Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis

Article abstract of DOI:10.1021/acs.joc.8b00620

The copper(I)-doped zeolite Cu^I-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prepare and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biological relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.

Full text of DOI:10.1021/acs.joc.8b00620

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Article
Copper(I)-USY as a Ligand-Free and Recyclable
Catalyst for Ullmann-Type O-, N-, S- and C-Arylation
Reactions: Scope and Application to Total Synthesis
Tony GARNIER, Mathieu DANEL, Valentin MAGNE, Anthony
PUJOL, Valérie BENETEAU, Patrick Pale, and Stefan CHASSAING
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00620 • Publication Date (Web): 23 May 2018
Downloaded from http://pubs.acs.org on May 23, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Copper(I)-USY as a Ligand-Free and Recyclable Catalyst
for Ullmann-Type O-, N-, S- and C-Arylation Reactions:
Scope and Application to Total Synthesis
9
Tony Garnier,a Mathieu Danel,a Valentin Magné,a Anthony Pujol,a Valérie Bénéteau,b
Patrick Pale*b and Stefan Chassaing*a,b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aITAV, Université de Toulouse, CNRS, Toulouse, France
bLaboratoire de Synthèse, Réactivité Organique et Catalyse (LASYROC), Institut de Chimie, CNRS-
UMR7177, Université de Strasbourg, 4 rue Blaise Pascal, 67070 Strasbourg, France
GRAPHICAL ABSTRACT
recyclable
application
OH
O
O
CuI
CuI
Nu
Nu
+
X
CuI
CuI-USY
R
3-Methylobovatol
R
> 50 examples
- ligand-free method
- wide scope
- high functional group tolerance
X = I, Br
Nu = O-, N-, S-, and C-nucleophiles
ABSTRACT
The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable
catalyst for various Ullmann-type coupling reactions. Easy-to-prepare and cheap, this
catalytic material enables the arylation and heteroarylation of diverse O-, N-, S- and C-
nucleophiles under ligand-free conditions, while exhibiting large functional group
compatibility. The facility of this catalyst to promote C-O bond formation was further
demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether
of biological relevance. From a mechanistic viewpoint, two competitive pathways depending
on the nature of the nucleophile and consistent with the obtained results have been
proposed.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
5
1-INTRODUCTION –
6
7
8
9
Originally found by Ullmann at the very end of the XIXth century,1 the copper-promoted
coupling of aryl halides with various O- and N-nucleophiles has been revamped in the past
decades and extended to C- and S-nucleophiles, while becoming a catalytic and useful tool
in organic synthesis.2 The original stoichiometric process, performed under harsh conditions,
was replaced a century later by one based on palladium complexes used in catalytic
amounts under much milder conditions, through the seminal works of Buchwald and
Hartwig.3 In an amazing reversal, copper came back again at the beginning of the XXIst
century, due to its lower cost and toxicity and to its higher abundance. Various combinations
of copper salts and specific ligands have thus been developed to set up mild and useful
copper-catalyzed arylation reactions.4 Such reactions allow the arylation of N-, O-, S-, and to
a lesser extend C-, nucleophiles such as anilines, amines, amides, alcohols, phenols and
thiols as well as some activated methylene compounds, that have led to numerous
applications in synthesis, medicinal chemistry, life and materials sciences.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Although milder and catalytic conditions have been set, mostly relying on specific ligands, not
much has so far been done for ‘greening’ further such arylation reactions through
heterogeneous catalysis, despite the interest of such catalysis within the Green Chemistry
context.6 Cu-nanoparticules, Cu-supported on carbon,7 alumina, titania, kaolin,8 and Cu-
complexes grafted on various materials9-12 have been reported, but with variable efficiency
and results.
Since we are exploring the potential of easy-to-prepare, inexpensive and highly stable CuI-
zeolites as ligand-free catalysts for organic synthesis,13,14 we have attempted applying CuI-
zeolites to Ullmann-type arylations.15 We report here that CuI-USY zeolite indeed acted as an
efficient ligand-free and recyclable catalyst for various Ullmann-type C-O, C-N, C-S and C-C
coupling reactions (Scheme 1) and we also report its application as key step in the total
synthesis of a naturally occurring diaryl ether, namely 3-methylobovatol.
CuI
X
Nu
R
+
Nu
CuI
R
CuI
CuI-USY
X = Halogen
Nu = O-, N-, S-, and C-nucleophiles
Scheme 1 – CuI-USY catalyzed Ullmann-type arylation reactions
2-RESULTS AND DISCUSSION –
2.1- O-, N-, S, and C-arylation reactions – scope and limitations
2.1.1- The C-O case – Simple aryl iodides or bromides readily react with electron-rich
phenols, such as 3,5-dimethylphenol, in the presence of CuI-USY and cesium carbonate in
toluene at 120 °C.15 However, aryl chlorides do not, as shown here. Indeed, chlorobenzene
only gave trace amounts of the expected diaryl ether 1a when submitted to these conditions
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
with 3,5-dimethylphenol in toluene or DMF and even after heating at 140 °C and prolonged
reaction times (Scheme 2).
Functionalized aryl bromides and iodides were then engaged in a series of O-arylation with
the model 3,5-dimethylphenol. Those carrying strongly electron-withdrawing group efficiently
gave the corresponding diaryl ethers 1b,c in high yields (78-83%), as already shown,15 but
those carrying carbonyl group gave variable but interesting results. Aryl halides bearing a
ketone, such as fluorenone or acetophenone, smoothly reacted to give the diaryl ethers 1d
and 1e in comparable yields. Not so surprisingly, aryl halides bearing an aldehyde were more
prone to side-reactions, and the expected diaryl ethers were thus obtained in more modest
yields (~ 40% for 1f). The latters could nevertheless be improved by performing the coupling
reaction in the more polar solvent DMF (up to 60%). As suspected from steric hindrance and
as already observed with ortho-methyl substituted derivatives,15 ortho-bromobenzaldehyde
gave the expected coupling product 1g in only low yield. Aryl iodide carrying an isopropyl
ester group readily reacted, giving 1h in good yield, while its methyl ester analog only led to
the expected product 1i in modest yield. Interestingly, the corresponding free carboxylic acid
could also be engaged in such coupling, but DMF proved to be a much more suitable solvent
than toluene, probably for solubility reasons. Thus, performing the O-arylation in DMF at
higher temperature – i.e., 140 °C – led to the formation of 1j in high yield (80%).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Other functional groups, including basic amines, ethers and acid-sensitive acetals, were
examined and all of them proved fully compatible with the reaction conditions, giving the
expected diaryl ethers 1k-p in good to excellent yields. Of particular relevance is the
compatibility of the present conditions with the allyl residue and the common acid-sensitive
methoxymethyl (MOM) protecting group, providing 1o,p in good to high yields depending on
the starting halide. Rewardingly, pyridinyl halides also appeared as suitable aryl sources,
despite their strongly coordinating motif. Indeed, 2- and 3-bromopyridines were very
efficiently converted into the corresponding pyridyl aryl ethers 1q and 1r, quantitatively for the
first and in high yield for the second.
In a second series of experiments, the phenol scope was examined further. The electron-rich
3-dimethylaminophenol readily reacted with phenyl iodide, furnishing diaryl ether 1s, while
phenols carrying strongly electron-withdrawing group, such as nitro or cyano groups, did not
react, no trace of the expected diaryl ethers 1t,u being detected.15 However, 4-chlorophenol
did, providing the 4-chlorophenyl phenyl ether 1v in reasonable yield (~60%). Surprisingly,
some amounts of the diether 1v’ were also isolated, revealing the possibility of coupling 4-
chlorophenol with 1v. Despite some hindrance, 2-naphtol reacted with phenyl iodide, giving
the expected 2-naphtyl phenyl ether 1w, but DMF was required to reach satisfactory yield, as
the reaction proved faster in DMF than in toluene in this case.
Interestingly, even aliphatic alcohols, such as ethanol and butan-1-ol, could be engaged with
iodobenzene into this coupling reaction, providing in good yields the corresponding aryl alkyl
ethers 1x,y (~75%).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
8
O
CuI-USY a
Ph
O
Cs2CO3
X
R
R'
R'
OH
85 %: X = I
83 %: X = Br
< 5 % (< 5 %b, < 5 %b,c): X = Cl
PhCH3
R
1a
120 °C, 24 h
1a-y
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
NO2
CN
1d 83 %: X = Br
83 %: X = I
78 %: X = Br
83 %: X = I
83 %: X = Br
1c
1b
H
O
O
O
O
O
O
H
36 % (39 %b): X = I
38 % (60 %b): X = Br
76 %: X = I
55 %: X = Br
1f
1e
1g 19 %: X = Br
O
O
O
O
O
O
O
OH
O
41 %d: X = I
-e (25 %b, 80 %c): X = I
1h
70 %: X = I
1i
1j
O
O
O
O
O
O
O
NEt2
66 %: X = I
74 %: X = Br
1k
84 %: X = Br
1m 84 %: X = I
1l
1n
77 %: X = I
O
O
O
O
N
N
O
O
O
84 %: X = I
64 %: X = Br
1r
79 %: X = Br
1p
1o
1q
quant.: X = Br
79 %: X = I
O
O
O
Ph
N
O
Ph
Cl
Ph
Ph
1v 58 %g: X = I
NC
O2N
1u 0 %g: X = I
1t 0 %f: X = I
1s
69 %: X = I
/
O
Ph
Cl
O
O
Ph
Ph
Ph
O
1v' 4 %: X = I
O
21 % (62 %b): X = I
75 %h: X = I
73 %h: X = I
1y
1w
1x
a Reactions run with CuI-USY (10 mol%), ROH (1.5 equiv), aryl halide (1.0 equiv) and Cs2CO3
(2.0 equiv), unless otherwise stated. b Reactions run in DMF in place of PhCH3. c Reactions run
at 140 °C. d The H NMR analysis of the crude revealed the formation of 1i together with
unidentified side products. e No conversion observed in PhCH3. f No trace of expected product
detected by LCMS. g Ph2O also isolated in a 35 % yield. h Reaction run in the nucleophilic
alcohol as solvent.
1
Scheme 2 – CuI-USY catalyzed O-arylation reactions
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.1.2- The C-N case – To go further with our CuI-USY arylation tool, we evaluated its
potential for C-N bond formation. Various anilines, aliphatic amines and amides as N-
nucleophiles were thus submitted to the set-up conditions.16 Rewardingly, the expected N-
arylated products were produced in most cases (Scheme 3). From our results, the solvent
nature and the electronic profile of the N-nucleophiles emerged as crucial factors in
governing the reactivity, thus the product yields.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CuI-USY a
Cs2CO3
R'
N
R'
I
R
R'
R'
NH
DMF
R
120 °C, 24 h
2a-k
H
H
N
H
N
F3C
NPh2
F3C
Ph
N
Ph
Ph
/
2c'
2c
CF3
CF3
32 % : 31 %d (0 %b)
52 % : 21 %c,e
19 % : 57 %c,f,g
< 5 %
(0 %b, 7 %c)
2b 0 % (0 %b)
2c/2c'
2a
H
N
H
N
NPh2
Ph
/
O2N
O2N
O
2d'
O2N
2d
88 % : 18 %e
traces : 72 %c,f
2e 77 %e,h
2d/2d'
H
N
Ph
N
X
N Ph
O
H
O2N
2h: X = CH2
2i: X = O
2g 0 % (0 %b,c
)
2f 75 %e,i
0 %
O
O
Ph
N Ph
Ph
N
H
75 %
24 %
2k
2j
(28 %b, 99 %c)
(0 %b, 83 %c)
aReactions run with CuI-USY (10 mol%), RNHR' (1.5 equiv), aryl
iodide (1.0 equiv), Cs2CO3 (2.0 equiv) and DMF as solvent, unless
c
otherwise stated. bReactions run in PhCH3. Reactions run at 140
e
°C. dIncomplete conversion . Reactions run with 2.5 equiv. RNHR'
and 1.0 equiv. aryl halide. fReactions run with 2.5 equiv. aryl halide
g
h
and 1.0 equiv. RNHR'. Reactions run for 72 h. Triarylated amine
i
2e' isolated in a 14 % yield. No traces of triarylated amine
detected.
