prepared according to the general procedure from 4ꢀiodoanisole (484 mg, 2.07 mmol).
for 45 min at 45 °C. Purification of the crude product by column chromatography on silica gel
afforded the product as a reddishꢀbrown solid (325 mg, 1.24 mmol, 60%). M. p. 58ꢀ59 °C; Rf
= 0.32 (hexaneꢀethyl acetate, 4:1).1H NMR (250 MHz, CDCl3) δ 7.56 – 7.37 (m, 2H), 7.25 (d,
J = 8.7 Hz, 2H), 7.12 (d, J = 8.9 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H),
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4.92 (s, 2H), 3.68 (s, 3H); C NMR (62.5 MHz, CDCl3) δ 160.5, 159.8, 134.6, 134.2, 133.8,
121.8, 116.8, 114.4, 114.2, 113.5, 102.8, 88.8, 81.6, 57.9, 55.7; IR νmax/cmꢀ1 (solid): 2232,
1605, 1510, 1492, 1291, 1249, 1231, 1175, 1034, 834; HRMS m/z [M+H]+ Calculated for
C17H14NO2: 264.1025; found 264.1023.
2-((3-(2-Chlorophenyl)prop-2-yn-1-yl)oxy)benzonitrile (1e)
Prepared according to the general procedure from 2ꢀchloroiodobenzene (493 mg, 253
µl, 2.07 mmol) for 30 min at 40 °C. Purification of the crude product by column
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chromatography on silica gel afforded the product as a drab solid (344 mg, 1.29 mmol, 62%).
M. p. 82ꢀ83 °C; Rf = 0.30 (hexaneꢀethyl acetate, 4:1). 1H NMR (250 MHz, CDCl3) δ 7.48 (t, J
= 7.3 Hz, 2H), 7.37 – 7.06 (m, 5H), 6.96 (t, J = 7.5 Hz, 1H), 5.01 (s, 2H); 13C NMR (62.5
MHz, CDCl3) δ 159.6, 136.6, 134.6, 134.2, 134.0, 130.5, 129.7, 126.9, 122.2, 122.0, 116.7,
113.7, 102.9, 88.0, 85.5, 57.7; IR νmax/cmꢀ1 (solid): 2232, 1600, 1492, 1475, 1455, 1290,
1231, 1015, 759, 739; HRMS m/z [M+H]+ Calculated for C16H11NOCl: 268.0524; found
268.0529.
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2-((3-(4-Chlorophenyl)prop-2-yn-1-yl)oxy)benzonitrile (1f)
Prepared according to the general procedure from 4ꢀchloroiodobenzene (493 mg, 2.07
mmol) for 30 min at 40 °C. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (460 mg, 1.72 mmol, 83%). M. p. 128ꢀ129 °C;
Rf = 0.62 (hexaneꢀethyl acetate, 7:3). 1H NMR (250 MHz, CDCl3) δ 7.49 (t, J = 8.0 Hz, 2H),
7.22 (q, J = 8.6 Hz, 4H), 7.11 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 4.95 (s, 2H); 13C
NMR (62.5 MHz, CDCl3) δ 159.6, 135.5, 134.6, 134.3, 133.4, 129.1, 122.0, 120.7, 116.7,
113.4, 102.9, 87.6, 83.9, 57.7; IR νmax/cmꢀ1 (solid): 2923, 2232, 1597, 1487, 1453, 1290,
1231, 1014, 827, 753; HRMS m/z [M+H]+ Calculated for C16H11NOCl: 268.0529; found
268.0528.
2-((3-(3-Bromophenyl)prop-2-yn-1-yl)oxy)benzonitrile (1g)
Prepared according to the general procedure from 3ꢀbromoiodobenzene (585 mg, 264
µl, 2.07 mmol) for 30 min at 35 °C. Purification of the crude product by column
chromatography on silica gel afforded the product as a drab solid (614 mg, 1.97 mmol, 95%).
M. p. 58ꢀ59 °C; Rf = 0.40 (hexaneꢀethyl acetate, 4:1). 1H NMR (250 MHz, CDCl3) δ 7.66 –
7.52 (m, 3H), 7.46 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.25 – 7.13 (m, 2H), 7.07 (t, J
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= 7.6 Hz, 1H), 5.04 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δ 159.6, 134.9, 134.6, 134.3,
132.5, 130.8, 130.2, 124.1, 122.5, 122.0, 116.6, 113.3, 102.9, 87.1, 84.2, 57.6; IR νmax/cmꢀ1
(solid): 2236, 1600, 1558, 1490, 1474, 1455, 1289, 1231, 1019, 786, 739, 683; HRMS m/z
[M+H]+ Calculated for C16H11NOBr: 312.0024; found 312.0028.