Scheme 3 – CuI-USY catalyzed N-arylation reactions with anilines, aliphatic amines and amides
Although the best solvent for CuI-USY catalyzed O-arylations, toluene proved to be
inappropriate for N-arylation. No trace of the expected products 2a-c,g-j was indeed detected
when performing the reaction in toluene, apart from product 2k isolated in low yields (28%).
However, shifting from toluene to DMF restored the reactivity in most cases, provided that
electronic effects were suitable. Indeed, simple aniline and its 4-methyl analog proved
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
5
6
7
8
9
ineffective as coupling partners and only traces of the expected products 2a,b could be
isolated, while 3,5-bis(trifluoromethyl)aniline and 4-nitroaniline smoothly reacted, providing
the diaryl amines 2c,d. The latter reactions furnished the monoarylated products 2c,d in ~20
to 88% yields, together with non-negligible amounts (~20%) of the corresponding doubly
arylated products 2c',d'. Interestingly enough, the ratio between mono- and bis-arylated
products could be balanced by simply adjusting the aniline:iodobenzene stoichiometry. In this
way, diaryl amine 2d or triaryl amine 2d' were selectively produced, both in good to high
yields. It is worth mentioning that these diaryl amines could be formed from electron-rich or
electron-poor phenyl iodide, as illustrated by the similar good yields in which 2e and 2f were
also formed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These results thus revealed that electronic effects in the amine nucleophile dramatically
influence the reaction efficiency, while they do not significantly in the aryl iodide partner.
The more basic and more strongly coordinating aliphatic amines as well as less coordinating
and more acidic amides were also engaged in the present coupling conditions. The formers
did not lead to the formation of the expected N-phenylated amines 2g-i. In contrast, primary
and secondary amides could be engaged in this coupling, although higher temperatures were
required in some cases in order to isolate the expected N-phenylated amides 2j and 2k in
excellent yields.
The potential of CuI-USY for catalyzing N-arylation reactions was also scrutinized with azoles
as N-nucleophiles (Scheme 4). Rewardingly, CuI-USY enabled the N-phenylation of pyrrole,
pyrazole and imidazole, possessing appropriate N-H acidity. N-Phenylated heterocycles 3a,
3e and 3i were obtained in excellent yields, provided iodobenzene was used instead of
bromobenzene. Various aryl iodides bearing electronically distinct substituents could also
furnished the corresponding N-arylated azoles. 3b-d, 3f-h and 3j-k were thus formed in
excellent yields under standard conditions or by slightly adjusting them regarding
stoichiometry or temperature. 4-Methylimidazole was also efficiently phenylated, but
furnished a regioisomeric mixture of 3l:3l’ in favor of the less sterically-demanding N-phenyl-
4-methylimidazole 3l.
Condensed heteroaromatic equivalents, i.e. indole, benzimidazole and benzotriazole, led to
lower conversions, and thus to moderate isolated yields under standard conditions, but
increasing reaction temperature allowed full conversions and significantly improved yields.
The N-phenylated products 3m and 3n were thus obtained in excellent yields (up to 95%).
The corresponding N-phenylated benzotriazole was obtained as a mixture of regioisomers
3o:3o’, in which the 1-phenyl-1H-benzotriazole 3o was the major product (8.5:1).
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CuI-USY a
Cs2CO3
Z
N
Y
Z
NH
Y
X
R'
N
R'
DMF
120 °C, 24 h
3a-o
Y, Z = CH or N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
NO2
N
O
N Ph
O
69 % (89 %b):
X = I
86 %: X = I
21 %: X = Br
3d
56 %: X = I
3c
3a
3e
3b
92 %: X = I
N
N
N Ph
N
N
N
N
O
N
N
O
57 % (86 %b):
X = I
96 %: X = I
8 %: X = Br
3g
3k
3h
76 %: X = Br
3f
3j
74 %: X = I
N
N
N
N
N
N Ph
N Ph
N
O
N Ph
N
/
O
3l
3l'
50 %b (92 %c):
X = I
88 %: X = I
14 %: X = Br
71 % (90 %b):
X = I
75 % : 19 %:
X = I
3i
3l/3l'
Ph
Ph
Ph
N
N
N
N
N Ph
N
/
N
N
N
62 %d (88 %c):
X = I
3o
3o'
57 %d (84 %b , 95 %c):
X = I
3n
3m
34 % : 7 %d (68 % : 8 %c):
X = I
3o/3o'
aReactions run with CuI-USY (10 mol%), heteroaryl compound (1.5
equiv), aryl halide (1.0 equiv) and Cs2CO3 (2.0 equiv), unless
otherwise stated. bReactions run with aryl halide (1.5 equiv) and
heteroaryl compound (1.0 equiv). cReactions run at 140 °C.
dIncomplete conversion.
Scheme 4 – CuI-USY catalyzed N-arylation reactions with azoles
2.1.3- The C-S case – As for N-nucleophiles, DMF proved to be better than toluene as
solvent for accomplishing efficient arylation of S-nucleophiles (Scheme 5). Only low yields of
phenylated aryl thiols 4a and 4b were indeed isolated in toluene whereas high yields were
obtained in DMF. As some disulfide was formed together with 4a,17 we briefly examined
stoichiometric effects and found that inverting the stoichiometric ratio allowed to avoid
disulfide formation. This simple change also increased yield by about 10%. Applying this
stoichiometric ratio enabled the efficient S-arylation of aryl thiols, thus furnishing the targeted
S-arylated products 4a-e in good to high yields, regardless of the electronic nature of the aryl
iodide partner. Taken as model for aliphatic thiol, (4-methylphenyl)methylthiol could also be
engaged under the present phenylation conditions, leading to the expected sulfide 4f.
Interestingly enough, toluene appeared suitable and even better than DMF as solvent for
forming 4f.
2.1.4- The C-C case – The C-arylation of activated methylene compounds was much more
difficult to perform owing to the formation of various side products. Using the optimal CuI-
USY catalyzed conditions with toluene or DMF as solvent, the desired products 5a-c were
nevertheless isolated in reasonable yields. In contrast to the preceding O-, N- or S-arylations,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
electronic effects may play a role, because the electron-rich aryl iodides gave better results
than the electron-poor iodides (cf 5b vs 5c).
6
7
8
9
SH
SH
CuI-USY a
Cs2CO3
Ar
CO2Et
Ar
S
S
EtO2C
Ar
R'
X
Ar
R'
R'
or
EtO2C
solvent
or
CO2Et
4a-f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
120 °C, 24 h
5a-c
S
S
Ph
S
Ph
O
80 %b,e
88 %b,d
(4 %c,e
56 %b,d,f
4b
4a
4c
4f
(88 %b,d, 15 %c,e
)
)
S
S
Ph
S
O
O
56 %b,d,e
(68 %c,e
4e 86 %b,d
4d 94 %b,d
)
EtO2C
EtO2C
EtO2C
EtO2C
O
EtO2C
O
Ph
EtO2C
53 %b,g
(47 %c,g, 38 %c,g,h
59 %b,g
19 %b,g
5c
5b
5a
)
aReactions run with CuI-USY (10 mol%), thiol or diethyl malonate (1.5
equiv), aryl iodide (1.0 equiv) and Cs2CO3 (2.0 equiv), unless
otherwise stated. bReactions run in DMF. cReactions run in
PhCH3.dReactions run with aryl iodide (1.5 equiv) and thiol (1.0
equiv).eDisulfide isolated as by-product. fIncomplete
conversion.gFormation of several unidentified side products, as
revealed by 1H NMR analysis of the crude. hReactions run with diethyl
malonate (3.0 equiv) and aryl iodide (1.0 equiv).
Scheme 5 – CuI-USY catalyzed S- and C-arylation reactions with thiols and activated methylene
compounds
2.2- Catalyst survey – recycling, stability and leaching studies
The recyclability and stability of the CuI-USY catalyst were evaluated through two of the
phenylation reactions, both implying iodobenzene as phenylating agent and 3,5-
dimethylphenol or imidazole as nucleophiles (Figure 1). After each reaction run, the
insoluble materials were recovered by filtration over a Nylon micromembrane and
successively washed with DMF, water and methanol to remove any organic materials and
salts, thus furnishing after drying the zeolitic catalyst ready to be submitted to the next run. In
both O- and N-arylation cases, the catalyst proved recyclable up to five times without
alteration of its activity. While the overall catalytic activity was maintained for five runs with
3,5-dimethylphenol, the reaction efficiency with imidazole remarkably and surprisingly
increased over the runs, the phenylation becoming even quantitative at the fifth run.
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
CuI-USY
OH
or
OPh
Ph
NH
Cs2CO3
N
+
I-Ph
or
DMF
N
N
120 °C, 24 h
3e
1a
7
8
9
Run 15
Run 24
Run 33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
Run 4
1
Run 5
0
20
40
60
80
100
Yield (%)
Figure 1 – Recycling studies: phenylation of 3,5-dimethylphenol (in red) or imidazole (in green)
with iodobenzene successively catalyzed by the same recovered CuI-USY material
In parallel, we looked at the possible leaching of copper ions species from the zeolite
framework. As a first evaluation, the CuI-USY catalyst was suspended in the reaction solvent
(i.e., toluene or DMF) with the base (i.e., Cs2CO3), and heating at 120 °C for 2 h, the resulting
mixture was filtered over a Nylon micromembrane to give clear and colourless solutions. 3,5-
Dimethylphenol, iodobenzene and cesium carbonate were then added to the so-obtained
toluene and DMF solutions, and the resulting suspension was heated at 120 °C. Both control
experiments were monitored by LCMS during 24 h in order to observe a possible conversion
of the starting materials together with the formation of diaryl ether 1a. The toluene solution
did not lead to any conversion of the starting materials, whereas traces of 1a were detected
in the DMF solution. Accordingly, it appears that little amounts of active copper species
leached from CuI-USY in DMF but not in toluene. It is nevertheless worth noting that the
resulting DMF solution promoted the reaction at a rate by far slower than the CuI-USY
catalyzed process (ca. 5 vs 89 % yield after 24 h). To go further in recycling studies, we
performed again the O-phenylation of iodobenzene with 3,5-dimethylphenol (see 1a in
Scheme 2) and then conducted ICP-AES analyses of the resulting crude and the recovered
CuI-USY catalyst. While no traces of copper species were detected in the crude, ICP-AES
analyses also revealed the same copper content in both the fresh and the recovered forms of
the CuI-USY catalyst. Remarkably, the catalyst was further shown to maintain its native
copper content even after the fifth run, thus explaining the recyclable feature of CuI-USY in
Ullmann-type coupling reactions.
2.3- O-vs N-selectivity
The differences in reactivity observed in the results discussed above suggested that the CuI-
USY catalyzed arylation could differentiate functional groups within a polyfunctional
compound. We thus explored the chemoselectivity profile of the reaction through a series of
competitive experiments (Scheme 6).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
5
H
O
N
NH2
Ph
6a
Ph
+
+
6
7
8
9
1a: 87 %
2a: 12 %
PhI, CuI-USY (10 mol%)
OH
H
N
Cs2CO3 (2.0 equiv)
1a: 33 %
+
+
Ph
3
DMF, 120 °C, 24 h
NH2
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2g: 0 %
3
Ph
N
1a: 56 %
NH
+
N
N
3i: 39 %
6b
Ph
Ph
PhI, CuI-USY (10 mol%)
Cs2CO3 (2.0 equiv)
N
OH
N
O
N
O
+
DMF, 140 °C, 24 h
6: 84 %
0 %
6c
PhI, CuI-USY (10 mol%)
Cs2CO3 (2.0 equiv)
Ph
N
H
N
H2N
H2N
DMF, 140 °C, 24 h
7: 89 %
6d
PhI, CuI-USY (10 mol%)
Cs2CO3 (2.0 equiv)
Ph
H
N
H2N
H2N
N
N
N
DMF, 140 °C, 24 h
8: 97 %
Scheme 6 – Chemoselectivity in CuI-USY catalyzed O- and N-arylation reactions
3,5-Dimethylphenol and various N-nucleophiles were engaged in reactions with phenyl iodide
(Scheme 6a). As expected from the above results, 3,5-dimethylphenol proved more reactive
than aniline as shown by the low amount of diphenylamine 2a isolated, while diaryl ether 1a
was produced with the same efficiency as in the absence of aniline. However, when a similar
competition was performed with butylamine, no traces of N-phenylbutylamine 2g was formed
as expected (see 2g in Scheme 3), and the phenol phenylation was negatively influenced by
the presence of the amine, as revealed by the modest yield obtained (33 % of 1a). As before
(see Scheme 3), aliphatic amines probably poisoned the catalyst, inhibiting its efficiency. In
contrast, competition between the same phenol and imidazole gave a mixture of both
coupling products 1a and 3i, the former being the major one. Again, O-phenylation appeared
favored over N-phenylation but with a significantly lower selectivity.
Alternatively, intramolecular O- vs N-coupling competitions were performed. 2-
Hydroxypyridine was investigated as ambident substrate with phenyl iodide as coupling
partner (Scheme 6b). Interestingly, only the N-phenyl pyridine-2(1H)-one 6 was produced,
without trace of its O-phenylated isomer as revealed by LCMS and 1H NMR analyses.
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Intramolecular N- vs N- selectivity was also examined with coupling reactions involving 6-
aminoindole and 6-aminoindazole (Schemes 6c,d). Both exhibited exclusive selectivity for
their azole moiety and only the 1N-phenyl derivatives 7 and 8 could be isolated and in
excellent yields. In the case of 6-aminoindazole, the phenylation proved also regioselective,
with the exclusive formation of the 1N-phenylated product 8 to the detriment of its
regioisomeric 2-phenylated form.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.4- Application to total synthesis
As we recently developed and validated the zeolite-based organic synthesis (ZeoBOS)
strategy,18 we took benefit of the present results to further demonstrate the ZeoBOS
pertinence, while illustrating CuI-USY catalyzed Ullmann-type O-arylation.
We elected as target the naturally occurring and biologically relevant diaryl ether, named 3-
methylobovatol 11, and we reported here its total synthesis based on zeolite-catalyzed steps
(Scheme 7). Isolated from Magnolia henryi and Illicium lanceolatum,19 known for the anti-
inflammatory and analgesic activities of their extracts, this diaryl ether and related analogs
were found to exhibit an attractive array of biological activities.20 A single synthesis has so far
been accomplished through a classical Ullmann coupling as the key step.21 The latter point
allows for an interesting and useful comparison of the homo- and heterogeneous conditions.
Eugenol, a natural, commercially available and cheap natural product, was first protected and
iodinated via a directed ortho-lithiation/iodination sequence. The MOM group was selected
due its compatibility with our Ullmann conditions as shown above (see compound 1p in
Scheme 2). Also encouraged by the proven compatibility of allyl moieties (see compound 1o
in Scheme 2), the resulting aryl iodide 9 was submitted to 4-allylphenol22 in the presence of
CuI-USY. Under our standard conditions, a complex and difficult-to-separate mixture of
products was obtained.23 Decreasing the temperature to 90 °C allowed the cleaner formation
of the expected product 10 in 51% yield. It is worth noting that this heterogeneous version
proved more efficient than the reported homogeneous conditions (51 % vs 36 %). The
removal of the MOM group was required to complete the synthesis. This could be
successfully performed using H-USY, a commercial and cheap acidic H-zeolite, in a 9:1
MeOH/H2O mixture as solvent. Again, the zeolite-mediated heterogeneous conditions
furnishing 11 proved to be more efficient than the reported homogeneous conditions (i.e.,
quantitative vs 74 %, Scheme 7). The total synthesis of 3-methylobovatol 11 was thus
achieved in four steps, half of which being zeolite-mediated reactions, with a better overall
yield than the only route so far reported (i.e., 28 % vs 6 %). This result further supports the
relevance of the ZeoBOS strategy.18
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
CuI
OH
OMOM
OMOM
I
c)
CuI
O
CuI
O
O
O
a), b)
7
HO
8
9
10
51 % (36 %)a
Eugenol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
H+
55 % from eugenol
d)
H+ H+
Reagents and conditions: a) CH2(OCH3)2, P2O5,
CH2Cl2, 0 °C, 4 h, 84 %. b) nBuLi, THF, - 30 to -10 °C,
then I2, - 30 to 0 °C, 6 h, 65 %. c) CuI-USY (10 mol%),
Cs2CO3, PhCH3, 90 °C, 4 d, 51 %. d) H-USY,
OH
O
O
MeOH/H2O (9:1), 100 °C, 24 h, quantitative yield.
11
3-Methylobovatol
quantitative yield (74 %)b
aYield reported in Ref. 21 starting from the brominated analog of 9 under homogeneous
conditions. bYield reported in Ref. 21 using 2 M HCl in MeOH as deprotection
conditions.
Scheme 7 – Total synthesis of 3-methylobovatol via the ZeoBOS strategy
2.5- Mechanistic aspects
The mechanism of Ullmann-type coupling reactions is still a matter of debate, although
significant advances have been gained, especially with liganded copper catalysts.24 The
more recent results suggested the intervention of discrete copper(I) phenoxyde, amido,
amidate or imidate complexes,24b,25 in which the ligand nature strongly influences the reaction
course, favouring oxidative addition pathways24a,b (Figure 2).
C-O coupling
ArOH
B
BH
Ph
ArO
PhI
CuI
+
CuIII
CuI
CuI
ArO
L
L
ArO
L
X
L
I
Ph
ArO
I
X
C-N coupling
RNH2
CuI
BH
RNH
B
Ph
PhI
RNH2
CuI
L
CuI
CuIII
L
CuI
L
L
RNH
X
X
L
RNH
Ph
I
X
Figure 2 – Recent mechanistic proposals for C-O and C-N Ullmann-type coupling reactions in
homogeneous conditions (with L = Ligand, B- = Base)
In copper-zeolites, the ligand role is played by the zeolite framework, acting as a large
oxygenated ligand (see Figure 3). It has indeed been demonstrated that copper(I) ions could
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
be located at various sites of the zeolite framework, interacting with 2 to 3 oxygen atoms.26 In
CuI-Y zeolite,27 the main copper ion positions are the hexagonal prism (S ) or cubooctahedral
I
(S , S and others) sites of the zeolite framework (Figure 3, green positions). Copper ions
II
I
6
located at the latter positions can further migrate to the supercage borders in the presence of
adsorbed molecules.28 In the particular case of CuI-Y zeolite prepared by solid-state ion
exchange, copper(I) ions are mostly located at site I* and some at site II*, with Cu-O
distances of 2.032 and 2.002 Å respectively (Figure 3, red positions).29
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3 – Location of copper ions in zeolite frameworks: the case of CuI-Y (adapted from Ref.
26-29)
Furthermore, quantum-chemical DFT calculations evidenced that copper(I) ions embedded in
zeolite had a relatively high HOMO energy, allowing the transfer of electron density on an
antibonding orbital of adsorbed molecules.30 In other words, such zeolite-bonded copper(I)
ions are prone to oxidative addition, facilitating coupling reactions involving such mechanism.
This effect could explain the relative lack of electronic influence regarding the aryl halide to
the present CuI-USY-catalyzed Ullmann-type coupling reactions (in Scheme 2, see 1b,c,e,h-
j vs 1k-p). This could parallel previous observations revealing that more electron-donating
ligands promote faster and more efficient coupling than less electron-donating ligands.25c
Control experiments performed under our standard coupling conditions (i.e., CuI-USY,
toluene, 120°C, 24 h) in the absence of any nucleophile revealed the progressive
consumption of the aryl halide (especially iodide) partner; this result further supports its
interaction with zeolite-bonded copper(I) ions likely via oxidative addition.
On the basis of these control experiments and our results, the first step of C-O coupling in
copper(I)-zeolites could be the oxidative addition to iodo(bromo)phenyl derivatives (Scheme
8 left, intermediate A). In the resulting intermediate, the halide would then be displaced by
the phenolate nucleophile , leading to intermediate B, and reductive elimination would next
occur, producing the expected diaryl ether and releasing the copper(I)-zeolite. Although
different from the mechanism of C-O coupling in solution (Figure 2, top), this order of events
helps rationalizing the lack of reactivity observed with electron-poor phenols (see 1t,u in
Scheme 2) and the good reactivity of electron-rich phenols (see 1a-s in Scheme 2, and
previous examples reported in Ref. 15). Nucleophilicity of the phenolic partner seems to be
the key factor here, in contrast to acidity in the now established mechanism in homogeneous
conditions.
With amines, their more coordinating ability might reverse the event order, in a way more
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
4
5
6
7
8
9
similar to the homogeneous conditions (Scheme 8, right vs Figure 2, bottom). An amino
complex C would first be formed and then deprotonated to zeolite-copper amide (D. The
latter could oxidatively add to phenyl iodide leading to complex E, the reductive elimination of
which then provides the coupling product. This event seems to be corroborated by the fact
that only the less nucleophilic but more acidic amines gave the expected coupling products
(see 2c-f,j,k vs 2a,b,g-I in Scheme 3). This may also explain why DMF is required, as
carbonate ions have to be solubilized to get into zeolite pores in theses cases.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This proposed mechanism is also in line with the results gained from the more coordinating
heteroaromatic N-nucleophiles (Scheme 4). This interpretation also matches very well with
the results obtained in our selectivity studies, for which the more coordinating N-H group is
exclusively phenylated (Scheme 6c,d).
C-O route
Ar-I
- L
C-N route
O
O
R'
H
RR'N-H
- L
O
O
CuI
O
N
R
CuI
L
Ar
I
O
O
CuIII
O
C
2
CO3
O
ArOAr'
ArNRR'
A
Ar'O-H
HCO3
L
2
CO3
- I
O
Ar'O
O
HCO3
O
O
Ar-I
CuI
Ar
O
Ar
O
CuIII
NRR'
CuIII
O
NRR' - I
OAr'
O
D
O
E
B
Scheme 8 – Mechanistic proposal for CuI-USY catalyzed Ullmann-type coupling reactions
(curved lines linking oxygen atoms represent the zeolite framework, i.e. -Si-O-Si/Al-O-Si-…)
3-CONCLUSION –
In conclusion, we have shown that the (hetero)arylation of O-, N-, S- and C-nucleophiles can
be efficiently performed with the copper(I)-doped zeolite CuI-USY as recyclable catalyst. The
so-elaborated ligand-free method offers a wide scope regarding both the aryl halide and the
nucleophilic partners, and tolerates a variety of functional groups. The high functional group
compatibility of the catalytic system has been successfully exploited in the synthesis of the
natural diaryl ether 3-methylobovatol, thus supporting the relevance of the zeolite-based
organic synthesis (ZeoBOS) strategy. Considering mechanistic aspects, the obtained results
are in line with the implication of two competitive catalytic pathways depending on the nature
of the nucleophilic partner.
This work constitutes a novel contribution to the remarkable application scope of zeolites,
especially CuI-USY, as ligand-free and polyvalent catalysts in organic synthesis.
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
EXPERIMENTAL SECTION
General. Most reactions were performed under inert atmosphere with magnetic stirring and
with anhydrous solvents. All starting materials were purchased at the highest commercial
quality and used without further purification unless otherwise stated. Sure/SealTM air-
sensitive and anhydrous packaging systems were purchased for toluene, tetrahydrofuran
(THF) and N,N-dimethylformamide (DMF) and used as received. Dichloromethane (DCM),
ethyl acetate (EtOAc), cyclohexane, petroleum ether (PET) and methanol (MeOH) were used
as received. – Reactions were monitored by thin-layer chromatography carried out on silica
plates (silica gel 60 F254, Merck) using UV-light for visualization. Column chromatographies
were performed on silica gel 60 (0.040-0.063 mm, Merck) using mixtures of EtOAc and
cyclohexane as eluents. – Evaporation of solvents were conducted under reduced pressure
at temperatures less than 30 °C. – Melting points (Mp) were measured in open capillary
tubes on a Stuart SMP30 apparatus and are uncorrected. – IR spectra were obtained from
the ‘Service Commun de Spectroscopie Infrarouge’ of the Plateforme Scientifique et
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Technique, Institut de Chimie de Toulouse (FR2599), and values are reported in cm-1. – H
and 13C NMR spectra were recorded on a Bruker Avance 300 spectrometer at 300 and 75
MHz, respectively. Chemical shifts (δ) and coupling constants (J) are given in ppm and Hertz
(Hz), respectively. The signal multiplicity is described according to the following
abbreviations: s (singlet), bs (broad singlet), d (doublet), and m (multiplet). Chemical shifts
(δ) are reported relative to the residual solvent as an internal standard (CDCl3: δ = 7.26 ppm
1
1
for H and δ = 77.0 ppm for 13C; DMSO-d6: δ = 2.50 ppm for H and δ = 39.5 ppm for 13C).