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2-((3-(4-Bromophenyl)prop-2-yn-1-yl)oxy)benzonitrile (1h)
Prepared according to the general procedure from 4ꢀbromoiodobenzene (585 mg, 2.07
mmol) for 45 min at 45 °C. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (598 mg, 1.92 mmol, 93%). M. p. 108ꢀ109 °C;
Rf = 0.40 (hexaneꢀethyl acetate, 4:1). 1H NMR (250 MHz, CDCl3) δ 7.49 (t, J = 8.0 Hz, 2H),
7.35 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 18.8, 8.1 Hz, 3H), 6.98 (t, J = 7.4 Hz, 1H), 4.95 (s, 2H);
13C NMR (62.5 MHz, CDCl3) δ 159.6, 134.6, 134.3, 133.6, 132.0, 123.7, 122.0, 121.1, 116.7,
113.4, 102.9, 87.6, 84.1, 57.7; IR νmax/cmꢀ1 (solid): 2233, 1601, 1487, 1458, 1290, 1231,
1015, 826, 738; HRMS m/z [M+H]+ Calculated for C16H11NOBr: 312.0024; found 312.0027.
2-((3-(4-Fluorophenyl)prop-2-yn-1-yl)oxy)benzonitrile (1i)
Prepared according to the general procedure from 4ꢀfluoroiodobenzene (459 mg, 238
µl, 2.07 mmol) for 25 min at 30 °C. Purification of the crude product by column
chromatography on silica gel afforded the product as a drab solid (378 mg, 1.51 mmol, 73%).
M. p. 64ꢀ65 °C; Rf = 0.63 (hexaneꢀethyl acetate, 7:3). 1H NMR (250 MHz, CDCl3) δ 7.56 –
7.42 (m, 2H), 7.31 (dd, J = 8.7, 5.4 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 – 6.83 (m, 3H),
4.95 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δ 159.7, 134.6, 134.3, 134.1, 121.9, 118.30,
118.25, 116.7, 116.3, 115.9, 113.4, 102.9, 87.7, 82.7, 57.70; IR νmax/cmꢀ1 (solid): 2227, 1700,
1559, 1541, 1508, 1491, 1458, 1231, 1017, 838; HRMS m/z [M+H]+ Calculated for
C16H11NOF: 252.0825; found 252.0820.
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2-((3-(4-Acetylphenyl)prop-2-yn-1-yl)oxy)benzonitrile (1j)
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Prepared according to the general procedure from 4ꢀiodoacetophenone (509 mg, 2.07
mmol) for 30 min at 40 °C. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (508 mg, 1.85 mmol, 89%). M. p. 88ꢀ89 °C; Rf =
0.26 (hexaneꢀethyl acetate, 3:1). 1H NMR (250 MHz, CDCl3) δ 7.80 (d, J = 7.4 Hz, 2H), 7.51
(d, J = 7.1 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 6.8 Hz, 1H),
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4.99 (s, 2H), 2.50 (s, 3H); C NMR (62.5 MHz, CDCl3) δ 197.6, 159.6, 137.2, 134.6, 134.3,
132.3, 128.6, 126.9, 122.1, 116.6, 113.4, 102.9, 87.8, 86.1, 57.6, 27.0; IR νmax/cmꢀ1 (solid):
2233, 1685, 1603, 1492, 1290, 1257, 1230, 1017, 844, 835, 734; HRMS m/z [M+H]+
Calculated for C18H14NO2: 276.1025; found 276.1018.
4-(3-(2-Cyanophenoxy)prop-1-yn-1-yl)phenyl acetate (1k)
Prepared according to the oneꢀpot synthesis described for compound 1c from 4ꢀ
iodophenyl acetate (611 mg, 2.33 mmol) for 5 h at 45 °C. Purification of the crude product by
column chromatography on silica gel afforded the product as a light brown solid (218 mg,
0.749 mmol, 32% for the two steps). M. p. 102ꢀ103 °C; Rf = 0.32 (hexaneꢀethyl acetate, 7:3).
1H NMR (250 MHz, CDCl3) δ 7.54 – 7.41 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.4
Hz, 1H), 7.03 – 6.90 (m, 3H), 4.94 (s, 2H), 2.19 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ
169.5, 159.7, 151.4, 134.6, 134.3, 133.4, 122.2, 121.9, 119.8, 116.7, 113.5, 102.8, 87.9, 83.0,
57.7, 21.5; IR νmax/cmꢀ1 (solid): 2234, 1769, 1599, 1506, 1492, 1229, 1198, 1016, 737; HRMS
m/z [M+Na]+ Calculated for C18H13NO3Na: 314.0793; found 314.0791.
Methyl 4-(3-(2-cyanophenoxy)prop-1-yn-1-yl)benzoate (1l)
Prepared according to the general procedure from methylꢀ4ꢀiodobenzoate (542 mg,
2.07 mmol) for 30 min at 35 °C. Purification of the crude product by column chromatography
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on silica gel afforded the product as a drab solid (531 mg, 1.82 mmol, 88%). M. p. 94ꢀ95 °C;
Rf = 0.50 (hexaneꢀethyl acetate, 7:3). 1H NMR (250 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H),
7.49 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 6.98 (t, J = 7.6 Hz,
1H), 4.98 (s, 2H), 3.82 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ 166.7, 159.6, 134.6, 134.3,
132.1, 130.6, 129.8, 126.8, 122.0, 116.6, 113.4, 102.9, 87.8, 85.8, 57.6, 52.7; IR νmax/cmꢀ1
(solid): 2235, 1723, 1601, 1491, 1287, 1231, 1111, 1020, 860, 737.698; HRMS m/z [M+H]+
Calculated for C18H14NO3: 292.0974; found 292.0975.