Carbon multiplicities were determined by DEPT135 experiments. – Electrospray (ESI),
Atmospheric-Pressure Chemical Ionization (APCI) and Desorption Chemical Ionization (DCI)
low/high-resolution mass spectra were obtained from the 'Service Commun de Spectroscopie
de Masse' of the Plateforme Technique, Institut de Chimie de Toulouse (FR2599). Accurate
mass measurements (HRMS) were performed with a Q-TOF analyzer.
General procedure for the preparation of CuI-USY. CuI-USY was prepared according
to a well-established solid/solid exchange procedure. Commercial NH4-USY was first loaded
in an oven and heated at 550°C for 4 h to give H-USY. A mixture of so-formed H-USY (1 g)
and CuCl (376 mg, 1.0 equiv. related to the number of H-zeolite protons) were ground by a
pestle and mortar and then heated in a furnace under flowing nitrogen at 350°C. After 3 days
heating, the furnace was cooled down to room temperature and nitrogen feed was stopped,
thus quantitatively furnishing the expected Cu-USY.
General procedure for the CuI-USY catalyzed arylation of O-, N-, S- and C-
nucleophiles. In a 2-5 mL Biotage microwave reaction vial were successively added CuI-
USY (ca. 15 mg, 10 mol% of copper species), toluene or DMF as solvent (0.5 mL), the aryl
halide (0.5 mmol, 1.0 equiv.), the nucleophile (0.75 mmol, 1.5 equiv.) and cesium carbonate
(1.0 mmol, 2.0 equiv.). The vial was sealed and after 24 h stirring at 120°C via conventional
heating (unless otherwise stated), the reaction was complete as revealed by either TLC or
LCMS analysis. After cooling to room temperature, the solid materials were removed by
filtration over a Millipore membrane and further washed with diethyl ether (1 × 20 mL). The
resulting organic phase was washed with 1M aqueous NaOH solution (3 × 10 mL), water (3 ×
10 mL), brine (1 × 10 mL), dried over Na2SO4, filtered and evaporated, thus giving the
1
resulting O-arylated product 1a-y usually at >95% purity as judged by H NMR. In the other
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
cases, purification of the resulting crude by column chromatography eluting with an
appropriate cyclohexane/EtOAc mixture furnished the expected products 2a-k, 3a-o, 4a-f
and 5a-c in pure forms.
1,3-Dimethyl-5-phenoxybenzene (1a).12a Using the general procedure with toluene as
solvent, from 3,5-dimethylphenol and either iodobenzene or bromobenzene, the expected
diaryl ether 1a was isolated as colourless oil. – Yields 85% (84 mg from the iodo derivative)
and 83% (82 mg from the bromo derivative). – Rf = 0.30 (cyclohexane). – FTIR-ATR (neat)
3040, 2920, 1610, 1580, 1490, 1300, 1220 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 7.36-7.29
(m, 2H), 7.12-7.06 (m, 1H), 7.02-6.98 (m, 2H), 6.75 (brs, 1H), 6.64 (brs, 2H), 2.29 (brs, 6H).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
13C NMR (75 MHz, CDCl3): δ = 157.4, 157.1, 139.6, 129.6, 125.0, 122.9, 118.8, 116.6,
21.3. – MS (DCI, positive mode) m/z (rel intensity) 199 ([MH]+, 100).
4-(3,5-Dimethylphenoxy)-benzonitrile (1b).12a Using the general procedure with toluene
as solvent, from 3,5-dimethylphenol and either 4-iodobenzonitrile or 4-bromobenzonitrile, the
expected diaryl ether 1b was isolated as a yellow solid. – Yields 83% (92 mg from the iodo
derivative) and 83% (92 mg from the bromo derivative). – Rf = 0.20 (90:10
cyclohexane/Et2O). – M.p. 57-58 °C. – FTIR-ATR (neat) 3040, 2920, 2220, 1590, 1500, 1240
1
cm-1. – H NMR (300 MHz, CDCl3): δ = 7.61-7.56 (m, 2H), 7.01-6.97 (m, 2H), 6.86 (brs, 1H),
6.67 (brs, 2H), 2.32 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 161.9, 154.7, 140.1, 134.0,
126.8, 118.9, 118.0, 117.8, 105.4, 21.2. – MS (DCI, positive mode) m/z (rel intensity) 224
([MH]+, 100).
1,3-Dimethyl-5-(4-nitrophenoxy)-benzene (1c).12a Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and either 4-nitro-1-iodobenzene or 4-nitro-1-
bromobenzene, the expected diaryl ether 1c was isolated as a white solid. – Yields 83% (100
mg from the iodo derivative) and 78% (95 mg from the bromo derivative). – Rf = 0.20 (90:10
cyclohexane/Et2O). – M.p. 78-79 °C. – FTIR-ATR (neat) 3070, 2920, 1580, 1500, 1490,
1
1350, 1290 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.22-8.16 (m, 2H), 7.02-6.97 (m, 2H),
6.89-6.87 (m, 1H), 6.68 (brs, 2H), 2.33 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 163.6,
154.6, 142.4, 140.3, 127.1, 125.9, 118.1, 117.0, 21.3. – MS (ESI, positive mode) m/z (rel
intensity) 266 ([MNa]+, 100).
2-(3,5-Dimethylphenoxy)-9H-fluoren-9-one (1d). Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and 2-bromo-9H-fluorenone, the expected diaryl
ether 1d was isolated as a yellow solid. – Yield 83% (125 mg). – Rf = 0.50 (90:10
cyclohexane/EtOAc). – M.p. 114-116 °C. – FTIR-ATR (neat) 3058, 2915, 1717, 1597, 1449,
1
1297, 1228 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.63-7.61 (m, 1H), 7.47-7.44 (m, 3H),
7.25-7.21 (m, 2H), 7.11 (dd, 3J = 8.1 Hz, 4J = 2.4 Hz, 1H), 6.80 (brs, 1H), 6.66 (brs, 2H), 2.30
(brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 193.2, 159.0, 156.1, 144.4, 139.8, 138.6, 135.9,
134.8, 134.3, 128.2, 125.8, 124.3, 123.9, 121.4, 119.8, 117.1, 114.2, 21.3. – HRMS (DCI,
positive mode): m/z: calcd for C21H17O2 301.1229, found 301.1226 [MH]+.
1-(4-(3,5-dimethylphenoxy)phenyl)-ethanone (1e).31a Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and either 4’-iodoacetophenone or 4’-
bromoacetophenone, the expected diaryl ether 1e was isolated as a white solid. – Yields
76% (91 mg from the iodo derivative) and 55% (66 mg from the bromo derivative). – Rf =
0.40 (98:2 cyclohexane/EtOAc). – M.p. 79 °C. – FTIR-ATR (neat) 3060, 2920, 1670, 1580,
1
1500, 1290, 1235 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.95-7.91 (m, 2H), 7.01-6.96 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
2H), 6.84 (brs, 1H), 6.68 (bs, 2H), 2.57 (s, 3H), 2.31 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ
= 196.7, 162.2, 155.3, 139.9, 131.6, 130.5, 126.3, 117.7, 117.2, 26.4, 21.2. – LRMS (DCI,
positive mode) m/z (rel intensity) 241 ([MH]+, 100), 258 ([MNH4]+, 25).
6
7
8
9
4-(3,5-Dimethylphenoxy)benzaldehyde (1f). Using the general procedure with DMF as
solvent, from 3,5-dimethylphenol and either 4-iodobenzaldehyde or 4-bromobenzaldehyde,
the expected diaryl ether 1f was isolated as a yellow solid. – Yields 39% (44 mg from the
iodo derivative) and 60% (68 mg from the bromo derivative). – Rf = 0.50 (90:10
cyclohexane/EtOAc). – M.p. 45-47 °C. – FTIR-ATR (neat) 2910, 2820, 2740, 1702, 1580,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1500, 1292, 1230, 1161 cm-1. – H NMR (300 MHz, CDCl3): δ = 9.92 (s, 1H), 7.86-7.81 (m,
2H), 7.07-7.02 (m, 2H), 6.86 (brs, 1H), 6.70 (brs, 2H), 2.32 (brs, 6H). – 13C NMR (75 MHz,
CDCl3): δ = 190.7, 163.4, 154.9, 140.0, 131.9, 131.0, 126.6, 118.0, 117.5, 21.2. – HRMS
(DCI, positive mode): m/z: calcd for C15H15O2 227.1072, found 227.1070 [MH]+.
2-(3,5-Dimethylphenoxy)benzaldehyde (1g).31b Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and 2-bromobenzaldehyde, the expected diaryl
ether 1g was isolated as an yellow oil. – Yield 19% (22 mg). – Rf = 0.60 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3010, 2920, 2850, 1690, 1600, 1480, 1460, 1300,
1230 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 10.51 (d, 4J = 0.8 Hz, 1H), 7.93 (dd, 3J = 7.8 Hz,
4J = 1.8 Hz, 1H), 7.51 (ddd, 3J = 8.4 Hz, 3J = 7.3 Hz, 4J = 1.8 Hz, 1H), 7.17 (brt, 3J = 7.6 Hz,
3
4
1H), 6.90 (dd, J = 8.4 Hz, J = 0.8 Hz, 1H), 6.82 (brs, 1H), 6.68 (brs, 2H), 2.31 (brs, 6H). –
13C NMR (75 MHz, CDCl3): δ = 189.5, 160.2, 156.3, 140.0, 135.7, 128.2, 126.8, 126.0, 123.1,
118.5, 117.0, 21.3. – LRMS (DCI, positive mode) m/z (rel intensity) 226 ([M]+, 10), 227
([MH]+, 100), 244 ([MNH4]+, 40).
Isopropyl 4-(3,5-dimethylphenoxy)benzoate (1h). Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and isopropyl 4-iodobenzoate, the expected
diaryl ether 1h was isolated as an orange oil. – Yield 70% (100 mg). – Rf = 0.80 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 2979, 2916, 1713, 1590, 1503, 1274, 1235, 1161,
1098 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 8.02-7.97 (m, 2H), 6.99-6.95 (m, 2H), 6.81 (brs,
3
3
1H), 6.67 (brs, 2H), 5.23 (sept, J = 6.3 Hz, 1H), 2.30 (brs, 6H), 1.36 (d, J = 6.3 Hz, 6H). –
13C NMR (75 MHz, CDCl3): δ = 165.6, 161.7, 155.7, 139.8, 131.5, 126.0, 125.0, 117.5, 117.3,
68.1, 22.0, 21.2. – HRMS (DCI, positive mode): m/z: calcd for C18H21O3 285.1491, found
285.1479 [MH]+.
Methyl 4-(3,5-dimethylphenoxy)benzoate (1i).12a Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and methyl 4-iodobenzoate, the expected diaryl
ether 1i was isolated as an orange oil. – Yield 41% (53 mg). – Rf = 0.50 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 2949, 2919, 2846, 1721, 1590, 1505, 1435, 1278,
1
1235, 1163, 1112 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.02-7.97 (m, 2H), 6.99-6.94 (m,
2H), 6.83 (brs, 1H), 6.68 (brs, 2H), 3.90 (s, 3H), 2.31 (s, 6H). – 13C NMR (75 MHz, CDCl3): δ
= 166.6, 162.0, 155.5, 139.9, 131.6, 126.2, 124.2, 117.7, 117.2, 51.9, 21.3. – LRMS (APCI,
positive mode) m/z (rel intensity) 257 ([MH]+, 100).
4-(3,5-Dimethylphenoxy)benzoic acid (1j).31c Using the general procedure with toluene
as solvent at 140°C, from 3,5-dimethylphenol and 4-iodobenzoic acid, the expected diaryl
ether 1j was isolated as a brown oil. – Yield 80% (97 mg). – Rf = 0.50 (50:50
cyclohexane/EtOAc). – FTIR-ATR (neat) 2920, 2850, 2560, 1680, 1590, 1510, 1430, 1290,
1
1230, 1160 cm-1. – H NMR (300 MHz, DMSO-d6): δ = 7.94-7.91 (m, 2H), 7.00-6.97 (m, 2H),
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6.85 (brs, 1H), 6.71 (brs, 2H), 2.25 (s, 6H). – 13C NMR (75 MHz, CDCl3): δ = 166.8, 161.2,
155.1, 139.7, 131.6, 126.2, 125.1, 117.5, 117.2, 20.8. – LRMS (APCI, positive mode): m/z
(rel intensity) 243 ([MH]+, 100).
6
4-(3,5-Dimethylphenoxy)-N,N-diethylaniline (1k).15 Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and 4-bromo-N,N-diethylaniline, the expected
diaryl ether 1k was isolated as a white solid. – Yield 84% (113 mg). – Rf = 0.60 (98:2
cyclohexane/EtOAc). – M.p. 41-43 °C. – FTIR-ATR (neat) 3043, 2968, 1613, 1588, 1508,
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1317, 1227 cm-1. – H NMR (300 MHz, CDCl3): δ = 6.94-6.91 (m, 2H), 6.69-6.65 (m, 3H),
6.57 (brs, 2H), 3.33 (q, 3J = 6.9 Hz, 4H), 2.26 (brs, 6H), 1.16 (t, 3J = 6.9 Hz, 6H). – 13C NMR
(75 MHz, CDCl3): δ = 159.2, 146.4, 144.7, 139.2, 123.6, 121.1, 114.7, 113.3, 44.7, 21.3,
12.6. – HRMS (DCI, positive mode): m/z: calcd for C18H23NO 269.1780, found 269.1793 [M]+.
1-(4-Methoxyphenoxy)-3,5-dimethylbenzene (1l).12a Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and either 4-iodoanisole or 4-bromoanisole, the
expected diaryl ether 1l was isolated as a white solid. – Yields 66% (75 mg from the iodo
derivative) and 74% (84 mg from the bromo derivative). – Rf = 0.80 (90:10
cyclohexane/EtOAc). – M.p. 66 °C. – FTIR-ATR (neat) 3000, 2949, 2832, 1616, 1590, 1502,
1440, 1295, 1213 cm-1. – H NMR (300 MHz, CDCl3): δ = 6.98-6.94 (m, 2H), 6.90-6.86 (m,
1
2H), 6.69 (brs, 1H), 6.56 (brs, 2H), 3.81 (s, 3H), 2.27 (s, 6H). – 13C NMR (75 MHz, CDCl3): δ
= 158.4, 155.7, 150.2, 139.4, 124.2, 120.8, 115.3, 114.7, 55.6, 21.3. – LRMS (APCI, positive
mode) m/z (rel intensity) 229 ([MH]+, 100).
1-(4-Ethoxyphenoxy)-3,5-dimethylbenzene (1m). Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and 4-ethoxy-1-iodobenzene, the expected
diaryl ether 1m was isolated as a colourless oil. – Yield 84% (102 mg). – Rf = 0.20
(cyclohexane). –FTIR-ATR (neat) 3044, 2921, 1613, 1590, 1503, 1210 cm-1. – H NMR (300
MHz, CDCl3): δ = 6.99-6.84 (m, 4H), 6.69 (brs, 1H), 6.57 (brs, 2H), 4.02 (q, 3J = 6.9 Hz, 2H),
1
2.27 (brs, 6H), 1.42 (t, J = 6.9 Hz, 3H). – 13C NMR (75 MHz, CDCl3): δ = 158.5, 155.1,
3
150.1, 139.4, 124.1, 120.8, 115.4, 115.3, 63.8, 21.3, 14.9. – LRMS (DCI, positive mode) m/z
(rel intensity) 242 ([M]+, 100), 243 ([MH]+, 50). – HRMS (DCI, positive mode): m/z: calcd for
C16H18O2 242.1307, found 242.1316 [M]+.
1-(4-Isopropyloxyphenoxy)-3,5-dimethylbenzene (1n). Using the general procedure
with toluene as solvent, from 3,5-dimethylphenol and 4-isopropyloxy-1-iodobenzene, the
expected diaryl ether 1n was isolated as a colourless oil. – Yield 77%. – Rf = 0.75 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3042, 2919, 2866, 1615, 1592, 1500, 1468, 1297,
1212 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 6.97-6.92 (m, 2H), 6.88-6.83 (m, 2H), 6.69 (brs,
1H), 6.57 (brs, 2H), 4.48 (sept, 3J = 6.0 Hz, 1H), 2.27 (s, 6H), 1.34 (d, 3J = 6.0 Hz, 6H). – 13C
NMR (75 MHz, CDCl3): δ = 158.4, 155.7, 150.2, 139.4, 124.2, 120.8, 115.3, 114.7, 55.6,
22.1, 21.3. – HRMS (DCI, positive mode): m/z: calcd for C17H21O2 257.1542, found 257.1538
[MH]+.
1-(4-(Allyloxy)phenoxy)-3,5-dimethylbenzene (1o). Using the general procedure with
toluene as solvent, from 3,5-dimethylphenol and 4-allyloxy-1-iodobenzene, the expected
diaryl ether 1o was isolated as a colourless oil. – Yield 79% (100 mg). – Rf = 0.60 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3017, 2919, 2861, 1615, 1593, 1504, 1210, 1028
cm-1. – 1H NMR (300 MHz, CDCl3): δ = 7.00-6.88 (m, 4H), 6.70 (brs, 1H), 6.58 (brs, 2H), 6.08
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
7
8
9
(ddt, J = 5.2, 10.6, 17.3 Hz, 1H), 5.44 (dq, J = 1.8, 17.4 Hz, 1H), 5.31 (dq, J = 1.5, 10.5 Hz,
1H), 4.54 (dt, J = 1.5, 5.4 Hz, 2H), 2.28 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 158.3,
154.7, 150.4, 139.4, 133.3, 124.2, 120.7, 117.6, 115.7, 115.3, 69.3, 21.3. – HRMS (DCI,
positive mode): m/z: calcd for C17H19O2 255.1385, found 255.1385 [MH]+.
1-(4-(Methoxymethoxy)phenoxy)-3,5-dimethylbenzene (1p). Using the general
procedure with toluene as solvent, from 3,5-dimethylphenol and either 1-iodo-4-
(methoxymethoxy)benzene or 1-bromo-4-(methoxymethoxy)benzene, the expected diaryl
ether 1p was isolated as a colourless oil. – Yields 84% (108 mg from the iodo derivative) and
64% (83 mg from the bromo derivative). – Rf = 0.60 (90:10 cyclohexane/EtOAc). – FTIR-ATR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(neat) 2952, 2919, 2826, 1589, 1502, 1300, 1216, 1192, 1011 cm-1. – H NMR (300 MHz,
CDCl3): δ = 7.04-6.99 (m, 2H), 6.97-6.92 (m, 2H), 6.70 (brs, 1H), 6.58 (brs, 2H), 5.16 (s, 2H),
3.51 (s, 3H), 2.27 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 158.1, 153.2, 151.4, 139.4,
124.4, 120.5, 117.5, 115.5, 95.0, 56.0, 21.3. – HRMS (DCI, positive mode): m/z: calcd for
C16H19O3 259.1334, found 259.1332 [MH]+.
2-(3,5-Dimethylphenoxy)pyridine (1q).12a Using the general procedure with toluene as
solvent, from 3,5-dimethylphenol and 2-bromopyridine, the expected diaryl ether 1q was
isolated as a yellow solid. – Quantitative yield (100 mg). – Rf = 0.40 (90:10
cyclohexane/EtOAc). – M.p. 50-51 °C. – FTIR-ATR (neat) 3055, 2913, 2856, 1616, 1582,
1467, 1429, 1293, 1249, 1134 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 8.21 (ddd, 3J = 4.8 Hz,
4J = 1.8 Hz, 5J = 0.6 Hz, 1H), 7.66 (ddd, 3J = 8.4 Hz, 3J = 7.2 Hz, 4J = 2.1 Hz, 1H), 6.97 (ddd,
3
4
3J = 7.2 Hz, J = 5.1 Hz, J = 0.9 Hz, 1H), 6.95-6.83 (m, 1H), 6.83 (brs, 1H), 6.75 (brs, 2H),
2.34 (brs, 6H). – 13C NMR (75 MHz, CDCl3): δ = 163.9, 154.0, 147.8, 139.4, 139.2, 126.4,
118.7, 118.1, 111.4, 21.2. – LRMS (DCI, positive mode) m/z (rel intensity) 200 ([MH]+, 100).
3-(3,5-Dimethylphenoxy)pyridine (1r).31d Using the general procedure with toluene as
solvent, from 3,5-dimethylphenol and 3-bromopyridine, the expected diaryl ether 1r was
isolated as a pale yellow oil. – Yield 79% (79 mg). – Rf = 0.20 (90:10 cyclohexane/EtOAc). –
1
FTIR-ATR (neat) 3030, 2916, 1615, 1572, 1473, 1421, 1297, 1225, 1136 cm-1. – H NMR
(300 MHz, CDCl3): δ = 8.39 (dd, 4J = 2.4 Hz, 5J = 0.9 Hz, 1H), 8.34 (dd, 3J = 3.9 Hz, 4J = 1.8
Hz, 1H), 7.30-7.22 (m, 2H), 6.79 (brs, 1H), 6.64 (brs, 2H), 2.23 (brs, 6H). – 13C NMR (75
MHz, CDCl3): δ = 156.1, 154.0, 143.9, 141.3, 139.8, 125.7, 125.2, 123.9, 116.6, 21.2. –
LRMS (DCI, positive mode) m/z (rel intensity) 200 ([MH]+, 100).
3-Phenoxy-N,N-dimethylaniline (1s).31e Using the general procedure with toluene as
solvent, from 3-(N,N-dimethylamino)phenol and iodobenzene, the expected diaryl ether 1s
was isolated as a pale yellow oil. – Yield 69% (74 mg). – Rf = 0.50 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3036, 2876, 2804, 1593, 1572, 1489, 1237 cm-1. –
3
1H NMR (300 MHz, CDCl3): δ = 7.36-7.29 (m, 2H), 7.18 (t, J = 8.1 Hz, 1H), 7.10-7.01 (m,
3H), 6.51-6.33 (m, 3H), 2.94 (s, 6H). – 13C NMR (75 MHz, CDCl3): δ = 158.0, 157.5, 152.0,
129.9, 129.5, 122.7, 118.5, 107.7, 106.9, 103.5, 40.5. – LRMS (DCI, positive mode) m/z (rel
intensity) 214 ([MH]+, 100).
(4-Chlorophenoxy)-benzene (1v)12a and 1-(4-chlorophenoxy)-4-phenoxybenzene
(1v’)31f. Using the general procedure with toluene as solvent, from 4-chlorophenol and
iodobenzene, the expected diaryl ether 1v as well as the twofold coupled side product 1v’
were obtained in pure forms after purification by column chromatography. (4-
Chlorophenoxy)-benzene (1v). Colourless oil. – Yield 58% (59 mg). – Rf = 0.40
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(cyclohexane). – FTIR-ATR (neat) 3040, 2910, 1580, 1220 cm-1. – H NMR (300 MHz,
CDCl3): δ = 7.38-7.32 (m, 2H), 7.31-7.27 (m, 2H), 7.15-7.09 (m, 1H), 7.02-6.97 (m, 2H), 6.96-
6.91 (m, 2H). – 13C NMR (75 MHz, CDCl3): δ = 156.8, 155.9, 129.8, 129.7, 128.2, 123.6,
120.0, 118.9. – LRMS (DCI, positive mode) m/z (rel intensity) 204 ([M(35Cl)]+, 95), 205
[M(35Cl)H]+, 100), 206 ([M(37Cl)]+, 40), 207 ([M(37Cl)H]+, 34). 1-(4-Chlorophenoxy)-4-
phenoxybenzene (1v’). White solid. – Yield 4% (6 mg). – Rf = 0.20 (cyclohexane). – M.p.
70-71 °C. – FTIR-ATR (neat) 3096, 3064, 3040, 2925, 2856, 1594, 1500, 1484, 1234 cm-1. –
1H NMR (300 MHz, CDCl3): δ = 7.37-7.26 (m, 4H), 7.12-7.07 (m, 1H), 7.03-6.96 (m, 6H),
6.96-6.90 (m, 2H). – 13C NMR (75 MHz, CDCl3): δ = 157.6, 156.5, 153.1, 152.2, 129.8, 129.7,
127.9, 123.1, 120.5, 120.4, 119.4, 118.4. – LRMS (DCI, positive mode) m/z (rel intensity) 296
([M(35Cl)]+, 100), 298 ([M(37Cl)]+, 30).