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5-Chloro-2-(3-phenylprop-2-ynyloxy)benzonitrile (1m)
Prepared according to the general procedure from 5ꢀchloroꢀ2ꢀ(propꢀ2ꢀ
ynyloxy)benzonitrile (382 mg, 2.00 mmol) and iodobenzene (340 mg, 1.67 mmol, 186 µl) for
30 min at 30ꢀ35 °C. Purification of the crude product by column chromatography on silica gel
afforded the product as a drab solid ( 236 mg, 0.884 mmol, 44%). M. p. 79ꢀ80 °C; Rf = 0.38
(hexaneꢀethyl acetate, 7:1). 1H NMR (250 MHz, CDCl3) δ 7.49 – 7.37 (m, 2H), 7.37 – 7.29
(m, 2H), 7.28 – 7.20 (m, 3H), 7.09 (dd, J = 8.2, 1.2 Hz, 1H), 4.95 (s, 2H); 13C NMR (62.5
MHz, CDCl3) δ 158.4, 134.6, 133.5, 132.2, 129.5, 128.8, 126.8, 122.0, 115.4, 114.9, 104.3,
89.2, 82.4, 58.2; IR νmax/cmꢀ1 (solid): 2237, 1485, 1285, 1235, 1138, 1010, 1000, 817, 738,
694; HRMS m/z [M+Na]+ Calculated for C16H10NOClNa: 290.0349; found 290.0359.
5-Bromo-2-(3-phenylprop-2-ynyloxy)benzonitrile (1n)
Prepared according to the general procedure from 5ꢀbromoꢀ2ꢀ(propꢀ2ꢀ
ynyloxy)benzonitrile (354 mg, 1.50 mmol) and iodobenzene (255 mg, 1.25 mmol, 140 µl) for
30 min at 30ꢀ35 °C. Purification of the crude product by column chromatography on silica gel
afforded the product as a white crystalline solid (225 mg, 0.723 mmol, 58%). M. p. 86ꢀ87 °C;
Rf = 0.33 (hexaneꢀethyl acetate, 5:1). 1H NMR (250 MHz, CDCl3) δ 7.66 – 7.50 (m, 1H), 7.39
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– 7.27 (m, 1H), 7.28 – 7.15 (m, 1H), 7.09 – 6.97 (m, 1H), 4.95 (s, 1H); 13C NMR (62.5 MHz,
CDCl3) δ 158.9, 137.4, 136.4, 132.2, 129.5, 128.8, 121.9, 115.3, 113.5, 104.7, 89.2, 82.3,
58.1; IR νmax/cmꢀ1 (solid): 2960, 2234, 1487, 1285, 1233, 1133, 1011, 813, 692; HRMS m/z
[M+Na]+ Calculated for C16H10NOBrNa: 333.9843; found 333.9856.
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4-Bromo-2-(3-phenylprop-2-ynyloxy)benzonitrile (1o)
Prepared according to the oneꢀpot synthesis described for compound 1c from 4ꢀ
bromoꢀ2ꢀhydroxybenzonitrile (500 mg, 2.53 mmol) and iodobenzene (396 mg, 1.94 mmol,
217 µl) for 3 h at 45ꢀ50 °C. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (112 mg, 0.360 mmol, 20%). M. p. 114ꢀ115 °C;
Rf = 0.36 (hexaneꢀethyl acetate, 5:1). 1H NMR (250 MHz, CDCl3) δ 7.41 – 7.28 (m, 4H), 7.27
– 7.15 (m, 4H), 7.15 – 7.05 (m, 1H), 4.94 (s, 2H); 13C NMR (62.5 MHz, CDCl3) δ 160.0,
134.9, 132.3, 129.6, 129.0, 128.8, 125.3, 121.9, 117.4, 116.0, 102.0, 89.5, 82.1, 58.2; IR
νmax/cmꢀ1 (solid): 2234, 1587, 1484, 1230, 1012, 1000, 854, 815, 738, 693; HRMS m/z
[M+Na]+ Calculated for C16H10NOBrNa: 333.9843; found 333.9853.
4-((3-Phenylprop-2-yn-1-yl)oxy)-[1,1'-biphenyl]-3-carbonitrile (1p)
5ꢀBromoꢀ2ꢀ(3ꢀphenylpropꢀ2ꢀynyloxy)benzonitrile (156 mg, 0.5 mmol), phenylboronic
acid (183 mg, 0.75 mmol), palladium acetate (5.61 mg, 0.025 mmol, 5 mol%) and triꢀtertꢀ
butylphosphonium tetrafluoroborate (7.25 mmol, 0.025 mmol, 5 mol%) and potassium
carbonate (138 mg, 1.00 mmol) were added to a 20 ml round bottom flask and the system was
charged with argon. Tetrahydrofurane (2.50 ml) and distilled water (2.50 ml) were added
dropwise under argon atmosphere then the reaction mixture was stirred at 50 °C for 1.5 h. The
reaction mixure was diluted with distilled water (10 ml) and extracted with ethyl acetate (4 x
10 ml). The combined organics were washed with brine (1 x 30 ml), dried over anhydrous
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magnesium sulfate, filtered and evaporated. Purification of the crude product by column
chromatography on silica gel afforded the product as a drab oil (135 mg, 0.438 mmol, 86%).