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Phenoxynaphthalene (1w).31g Using the general procedure with DMF as solvent, from
β-naphthol and iodobenzene, the expected diaryl ether 1w was isolated as a pale yellow
solid. – Yield 62% (68 mg). – Rf = 0.50 (50:50 cyclohexane/EtOAc). – M.p. 42 °C. – FTIR-
ATR (neat) 3057, 2925, 2853, 1631, 1589, 1510, 1489, 1464, 1251, 1224 cm-1. – H NMR
1
(300 MHz, CDCl3): δ = 7.85-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.49-7.25 (m, 6H), 7.18-7.00
(m, 3H). – 13C NMR (75 MHz, CDCl3): δ = 157.1, 155.0, 134.3, 130.1, 129.83, 129.79, 127.7,
127.1, 126.5, 124.7, 123.4, 120.0, 119.1, 114.0. – LRMS (DCI, positive mode) m/z (rel
intensity) 220 ([M]+, 70), 221 ([MH]+, 100).
1-Ethoxybenzene (1x).31h Using the general procedure with ethanol as solvent, from
ethanol and iodobenzene, the expected ether 1x was isolated as a pale yellow oil. – Yield
75% (46 mg). – Rf = 0.20 (cyclohexane). – FTIR-ATR (neat) 2955, 2921, 2850, 1601, 1488,
1463, 1260, 802 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.31-7.24 (m, 2H), 6.96-6.87 (m,
3H), 4.03 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 6.9 Hz, 3H). – 13C NMR (75 MHz, CDCl3): δ =
1
3
3
158.9, 129.4, 120.5, 114.4, 63.2, 14.8.
1-Butoxybenzene (1y).31h Using the general procedure with butan-1-ol as solvent, from
butan-1-ol and iodobenzene, the expected ether 1y was isolated as a colourless oil. – Yield
73% (55 mg). – Rf = 0.20 (cyclohexane). – FTIR-ATR (neat) 3058, 2959, 2934, 2872, 1601,
1497, 1473, 1245, 1030, 753, 691 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 7.32-7.25 (m, 2H),
6.96-6.88 (m, 3H), 3.97 (t, 3J = 6.6 Hz, 2H), 1.82-1.73 (m, 2H), 1.57-1.44 (m, 2H), 0.98 (t, 3J
= 7.2 Hz, 3H). – 13C NMR (75 MHz, CDCl3): δ = 159.1, 129.4, 120.4, 114.5, 67.5, 31.3, 19.3,
13.8. – LRMS (DCI, positive mode) m/z (rel intensity) 151 ([MH]+, 100).
N-Phenyl-3,5-bis(trifluoromethyl)-benzenamine
(2c)
and
N,N-diphenyl-3,5-
bis(trifluoromethyl)-benzenamine (2c’).32a Using the general procedure with DMF as
solvent, from 3,5-bis(trifluoromethyl)aniline and iodobenzene, the monophenylated aniline 2c
and its diphenylated analog 2c’ were obtained in pure forms after purification by column
chromatography (for the respective yields depending on the stoichiometry, see Scheme 3).
N-Phenyl-3,5-bis(trifluoromethyl)-benzenamine (2c). Brown solid
–
Rf
=
0.10
(cyclohexane). – M.p. 81-82 °C. – FTIR-ATR (neat) 3441, 3045, 1598, 1522, 1385, 1282,
1175, 1122 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.40-7.32 (m, 5H), 7.16-7.10 (m, 3H),
6.00 (brs, 1H). – 13C NMR (75 MHz, CDCl3): δ = 145.3, 140.3, 132.6 (q, JC-F = 32.7 Hz),
129.8, 123.8, 123.3 (q, 1JC-F = 271.1 Hz), 120.4, 115.2-115.1 (m), 113.0 (sept, 4JC-F = 3.9 Hz).
– LRMS (DCI, positive mode) m/z (rel intensity) 305 ([M]+, 100), 306 ([MH]+, 30). N,N-
1
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
5
6
7
8
9
Diphenyl-3,5-bis(trifluoromethyl)-benzenamine (2c’). Yellow oil – Rf = 0.70 (cyclohexane).
1
– FTIR-ATR (neat) 3066, 3038, 1594, 1496, 1379, 1277, 1169, 1130 cm-1. – H NMR (300
MHz, CDCl3): δ = 7.37-7.31 (m, 7H), 7.19-7.10 (m, 6H). – 13C NMR (75 MHz, CDCl3): δ =
2
1
149.3, 146.1, 132.4 (q, JC-F = 32.7 Hz), 129.9, 125.4, 125.0, 123.3 (q, JC-F = 270.7 Hz),
120.3-120.2 (m), 114.0 (sept, 4JC-F = 3.9 Hz). – LRMS (DCI, positive mode) m/z (rel intensity)
382 ([MH]+, 100).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Nitro-N-phenylaniline (2d) and (4-nitrophenyl)diphenylamine (2d’).32b Using the
general procedure with DMF as solvent, from 4-nitroaniline and iodobenzene, the
monophenylated aniline 2d and its diphenylated analog 2d’ were obtained in pure forms after
purification by column chromatography (for the respective yields depending on the
soichiometry, see Scheme 3). 4-Nitro-N-phenylaniline (2d). Orange solid – Rf = 0.20 (90:10
cyclohexane/EtOAc). – M.p. 132 °C. – FTIR-ATR (neat) 3341, 3064, 1603, 1583, 1495,
1
1321, 1300, 1107, 747, 702 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.15-8.10 (m, 2H), 7.43-
7.36 (m, 2H), 7.23-7.14 (m, 3H), 6.97-6.92 (m, 2H), 6.27 (brs, 1H). – 13C NMR (75 MHz,
CDCl3): δ = 150.3, 139.5, 139.4, 129.6, 126.2, 124.5, 121.8, 113.6. – LRMS (APCI, positive
mode) m/z (rel intensity) 215 ([MH]+, 100). (4-Nitrophenyl)diphenylamine (2d’). Orange to
red solid – Rf = 0.70 (90:10 cyclohexane/EtOAc). – M.p. 140 °C. – FTIR-ATR (neat) 3038,
1
1594, 1580, 1487, 1312, 1287, 1110, 750, 695 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.06-
8.01 (m, 2H), 7.39-7.34 (m, 4H), 7.24-7.17 (m, 6H), 6.95-6.90 (m, 2H). – 13C NMR (75 MHz,
CDCl3): δ = 153.4, 145.6, 140.1, 129.9, 126.5, 125.7, 125.4, 118.1. – LRMS (APCI, positive
mode) m/z (rel intensity) 291 ([MH]+, 100).
4-Methoxy-N-(4-nitropheny)-benzenamine (2e) and N,N-bis(4-methoxyphenyl)-4-
nitro-benzenamine (2e’).32c Using the general procedure with DMF as solvent, from 4-
nitroaniline and 4-iodoanisole, the diarylated amine 2e and its triarylated analog 2e’ were
obtained in pure forms after purification by column chromatography (for the respective yields
depending on the soichiometry, see Scheme 3). 4-Methoxy-N-(4-nitropheny)-benzenamine
(2e). Orange solid – Rf = 0.30 (80:20 cyclohexane/EtOAc). – M.p. 150-151 °C. – FTIR-ATR
(neat) 3326, 3043, 2955, 2835, 1597, 1510, 1294, 1112 cm-1. – 1H NMR (300 MHz, CDCl3): δ
= 8.11-8.06 (m, 2H), 7.18-7.13 (m, 2H), 6.96-6.91 (m, 2H), 6.79-6.73 (m, 2H), 6.10 (brs, 1H),
3.83 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 157.4, 151.7, 139.0, 132.0, 126.3, 125.5,
114.9, 112.6, 55.5. – LRMS (DCI, positive mode) m/z (rel intensity) 245 ([MH]+, 45), 262
([MNH4]+, 100). N,N-bis(4-Methoxyphenyl)-4-nitro-benzenamine (2e’). Orange to red solid
– Rf = 0.50 (80:20 cyclohexane/EtOAc). – M.p. 120-121 °C. – FTIR-ATR (neat) 3000, 2954,
1
2930, 2835, 1588, 1505, 1494, 1313, 1241, 1110 cm-1. – H NMR (300 MHz, CDCl3): δ =
8.02-7.97 (m, 2H), 7.16-7.11 (m, 4H), 6.93-6.88 (m, 4H), 6.78-6.73 (m, 2H), 3.82 (s, 3H). –
13C NMR (75 MHz, CDCl3): δ = 157.6, 154.1, 139.0, 138.3, 128.1, 125.6, 115.7, 115.2, 55.5.
– LRMS (DCI, positive mode) m/z (rel intensity) 351 ([MH]+, 100).
1-(4-((4-Nitrophenyl)amino)phenyl)-ethanone (2f). Using the general procedure with
DMF as solvent, from 4-nitroaniline and 4’-iodoacetophenone, the expected diaryl amine 2f
was isolated as a yellow solid. – Yield 75% (96 mg). – Rf = 0.25 (80:20 cyclohexane/EtOAc).
1
– M.p. 155-156 °C. – FTIR-ATR (neat) 3302, 1660, 1608, 1578, 1504, 1320 cm-1. – H NMR
(300 MHz, CDCl3): δ = 8.22-8.17 (m, 2H), 8.00-7.95 (m, 2H), 7.24-7.20 (m, 2H), 7.17-7.11
(m, 2H), 6.52 (brs, 1H), 2.59 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 196.5, 147.8, 144.6,
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
141.2, 132.0, 130.5, 126.1, 118.3, 116.0, 26.4. – HRMS (DCI, positive mode): m/z: calcd for
C14H13N2O3 257.0926, found 257.0925 [MH]+.
N-Phenylbenzamide (2j).32b Using the general procedure with DMF as solvent at 140°C,
from benzamide and iodobenzene, the expected arylated amide 2j was isolated as a white
solid. – Yield 83% (82 mg). – Rf = 0.80 (50:50 cyclohexane/EtOAc). – M.p. 160-162 °C. –
FTIR-ATR (neat) 3343, 3053, 1654, 1599, 1527, 1464, 1321, 749 cm-1. – 1H NMR (300 MHz,
CDCl3): δ = 7.90-7.86 (m, 2H), 7.80 (brs, 1H), 7.66-7.63 (m, 2H), 7.59-7.47 (m, 3H), 7.41-
7.35 (m, 2H), 7.19-7.13 (m, 1H). – 13C NMR (75 MHz, CDCl3): δ = 165.8, 137.9, 135.0, 131.8,
129.0, 128.7, 127.0, 124.5, 120.2. – LRMS (DCI, positive mode) m/z (rel intensity) 198
([MH]+, 100), 215 ([MNH4]+, 25).
1-Phenylpyrrolidin-2-one (2k).32b Using the general procedure with DMF as solvent at
140°C, from pyrrolidin-2-one and iodobenzene, the expected arylated amide 2k was isolated
as a white solid. – Yield 99% (80 mg). – Rf = 0.40 (50:50 cyclohexane/EtOAc). – M.p. 65-66
°C. – FTIR-ATR (neat) 3061, 2970, 2919, 2903, 1679, 1595, 1499, 1400, 1307, 1230, 763,
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
695 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.62-7.58 (m, 2H), 7.40-7.33 (m, 2H), 7.17-7.11
(m, 1H), 3.86 (t, 3J = 6.9 Hz, 2H), 2.61 (t, 3J = 8.1 Hz, 2H), 2.21-2.11 (m, 2H). – 13C NMR (75
MHz, CDCl3): δ = 174.0, 139.2, 128.6, 124.2, 119.7, 48.5, 32.6, 17.8. – LRMS (DCI, positive
mode) m/z (rel intensity) 162 ([MH]+, 100), 179 ([MNH4]+, 25).
1-Phenyl-1H-pyrrole (3a).33a Using the general procedure with DMF as solvent, from
pyrrole and either iodobenzene or bromobenzene, the expected N-phenylated heterocycle 3a
was isolated as a white solid. – Yields 86% (61 mg from the iodo derivative) and 21% (15 mg
from the bromo derivative). – Rf = 0.40 (cyclohexane). – M.p. 58 °C. – FTIR-ATR (neat)
1
3142, 3048, 1604, 1514, 1326, 1085, 759, 718 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.46-
3
3
7.38 (m, 4H), 7.27-7.22 (m, 1H), 7.10 (t, J = 2.2 Hz, 2H), 6.35 (t, J = 2.3 Hz, 2H). – 13C
NMR (75 MHz, CDCl3): δ = 140.7, 129.5, 125.5, 120.4, 119.2, 110.3. – LRMS (APCI, positive
mode) m/z (rel intensity) 144 ([MH]+, 100).
1-(4-Methoxyphenyl-1H-pyrrole (3b).33b Using the general procedure with DMF as
solvent, from pyrrole and 4-iodoanisole, the expected N-arylated heterocycle 3b was isolated
as a white solid. – Yield 92% (80 mg). – Rf = 0.65 (90:10 cyclohexane/EtOAc). – M.p. 111
°C. – FTIR-ATR (neat) 3143, 3014, 2963, 2838, 1520, 1260, 1030, 827, 721 cm-1. – 1H NMR
(300 MHz, CDCl3): δ = 7.34-7.29 (m, 2H), 7.00 (t, 3J = 2.1 Hz, 2H), 6.97-6.92 (m, 2H), 6.32 (t,
3J = 2.1 Hz, 2H), 3.84 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 157.6, 134.4, 122.1, 119.6,
114.5, 109.8, 55.5. – LRMS (APCI, positive mode) m/z (rel intensity) 174 ([MH]+, 100).
1-(4-(1H-Pyrrol-1-yl)phenyl)-ethanone (3c).33c Using the general procedure with DMF as
solvent, from pyrrole and 4’-iodoacetophenone, the expected N-arylated heterocycle 3c was
isolated as a pale brown oil. – Yield 89% (82 mg). – Rf = 0.30 (90:10 cyclohexane/EtOAc). –
FTIR-ATR (neat) 3141, 3006, 2918, 2852, 1666, 1603, 1522, 1326, 1278, 1198, 842, 737
cm-1. – 1H NMR (300 MHz, CDCl3): δ = 8.06-8.01 (m, 2H), 7.50-7.45 (m, 2H), 7.17 (t, 3J = 2.4
Hz, 2H), 6.40 (t, 3J = 2.1 Hz, 2H), 2.62 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 196.6, 143.9,
133.8, 130.0, 119.1, 118.9, 111.5, 26.4. – LRMS (APCI, positive mode) m/z (rel intensity) 186
([MH]+, 100).
1-Phenyl-1H-pyrazole (3e).11b Using the general procedure with DMF as solvent, from
pyrazole and either iodobenzene or bromobenzene, the expected N-phenylated heterocycle
3e was isolated as a pale yellow oil. – Yields 96% (71 mg from the iodo derivative) and 8% (6
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
5
6
7
8
9
mg from the bromo derivative). – Rf = 0.80 (50:50 cyclohexane/EtOAc). – FTIR-ATR (neat)
1
3110, 2922, 1600, 1521, 1501, 1393, 936, 755 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.93
(brd, 3J = 2.4 Hz, 1H), 7.73-7.68 (m, 3H), 7.48-7.43 (m, 2H), 7.32-7.27 (m, 1H), 6.47 (brt, 3J =
2.3 Hz, 1H). – 13C NMR (75 MHz, CDCl3): δ = 141.0, 140.1, 129.3, 126.7, 126.4, 119.1,
107.5. – LRMS (DCI, positive mode) m/z (rel intensity) 145 ([MH]+, 100).
1-(4-Methoxyphenyl-1H-pyrazole (3f).11b Using the general procedure with DMF as
solvent, from pyrazole and 4-iodoanisole, the expected N-arylated heterocycle 3f was
isolated as a pale yellow oil. – Yield 74% (64 mg). – Rf = 0.30 (90:10 cyclohexane/EtOAc). –
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
FTIR-ATR (neat) 3124, 3002, 2835, 1521, 1247, 1039, 831, 751 cm-1. – H NMR (300 MHz,
3
CDCl3): δ = 7.83-7.82 (m, 1H), 7.70 (brd, J = 1.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.00-6.95 (m,
3
2H), 6.44 (brt, J = 2.1 Hz, 1H), 3.85 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 158.1, 140.5,
133.9, 126.7, 120.8, 144.4, 107.1, 55.5. – LRMS (APCI, positive mode) m/z (rel intensity) 175
([MH]+, 100).
1-(4-(1H-Pyrazol-1-yl)phenyl)-ethanone (3g).11b Using the general procedure with DMF
as solvent, from pyrazole and 4’-iodoacetophenone, the expected N-arylated heterocycle 3f
was isolated as a pale yellow solid. – Yield 86% (80 mg). – Rf = 0.10 (90:10
cyclohexane/EtOAc). – M.p. 101 °C. – FTIR-ATR (neat) 3136, 3046, 2911, 1674, 1606,
1525, 1412, 1395, 757 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 8.09-8.05 (m, 2H), 8.01 (dd, 3J
= 2.4 Hz, 4J = 0.3, 1H), 7.84-7.79 (m, 2H), 7.77 (brd, 3J = 1.5 Hz, 1H), 6.52 (dd, 3J = 2.4 Hz,
3J = 1.8 Hz, 1H), 2.63 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 196.7, 143.1, 141.9, 134.6,
129.8, 126.8, 118.2, 108.4, 26.4. – LRMS (APCI, positive mode) m/z (rel intensity) 187
([MH]+, 100).
2-(1H-Pyrazol-1-yl)pyridine (3h).33b Using the general procedure with DMF as solvent,
from pyrazole and 2-bromopyridine, the expected N-arylated heterocycle 3h was isolated as
a white solid. – Yield 76% (55 mg). – Rf = 0.45 (80:20 cyclohexane/EtOAc). – M.p. 35 °C. –
1
FTIR-ATR (neat) 3151, 3067, 3017, 1595, 1522, 1475, 1458, 1393, 1052, 779 cm-1. – H
3
3
NMR (300 MHz, CDCl3): δ = 8.57 (d, J = 1.8 Hz, 1H), 8.42 (brs, 1H), 7.99 (d, J = 8.4 Hz,
3
3
4
3
1H), 7.82 (ddd, J = 8.1 Hz, J = 7.2 Hz, J = 1.8 Hz, 1H), 7.74 (brs, 1H), 7.19 (dd, J = 6.6
3
Hz, J = 5.1 Hz, 1H), 6.47 (brs, 1H). – 13C NMR (75 MHz, CDCl3): δ = 151.4, 147.9, 141.9,
138.5, 126.9, 121.2, 112.3, 107.6. – LRMS (DCI, positive mode) m/z (rel intensity) 146
([MH]+, 100).
1-Phenyl-1H-imidazole (3i).11b Using the general procedure with DMF as solvent, from
imidazole and either iodobenzene or bromobenzene, the expected N-phenylated heterocycle
3i was isolated as a pale yellow oil. – Yields 88% (64 mg from the iodo derivative) and 14%
(10 mg from the bromo derivative). – Rf = 0.30 (20:80 cyclohexane/EtOAc). – FTIR-ATR
(neat) 3107, 3059, 1600, 1509, 1304, 1058, 760 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 7.85
(brs, 1H), 7.51-7.45 (m, 2H), 7.41-7.34 (m, 3H), 7.28 (t, J = 1.2 Hz, 1H), 7.21 (brs, 1H). – 13C
NMR (75 MHz, CDCl3): δ = 137.1, 135.3, 130.2, 129.7, 127.2, 121.2, 118.0. – LRMS (DCI,
positive mode) m/z (rel intensity) 145 ([MH]+, 100).
1-(4-Methoxyphenyl-1H-imidazole (3j).11b Using the general procedure with DMF as
solvent at 140°C, from imidazole and 4-iodoanisole, the expected N-arylated heterocycle 3j
was isolated as a beige solid. – Yield 92% (80 mg). – Rf = 0.35 (20:80 cyclohexane/EtOAc).
– M.p. 62-63 °C. – FTIR-ATR (neat) 3118, 3005, 2837, 1611, 1520, 1250, 1060, 832 cm-1. –
1H NMR (300 MHz, CDCl3): δ = 7.75 (brs, 1H), 7.32-7.27 (m, 2H), 7.19-7.17 (m, 2H), 7.00-
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6.95 (m, 2H), 3.84 (s, 3H). – 13C NMR (75 MHz, CDCl3): δ = 158.8, 135.7, 130.6, 129.9,
123.0, 118.6, 114.7, 55.5. – LRMS (DCI, positive mode) m/z (rel intensity) 175 ([MH]+, 100).
1-(4-(1H-Imidazol-1-yl)phenyl)-ethanone (3k).33b Using the general procedure with DMF
as solvent, from imidazole and 4’-iodoacetophenone, the expected N-arylated heterocycle 3k
was isolated as a pale yellow solid. – Yield 90% (84 mg). – Rf = 0.30 (20:80
cyclohexane/EtOAc). – M.p. 116-117 °C. – FTIR-ATR (neat) 3108, 3062, 2999, 1675, 1606,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1520, 1306, 1251, 743 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.12-8.08 (m, 2H), 8.03 (brs,
1H), 7.53-7.49 (m, 2H), 7.37 (brs, 1H), 7.27 (brs, 1H), 2.64 (s, 3H). – 13C NMR (75 MHz,
CDCl3): δ = 196.3, 140.4, 135.4, 135.1, 130.8, 130.1, 120.4, 117.5, 26.4. – LRMS (DCI,
positive mode) m/z (rel intensity) 187 ([MH]+, 100).
1-Phenyl-1H-indole (3m).33b Using the general procedure with DMF as solvent at 140°C,
from indole and iodobenzene, the expected N-phenylated heterocycle 3m was isolated as a
colourless oil. – Yield 95% (92 mg). – Rf = 0.80 (90:10 cyclohexane/EtOAc). – FTIR-ATR
(neat) 3104, 3054, 1597, 1515, 1497, 1456, 1331, 1233, 741 cm-1. – H NMR (300 MHz,
1
CDCl3): δ = 7.72-7.69 (m, 1H), 7.60-7.57 (m, 1H), 7.53-7.50 (m, 4H), 7.41-7.34 (m, 2H), 7.24-
7.15 (m, 2H), 6.70 (brd, J = 3.3 Hz, 1H). – 13C NMR (75 MHz, CDCl3): δ = 139.7, 135.8,
3
129.5, 129.3, 127.9, 126.3, 124.3, 122.3, 121.1, 120.3, 110.5, 103.5. – LRMS (DCI, positive
mode) m/z (rel intensity) 194 ([MH]+, 100).
1-Phenyl-1H-benzimidazole (3n).33d Using the general procedure with DMF as solvent at
140°C, from benzimidazole and iodobenzene, the expected N-phenylated heterocycle 3n
was isolated as a pale yellow oil. – Yield 88% (85 mg). – Rf = 0.40 (50:50
cyclohexane/EtOAc). – FTIR-ATR (neat) 3104, 3050, 1599, 1502, 1457, 1291, 1231, 745 cm-
1. – 1H NMR (300 MHz, CDCl3): δ = 8.12 (s, 1H), 7.92-7.86 (m, 1H), 7.62-7.44 (m, 6H), 7.37-
7.31 (m, 2H). – 13C NMR (75 MHz, CDCl3): δ = 143.9, 142.2, 136.2, 133.6, 129.9, 127.9,
123.9, 123.6, 122.7, 120.5, 110.4. – LRMS (DCI, positive mode) m/z (rel intensity) 195
([MH]+, 100).
1-Phenyl-1H-benzo[1,2,3]triazole (3o).33e Using the general procedure with DMF as
solvent at 140°C, from benzo[1,2,3]triazole and iodobenzene, the expected N-phenylated
heterocycle 3o was isolated as a colourless oil. – Yield 68% (66 mg). – Rf = 0.40 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3036, 2876, 2804, 1593, 1572, 1489, 1237 cm-1. –
1H NMR (300 MHz, CDCl3): δ = 8.17-8.14 (brd, 1H), 7.82-7.75 (m, 3H), 7.65-7.42 (m, 5H). –
13C NMR (75 MHz, CDCl3): δ = 146.5, 137.0, 132.3, 129.8, 128.6, 128.2, 124.3, 122.8, 120.3,
110.3. – LRMS (DCI, positive mode) m/z (rel intensity) 196 ([MH]+, 100).