Rf = 0.35 (hexaneꢀethyl acetate, 5:1). 1H NMR (250 MHz, CDCl3) δ 7.70 – 7.61 (m, 2H), 7.43
– 7.37 (m, 2H), 7.40 – 7.25 (m, 4H), 7.29 – 7.15 (m, 5H), 4.97 (s, 2H); 13C NMR (62.5 MHz,
CDCl3) δ 159.0, 138.9, 135.3, 133.1, 132.6, 132.2, 129.5, 129.4, 128.8, 128.2, 127.1, 122.2,
116.7, 113.9, 103.3, 88.9, 82.9, 58.0; IR νmax/cmꢀ1 (solid): 2231, 1487, 1282, 1236, 1129,
1013, 999, 763, 738, 692; HRMS m/z [M+Na]+ Calculated for C22H15NONa: 332.1051; found
332.1059.
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N-(2-(3-(2-Cyanophenoxy)prop-1-yn-1-yl)phenyl)acetamide (1q)
Prepared according to the general procedure from Nꢀ(2ꢀiodophenyl)acetamide (362
mg, 2.30 mmol) for 2 h at 30ꢀ35 °C. Purification of the crude product by column
chromatography on silica gel afforded the product as a drab solid (400 mg, 1.38 mmol, 60%).
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M. p. 119ꢀ120 °C; Rf = 0.35 (hexaneꢀethyl acetate, 3:2); H NMR (250 MHz, CDCl3) δ 8.24
(d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.57 – 7.46 (m, 2H), 7.33 – 7.20 (m, 2H), 7.11 (d, J = 8.4
Hz, 1H), 6.97 (dt, J = 16.3, 7.5 Hz, 2H), 5.05 (s, 2H), 1.99 (s, 3H); 13C NMR (62.5 MHz,
CDCl3) δ 168.8, 159.4, 139.6, 134.7, 134.5, 132.3, 130.7, 123.8, 122.3, 120.1, 116.5, 113.2,
110.9, 103.0, 89.8, 84.2, 57.7, 25.1; IR νmax/cmꢀ1 (solid); 2233, 1699, 1600, 1581, 1517, 1492,
1446, 1301, 1231, 1016761, 740; HRMS m/z [M+Na]+ Calculated for C18H14N2O2Na:
313.0953; found 313.0940.
General procedure 3 for the one-pot synthesis of aryl-mesityliodonium triflates
Arylmesityliodonium triflates (2a-2m) were synthesized in a oneꢀpot procedure from
the appropriate iodoarene and mesitylene according to the modified procedure5a of Olofsson13.
mꢀChloroperbenzoic acid (65% active oxidant, 1.32 g, 5.00 mmol) and the appropriate
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iodoarene (4.50 mmol) were dissolved in dichloromethane (20 ml). Mesitylene (696 µl, 5.00
mmol) was added and the solution was cooled to 0 °C. Triflouromethanesulfonic acid (825
mg, 486 ꢁl, 5.50 mmol) was added dropwise in 5 min and the resulting reaction mixture was
allowed to warm to room temperature over 2 h. The volatile components were removed under
reduced pressure and the resulting material was suspended in diethyl ether (40 ml). The
suspension was stored at ꢀ20 °C for 2 h. The resulting crystals were filtered off and were
washed with ether to give the appropriate arylꢀmesityliodonium triflate as a solid, which was
dried at 100 °C under vacuum.
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Mesityl(phenyl)iodonium triflouromethanesulfonate (2a)5a
Prepared according to the general procedure from iodobenzene. The product was
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obtained as a white solid (1.71 g, 3.62 mmol, 80%). M. p. 147ꢀ148°C; H NMR (250 MHz,
DMSOꢀd6) δ 7.99 (d, 2H, J = 7.7 Hz), 7.64 (t, 1H, J = 7.3 Hz), 7.50 (t, 2H, J = 7.4 Hz), 7.22
(s, 2H), 2.60 (s, 6H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.1, 141.5, 134.5,
131.8, 131.7, 129.7, 122.5, 114.5, 26.2, 20.5; IR νmax/cmꢀ1 (solid): 1443, 1246, 1157, 1025,
856, 742, 632, 572, 515, 454; HRMS m/z [MꢀOTf]+ Calculated for C15H16I: 323.0291; found
323.0289.
2-Methylphenyl(mesityl)iodonium trifluoromethanesulfonate (2b)5a
Prepared according to the general procedure from 2ꢀiodotoluene. The product was
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obtained as a white solid (2.02 g, 4.16 mmol, 93%). M. p. 166ꢀ167 °C; H NMR (250 MHz,
DMSOꢀd6) δ 7.97 (d, 1H, J = 7.9 Hz), 7.55 (d, 2H, J = 4.4 Hz), 7.26 (m, 1H, J = 4.3Hz), 7.21
(s, 2H), 2.57 (s, 9H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 142.9, 141.6, 140.7,
136.7, 132.4, 131.8, 129.9, 129.3, 121.8, 118.5, 26.1, 24.4, 20.4; IR νmax/cmꢀ1 (solid): 1467,
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1245, 1156, 1027, 855, 759, 634, 516; HRMS m/z [MꢀOTf]+ Calculated for C16H18I:
337.0448; found 337.0443.
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3-Methylphenyl(mesityl)iodonium trifluoromethanesulfonate (2c)5a
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Prepared according to the general procedure from 3ꢀiodotoluene. The product was
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obtained as a white solid (1.59 g, 3.26 mmol, 73%). M. p. 171ꢀ172 °C; H NMR (250 MHz,
DMSOꢀd6): δ 7.87 (s, 1H), 7.78 (d, 1H, J = 7.6 Hz), 7.45 (d, 1H, J = 7.6 Hz), 7.38 (t, 1H, J =
7.7 Hz), 7.21 (s, 2H), 2.61 (s, 6H), 2.32 (s, 3H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀ
d6): δ 143.0, 141.9, 141.5, 134.6, 132.5, 131.6, 131.5, 129.7, 122.4, 114.3, 26.3, 20.7, 20.4; IR
νmax/cmꢀ1 (solid): 1455, 1275, 1245, 1156, 1025, 634, 516; HRMS m/z [MꢀOTf]+ Calculated
for C16H18I: 337.0448; found 337.0440.
4-Methylphenyl(mesityl)iodonium trifluoromethanesulfonate (2d)5a
Prepared according to the general procedure from 4ꢀiodotoluene. The product was
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obtained as a white solid (2.07 g, 4.26 mmol, 95%). M. p. 183ꢀ184 °C; H NMR (250 MHz,
DMSOꢀd6) δ 7.88 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.2 Hz), 7.20 (s, 2H), 2.60 (s, 6H), 2.32
(s, 3H), 2.28 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 142.9, 142.2, 141.4, 134.5, 132.4,
129.7, 122.7, 110.8, 26.2, 20.7, 20.4; IR νmax/cmꢀ1 (solid): 1452, 1246, 1157, 1024, 804, 632,
481; HRMS m/z [MꢀOTf]+ Calculated for C16H18I: 337.0448; found 337.0444.
(2-Chlorophenyl)(mesityl)iodonium trifluoromethanesulfonate (2e)5a
Prepared according to the general procedure from 1ꢀchloroꢀ2ꢀiodobenzene. The
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product was obtained as an offꢀwhite solid (1.41 g, 2.78 mmol, 62%). M. p. 167ꢀ168 °C; H
NMR (250 MHz, DMSOꢀd6) δ 8.27 (dd, 1H, J = 8.1 Hz and 1.3 Hz), 7.82 (dd, 1H, J = 8.1 Hz
and 1.4 Hz), 7.68 (td, 1H, J = 7.9 Hz and 1.4 Hz), 7.45 (td, 1H, J = 7.9 Hz and 1.4 Hz), 7.21
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(s, 2H), 2.62 (s, 6H), 2.28 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.2, 141.8, 138.9,
135.7, 134.3, 130.7, 130.0 (d, J = 7.8 Hz), 122.6, 116.4, 26.1, 20.4; IR νmax/cmꢀ1 (solid): 1449,
1276, 1239, 1160, 1024, 759, 631, 516,432; HRMS m/z [MꢀOTf]+ Calculated for C15H15ClI:
356.9901; found 356.9899.
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(4-Chlorophenyl)(mesityl)iodonium trifluoromethanesulfonate (2f)5a
Prepared according to the general procedure from 1ꢀchloroꢀ4ꢀiodobenzene. The
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product was obtained as a white solid (1.37 g, 2.70 mmol, 60%). M. p. 177ꢀ178 °C; H NMR
(250 MHz, DMSOꢀd6) δ 7.98 (d, 2H, J = 8.7 Hz), 7.57 (d, 2H, J = 8.7 Hz), 7.23 (s, 2H), 2.59
(s, 6H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.2, 141.5, 136.9, 136.2, 131.7,
129.8, 122.7, 112.2, 26.2, 20.4; IR νmax/cmꢀ1 (solid): 1473, 1245, 1163, 1024, 807, 631, 516;
HRMS m/z [MꢀOTf]+ Calculated for C15H15ClI: 356.9901; found 356.9901.
2-Bromophenyl(mesityl)iodonium trifluoromethanesulfonate (2g)5a
Prepared according to the general procedure from 2ꢀbromoiodobenzene. The product
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was obtained as an offꢀwhite solid (1.65 g, 2.98 mmol, 66%). M. p. 167ꢀ168 °C; H NMR
(250 MHz, DMSOꢀd6) δ 8.18 (dd, 1H, J = 7.9 and 1.4 Hz), 7.95 (dd, 1H, J = 7.9 and 1.4 Hz),
7.59 (td, 1H, J = 7.9 and 1.4 Hz), 7.47 (td, 1H, J = 7.9 and 1.4 Hz), 7.22 (s, 2H) 2.62 (s, 6H),
2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.2, 141.8, 139.0, 134.1, 130.4, 130.0,
126.5, 119.4, 26.3, 20.4; IR νmax/cmꢀ1 (solid): 1442, 1276, 1241, 1160, 1025, 757, 631, 516;
HRMS m/z [MꢀOTf]+ Calculated for C15H15BrI: 400.9396; found 400.9386.
3-Bromophenyl(mesityl)iodonium trifluoromethanesulfonate (2h)5a
Prepared according to the general procedure from 3ꢀbromoiodobenzene. The product
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was obtained as an offꢀwhite solid (1.35 g, 2.45 mmol, 55%). M. p. 173ꢀ174 °C; H NMR
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(250 MHz, DMSOꢀd6) δ 8.29 (s, 1H), 7.90 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 7.4 Hz), 7.44
(t, 1H, J = 7.9), 7.23 (s, 2H), 2.60 (s, 6H), 2.30 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ
144.0, 143.3, 141.7, 136.1, 134.7, 133.5, 133.1, 129.8, 123.4, 122.6, 114.9, 26.3, 20.5; IR
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ν
max/cmꢀ1 (solid): 1454, 1222, 1024, 797, 634, 516; HRMS m/z [MꢀOTf]+ Calculated for
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C15H15BrI: 400.9396; found: 400.9402.
4-Bromophenyl(mesityl)iodonium trifluoromethanesulfonate (2i)5a
Prepared according to the general procedure from 4ꢀbromoiodobenzene. The product
1
was obtained as a white solid (1.69 g, 3.07 mmol, 68%). M. p. 179ꢀ180 °C; H NMR (250
MHz, DMSOꢀd6) δ 7.90 (d, 2H, J = 8.5 Hz), 7.70 (d, 2H, J = 8.5 Hz), 7.22 (s, 2H), 2.60 (s,
6H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.2, 141.5, 136.3, 134.6, 129.8,
125.7, 122.7, 113.0, 26.2, 20.5; IR νmax/cmꢀ1 (solid): 1473, 1245, 1232, 1024, 807, 631, 518,
475; HRMS m/z [MꢀOTf]+ Calculated for C15H15BrI: 400.9396; found: 400.9399.
2-Fluorophenyl(mesityl)iodonium trifluoromethanesulfonate (2j)5a
Prepared according to the general procedure from 2ꢀfluoroiodobenzene. The product
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was obtained as an offꢀwhite solid (1.04 g, 2.12 mmol, 47%). M. p. 161ꢀ162 °C; H NMR
(250 MHz, DMSOꢀd6) δ 8.27 (m, 1H), 7.72 (m, 1H), 7.56 (td, 1H, J = 8.8 Hz and 1.3 Hz),
7.35 (td, 1H, J = 7.9 Hz and 1.3 Hz), 7.20 (s, 2H), 2.62 (s, 6H), 2.27 (s, 3H); 13C NMR (62.5
MHz, DMSOꢀd6) δ 143.2, 141.5, 137.4, 135.3 (d, J = 8.3 Hz), 129.8, 127.5 (d, J = 2.6 Hz),
122.7, 117.3, 116.9, 101.6, 101.3, 26.0, 20.4; IR νmax/cmꢀ1 (solid): 1476, 1279, 1236, 1161,
1027, 770, 635, 515; HRMS m/z [MꢀOTf]+ Calculated for C15H15FI: 341.0197; found:
341.0194.
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Prepared according to the general procedure from 3ꢀfluoroiodobenzene. The product
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was obtained as an offꢀwhite solid (1.31 g, 2.67 mmol, 59%). M. p. 177ꢀ178 °C; H NMR
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(250 MHz, DMSOꢀd6) δ 7.97 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 9.6 Hz,
2H), 7.22 (s, 2H), 2.60 (s, 6H), 2.29 (s, 3H); 13C NMR (62.5 MHz, DMSOꢀd6) δ 143.70,
142.05, 133.87, 133.75, 130.94, 130.90, 130.19, 123.05, 122.17, 121.77, 119.67, 119.33,
114.16, 26.65, 20.83; IR νmax/cmꢀ1 (solid): 2045, 1592, 1582, 1471, 1286, 1239, 1225, 1168,
1025, 839, 735, 668; HRMS m/z [MꢀOTf]+ Calculated for C15H15FI: 341.0203; found
341.0217.
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4-Fluorophenyl(mesityl)iodonium trifluoromethanesulfonate (2l)5a
Prepared according to the general procedure from 4ꢀfluoroiodobenzene. The product
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was obtained as an offꢀwhite solid (1.63 g, 3.33 mmol, 74%). M. p. 178ꢀ179 °C; H NMR
(250 MHz, DMSOꢀd6) δ 7.37 (t, 2H, J = 8.7 Hz), 7.22 (s, 2H), 2.60 (s, 6H), 2.29 (s, 3H); 13C
NMR (62.5 MHz, DMSOꢀd6) δ 143.1, 141.5, 137.4, 137.2, 129.7, 119.4, 119.0, 26.2, 20.5; IR
νmax/cmꢀ1 (solid): 1575, 1483, 1224, 1168, 1024, 849, 632, 508; HRMS m/z [MꢀOTf]+
Calculated for C15H15FI: 341.0203; found: 341.0195.
(4-(Ethoxycarbonyl)phenyl)(mesityl)iodonium trifluoromethanesulfonate (2m)5a
Prepared according to the general procedure from ethyl 4ꢀiodobenzoate with the
exception that 3ꢀchloroperoxybenzoic acid, mesitylene and the aryl iodide were stirred
together at room temperature for 4 hours before the addition of the trifluoromethanesulfonic
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acid. The product was obtained as a white solid (1.159 g, 47%). M. p. 174ꢀ175 °C; H NMR
(250 MHz, DMSOꢀd6): δ 8.09 (d, 2H, J = 8.4 Hz), 7.99 (d, 2H, J = 8.4 Hz), 7.24 (s, 2H), 4.31
(q, 2H, J = 6.9 Hz), 2.59 (s, 2H), 2.30 (s, 1H), 1.29 (t, 3H, J = 7.0 Hz); 13C NMR (62.5 MHz,
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DMSOꢀd6): δ 164.5, 143.4, 141.7, 134.7, 132.7, 131.9, 129.9, 122.6, 119.3, 61.4, 26.3, 20.5,
14.0; IR νmax/cmꢀ1 (solid): 1723, 1584, 1458, 1395, 1272, 1238, 1161, 1103, 1025, 849, 753,
634, 516; HRMS m/z [MꢀOTf]+ Calculated for C18H20IO2: 395.0502; found: 395.0504.
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General procedure 4 for the synthesis of 7-aryl-6H-chromeno[4,3-b]quinolines
2ꢀ(3ꢀPhenylpropꢀ2ꢀynyloxy)benzonitrile (1a) (117 mg, 0.500 mmol), diaryl iodonium
salt (0.600 mmol, 1.2 eq.) and copper(I)chloride (4.96 mg; 0.050 mmol, 10 mol%) were added
to a 4 ml vial then the system was charged with argon. Ethyl acetate (1 ml) was added under
argon atmosphere then the reaction mixture was stirred at 75°C for the appropriate time.
Saturated sodium hydrogen carbonate solution (10 ml) was added to the mixture, the aqueous
layer was extracted with dichloromethane (4 x 10 ml) the combined organics were washed
with brine (1 x 25 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The
crude residue was purified by column chromatography.
7-Phenyl-6H-chromeno[4,3-b]quinoline (3aa)14
Prepared according to the general procedure from 2ꢀ(3ꢀphenylpropꢀ2ꢀ
ynyloxy)benzonitrile and phenyl(mesityl)iodonium trifluoromethanesulfonate (283 mg, 0.600
mmol) for 1 h. Purification of the crude product by column chromatography on silica gel
afforded the product as a drab solid (120 mg, 0.388 mmol, 78%). M. p. 159ꢀ160 °C; Rf = 0.45
(hexaneꢀethyl acetate, 10:1). 1H NMR (250 MHz, CDCl3) δ 8.42 (d, J = 6.7 Hz, 1H), 8.05 (d,
J = 7.8 Hz, 1H), 7.62 – 7.48 (m, 1H), 7.46 – 7.29 (m, 4H), 7.30 – 7.11 (m, 4H), 7.09 – 6.97
(m, 1H), 6.84 (d, J = 7.4 Hz, 1H), 4.96 (s, 2H).; 13C NMR (62.5 MHz, CDCl3) δ 157.7, 149.1,
148.4, 144.1, 135.3, 132.3, 130.0, 129.73, 129.65, 129.2, 128.9, 127.5, 126.6, 126.5, 126.21,
123.9, 123.2, 122.9, 117.6, 67.1; IR νmax/cmꢀ1 (solid): 2927, 2910, 1583, 1560, 1506, 1490,
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1465, 1222, 1044, 769, 737, 700; HRMS m/z [M+H]+ Calculated for C22H16NO: 310.1232;
found 310.1236.
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Prepared according to the general procedure from 2ꢀ(3ꢀphenylpropꢀ2ꢀ
ynyloxy)benzonitrile and 2ꢀmethylphenyl(mesityl)iodonium trifluoromethanesulfonate (292
mg, 0.600 mmol) for 5 h. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (52.0 mg, 0.161 mmol, 32%). M. p. 124ꢀ125 °C;
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Rf = 0.30 (hexaneꢀethyl acetate, 30:1). H NMR (250 MHz, CDCl3): δ= 8.48 (dd, J = 7.7, 1.3
Hz, 1H), 7.39 (d, J = 5.6 Hz, 4H), 7.30 – 6.98 (m, 7H), 6.84 (d, J = 8.1 Hz, 1H), 4.96 (s, 2H),
2.81 (s, 3H); 13C NMR (62.5 MHz, CDCl3): δ= 157.6, 147.6, 147.3, 144.2, 137.9, 135.8,
132.0, 129.9, 129.7, 129.1, 128.8, 127.4, 126.3, 126.2, 124.5, 124.3, 122.8, 122.7, 117.5, 67.2,
18.6; IR νmax/cmꢀ1 (solid): 2928, 2365, 1588, 1489, 1394, 1369, 1222, 1040, 769, 741; HRMS
m/z [M+H]+ Calculated for C23H18NO: 324.1388; found 324.1392.
8-Methyl-7-phenyl-6H-chromeno[4,3-b]quinoline and 10-methyl-7-phenyl-6H-chromeno[4,3-
b]quinoline (3ac)
Prepared according to the general procedure from 2ꢀ(3ꢀphenylpropꢀ2ꢀ
ynyloxy)benzonitrile and 3ꢀmethylphenyl(mesityl)iodonium trifluoromethanesulfonate (292
mg, 0.600 mmol) for 20 min. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (105 mg, 0.325 mmol, 65%). M. p. 99ꢀ100 °C;
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Rf = 0.35 (hexaneꢀethyl acetate, 25:1). H NMR (250 MHz, CDCl3) δ 8.52 – 8.28 (m, 1H),
7.94 (d, J = 8.3 Hz, 0.5H), 7.84 (s, 0.5H), 7.50 – 6.94 (m, 9H), 6.82 (t, J = 7.6 Hz, 1H), 4.94
(s, 1H), 4.77 (s, 1H), 2.40 (s, 1.5H), 1.77 (s, 1.5H); 13C NMR (62.5 MHz, CDCl3) δ 157.7,
157.6, 149.6, 149.0, 148.6, 147.9, 144.3, 144.0, 140.0, 139.4, 136.1, 135.5, 132.1, 130.3,
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The Journal of Organic Chemistry
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129.7, 129.5, 129.3, 129.2, 129.13, 129.06, 128.91, 128.87, 128.8, 128.6, 126.2, 126.1, 126.0,
125.5, 124.4, 124.0, 123.6, 122.83, 122.78, 122.4, 117.5, 117.4, 67.2, 67.1, 24.5, 22.1; IR
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ν
max/cmꢀ1 (solid): 2928, 2366, 2340, 1701, 1577, 1558, 1539, 1506, 1487, 1219, 1042, 738;
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HRMS m/z [M+H]+ Calculated for C23H18NO: 324.1388; found 324.1392.
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9-Methyl-7-phenyl-6H-chromeno[4,3-b]quinoline (3ad)15
Prepared according to the general procedure from 2ꢀ(3ꢀphenylpropꢀ2ꢀ
ynyloxy)benzonitrile and 4ꢀmethylphenyl(mesityl)iodonium trifluoromethanesulfonate (292
mg, 0.600 mmol) for 30 min. Purification of the crude product by column chromatography on
silica gel afforded the product as a drab solid (81.5 mg, 0.252 mmol, 50%). M. p. 193ꢀ194 °C;
Rf = 0.35 (hexaneꢀethyl acetate, 15:1). 1H NMR (250 MHz, CDCl3) δ 8.41 (d, J = 7.3 Hz, 1H),
7.96 (d, J = 8.5 Hz, 1H), 7.53 – 7.29 (m, 4H), 7.28 – 6.96 (m, 5H), 6.84 (d, J = 8.0 Hz, 1H),
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4.94 (s, 2H), 2.26 (s, 3H); C NMR (62.5 MHz, CDCl3) δ 157.6, 148.2, 146.9, 143.5, 136.6,
135.5, 132.0, 129.7, 129.2, 128.9, 127.4, 126.1, 125.4, 124.0, 123.2, 122.9, 117.5, 67.2, 22.2;
IR νmax/cmꢀ1 (solid): 2924, 2367, 2340, 1585, 1495, 1467, 1221, 1049, 1000, 831, 737; HRMS
m/z [M+H]+ Calculated for C23H18NO: 324.1388; found 324.1390.
9-Chloro-7-phenyl-6H-chromeno[4,3-b]quinoline (3af)16
Prepared according to the general procedure from 2ꢀ(3ꢀphenylpropꢀ2ꢀ
ynyloxy)benzonitrile and (4ꢀchlorophenyl)(mesityl)iodonium trifluoromethanesulfonate (302
mg, 0.600 mmol) for 2 h. Purification of the crude product by column chromatography on
silica gel afforded the product as a white solid (95.0 mg, 0.277 mmol, 55%). M. p. 174ꢀ175
°C; Rf = 0.38 (hexaneꢀethyl acetate, 20:1). 1H NMR (250 MHz, CDCl3) δ 8.47 – 8.25 (m, 1H),
7.95 (d, J = 8.9 Hz, 1H), 7.54 – 7.36 (m, 4H), 7.30 (d, J = 2.1 Hz, 1H), 7.28 – 7.20 (m, 1H),
7.19 – 7.10 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.94 (s, 2H); 13C NMR
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