(3,5-Dimethylphenyl)phenyl sulfide (4a).34a Using the general procedure with DMF as
solvent, from 3,5-dimethylbenzenethiol and iodobenzene, the expected diaryl sulfide 4a was
isolated as a colourless oil. – Yield 88% (94 mg). – Rf = 0.50 (cyclohexane). – FTIR-ATR
(neat) 3057, 2913, 1600, 1579, 1477, 1439, 1024, 846, 740, 687 cm-1. – H NMR (300 MHz,
1
CDCl3): δ = 7.35-7.19 (m, 5H), 7.01 (brs, 2H), 6.90 (brs, 1H), 2.28 (s, 6H). – 13C NMR (75
MHz, CDCl3): δ = 138.8, 136.4, 134.7, 130.5, 129.10, 129.08, 129.03, 126.6, 21.1. – LRMS
(APCI, positive mode) m/z (rel intensity) 215 ([MH]+, 100).
Diphenyl sulfide (4b).34a Using the general procedure with DMF as solvent, from
benzenethiol and iodobenzene, the expected diphenyl sulfide 4b was isolated as a colourless
oil. – Yield 88% (82 mg). – Rf = 0.60 (cyclohexane). – FTIR-ATR (neat) 3071, 3058, 1580,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
1475, 1439, 737, 689 cm-1. – 1H NMR (300 MHz, CDCl3): δ = 7.37-7.21 (m, 10H). – 13C NMR
(75 MHz, CDCl3): δ = 135.7, 131.0, 129.1, 127.0. – LRMS (DCI, positive mode) m/z (rel
intensity) 186 ([M]+, 60), 187 ([MH]+, 100).
6
1-((4-Methoxyphenyl)thio)-3,5-demethylbenzene (4c).34a Using the general procedure
with DMF as solvent, from 3,5-dimethylbenzenethiol and 4-iodoanisole, the expected diaryl
sulfide 4c was isolated as a colourless oil. – Yield 56% (68 mg). – Rf = 0.60 (90:10
cyclohexane/EtOAc). – FTIR-ATR (neat) 3024, 2939, 2914, 2834, 1593, 1493, 1248 1033,
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
829 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.42-7.37 (m, 2H), 6.91-6.86 (m, 2H), 6.82 (brs,
2H), 6.79 (brs, 1H), 3.83 (s, 3H), 2.24 (brs, 3H). – 13C NMR (75 MHz, CDCl3): δ = 159.6,
138.6, 137.7, 134.9, 127.8, 126.2, 124.8, 114.8, 55.3, 21.2. – LRMS (DCI, positive mode)
m/z (rel intensity) 244 ([M]+, 25), 245 ([MH]+, 100).
1-((4-Isopropyloxyphenyl)thio)-3,5-demethylbenzene
(4d). Using the general
procedure with DMF as solvent, from 3,5-dimethylbenzenethiol and 4-isopropyloxy-1-
iodobenzene, the expected diaryl sulfide 4d was isolated as a pale yellow oil. – Yield 94%
(128 mg). – Rf = 0.75 (90:10 cyclohexane/EtOAc). – FTIR-ATR (neat) 3030, 2977, 2919,
2857, 1593, 1490, 1282, 1244, 1118, 954, 836 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.39-
1
3
7.34 (m, 2H), 6.89-6.84 (m, 2H), 6.82 (brs, 2H), 6.79 (brs, 1H), 4.56 (sept, J = 6.0 Hz, 1H),
2.24 (s, 6H), 1.35 (d, 3J = 6.0 Hz, 6H). – 13C NMR (75 MHz, CDCl3): δ = 157.9, 138.5, 137.8,
134.9, 127.8, 126.2, 124.3, 116.6, 69.9, 22.0, 21.2. – HRMS (DCI, positive mode): m/z: calcd
for C17H21OS 273.1313, found 273.1310 [MH]+.
1-(4-(3,5-Dimethylphenylthio)phenyl)ethanone (4e). Using the general procedure with
DMF as solvent, from 3,5-dimethylbenzenethiol and 4’-iodoacetophenone, the expected
diaryl sulfide 4e was isolated as white needles. – Yield 86% (110 mg). – Rf = 0.45 (90:10
cyclohexane/EtOAc). – M.p. 89-90 °C. – FTIR-ATR (neat) 3002, 2918, 2857, 1681, 1589,
1356, 1263 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.83-7.79 (m, 2H), 7.22-7.18 (m, 2H),
1
7.13 (brs, 2H), 7.13 (brs, 1H), 2.55 (s, 3H), 2.32 (s, 6H). – 13C NMR (75 MHz, CDCl3): δ =
197.1, 145.5, 139.4, 134.2, 131.6, 131.1, 130.7, 128.8, 127.1, 26.4, 21.1. – HRMS (DCI,
positive mode) m/z: calcd for C16H17OS 257.1000, found 257.1001 [MH]+.
(4-Methylbenzyl)phenyl sulfide (4f).34b Using the general procedure with toluene as
solvent, from para-xylene-α-thiol and iodobenzene, the expected alkyl aryl sulfide 4f was
isolated as a white solid. – Yield 68% (73 mg). – Rf = 0.30 (cyclohexane). – M.p. 66-67 °C. –
FTIR-ATR (neat) 3058, 2919, 1583, 1511, 1479, 1436, 738 cm-1. – H NMR (300 MHz,
1
CDCl3): δ = 7.33-7.15 (m, 7H), 7.11-7.09 (m, 2H), 4.10 (s, 2H), 2.32 (s, 3H). – 13C NMR (75
MHz, CDCl3): δ = 136.8, 136.6, 134.3, 129.5, 129.1, 128.8, 128.7, 126.1, 38.6, 21.1. – LRMS
(DCI, positive mode) m/z (rel intensity) 214 ([M]+, 100).
Diethyl 2-phenylmalonate (5a).33a Using the general procedure with DMF as solvent,
from diethyl malonate and iodobenzene, the expected phenylated malonate 5a was isolated
as a colourless oil. – Yield 53% (63 mg). – Rf = 0.35 (90:10 cyclohexane/EtOAc). – FTIR-
ATR (neat) 3060, 2979, 2938, 2907, 1752, 1731, 1301, 1217, 1144, 1027, 728 cm-1. – H
3
NMR (300 MHz, CDCl3): δ = 7.42-7.32 (m, 5H), 4.61 (s, 1H), 4.29-4.14 (m, 4H), 1.26 (t, J =
6.9 Hz, 6H). – 13C NMR (75 MHz, CDCl3): δ = 168.1, 132.7, 129.2, 128.5, 128.1, 61.7, 57.9,
13.9. – LRMS (DCI, positive mode) m/z (rel intensity) 237 ([MH]+, 100), 254 ([MNH4]+, 70).
1
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Diethyl 2-(4-methoxyphenyl)malonate (5b).34c Using the general procedure with DMF
as solvent, from diethyl malonate and 4-iodoanisole, the expected arylated malonate 5b was
isolated as a colourless oil. – Yield 59% (78 mg). – Rf = 0.25 (90:10 cyclohexane/EtOAc). –
1
FTIR-ATR (neat) 2982, 2939, 2907, 2838, 1733, 1613, 1514, 1251, 1179, 1032 cm-1. – H
NMR (300 MHz, CDCl3): δ = 7.35-7.30 (m, 2H), 6.91-6.86 (m, 2H), 4.55 (s, 1H), 4.28-4.13 (m,
3
4H), 3.80 (s, 3H), 1.26 (t, J = 6.9 Hz, 6H). – 13C NMR (75 MHz, CDCl3): δ = 168.4, 159.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
130.3, 124.9, 113.9, 61.7, 57.1, 55.2, 14.0. – LRMS (DCI, positive mode) m/z (rel intensity)
267 ([MH]+, 90), 284 ([MNH4]+, 100).
1-Phenyl-1H-pyridin-2-one (6).33a Using the general procedure with DMF as solvent at
140°C, from 1H-pyridin-2-one and iodobenzene, the N-phenylated product 6 was isolated as
a white solid. – Yield 84% (72 mg). – Rf = 0.15 (50:50 cyclohexane/EtOAc). – M.p. 125-126
1
°C. – FTIR-ATR (neat) 3054, 1660, 1603, 1581, 1529, 1492, 767 cm-1. – H NMR (300 MHz,
CDCl3): δ = 7.52-7.32 (m, 7H), 6.66 (ddd, 3J = 9.3 Hz, 4J = 1.2 Hz, 4J = 0.9 Hz, 1H), 6.23 (dt,
4
3J = 6.6 Hz, J = 1.2 Hz, 1H). – 13C NMR (75 MHz, CDCl3): δ = 162.3, 140.8, 139.8, 137.9,
129.2, 128.4, 126.4, 121.8, 105.8. – LRMS (DCI, positive mode) m/z (rel intensity) 172
([MH]+, 100).
1-Phenyl-1H-indol-6-amine (7). Using the general procedure with DMF as solvent at
140°C, from 1H-indol-6-amine and iodobenzene, the N-phenylated product 7 was isolated as
a dark brown oil. – Yield 89% (93 mg). – Rf = 0.60 (50:50 cyclohexane/EtOAc). – FTIR-ATR
(neat) 3431, 3354, 3098, 3060, 1627, 1596, 1500, 1222 cm-1. – 1H NMR (300 MHz, CDCl3): δ
3
= 7.53-7.44 (m, 5H), 7.36-7.30 (m, 1H), 7.15 (d, J = 3.3 Hz, 1H), 6.88-6.87 (m, 1H), 6.62
3
4
3
4
(dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 6.56 (dd, J = 3.3 Hz, J = 0.6 Hz, 1H), 3.62 (brs, 2H). –
13C NMR (75 MHz, CDCl3): δ = 142.5, 140.0, 137.0, 129.4, 126.1, 126.0, 124.2, 122.4, 121.6,
111.0, 103.5, 95.9. – HRMS (DCI, positive mode): m/z: calcd for C14H13N2 209.1079, found
209.1085 [MH]+.
1-Phenyl-1H-indazol-6-amine (8).35 Using the general procedure with DMF as solvent at
140°C, from 1H-indol-6-amine and iodobenzene, the N-phenylated product 8 was isolated as
an orange solid. – Yield 97% (101 mg). – Rf = 0.60 (50:50 cyclohexane/EtOAc). – M.p. 146-
148 °C. – FTIR-ATR (neat) 3482, 3386, 3200, 3054, 1629, 1595, 1500, 1476, 1418, 1297,
1
4
1130 cm-1. – H NMR (300 MHz, CDCl3): δ = 8.02 (brd, J = 0.6 Hz, 1H), 7.71-7.67 (m, 2H),
7.57-7.49 (m, 3H), 7.35-7.30 (m, 1H), 6.935-6.629 (m, 1H), 6.64 (dd, 3J = 8.7 Hz, 4J = 2.1 Hz,
1H), 3.89 (brs, 2H). – 13C NMR (75 MHz, CDCl3): δ = 146.5, 140.36, 140.35, 135.4, 129.2,
126.1, 122.5, 122.0, 118.9, 113.0, 93.2. – LRMS (DCI, positive mode) m/z (rel intensity) 210
([MH]+, 100).
4-Allyl-2-methoxy-1-(methoxymethoxy)benzene (intermediate towards 9 – 9a).21 To
a stirred ice-cold solution of eugenol (2.00 g, 12.2 mmol, 1.0 equiv.) in dry CH2Cl2 (50 mL)
was added CH2(OCH3)2 (16 mL, 183 mmol, 15 equiv.) in one portion and P2O5 (8.66 g, 61
mmol, 5 equiv.) in three portions, the resulting mixture was stirred at 0°C for 4 h. The liquid
phase was then transferred into a separatory funnel and the solid residue was washed with
CH2Cl2 (3 × 60 mL). The combined CH2Cl2 layers were washed with saturated aq. NaHCO3 (1
× 60 mL), 1 M aq. NaOH (2 × 60 mL), water (60 mL), brine (60 mL), dried over Na2SO4,
filtered and evaporated. Purification of the crude materials by column chromatography,
eluting with cyclohexane/acetone (10:0 to 97:3), furnished 9a (2.13 g, 84%) in pure forms as
a pale yellow oil. – FTIR-ATR (neat) 2954, 2901, 2828, 1591, 1512, 1263, 1155, 1078, 999
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
4
5
6
7
8
9
1
cm-1. – H NMR (300 MHz, CDCl3): δ = 7.09-7.06 (m, 1H), 6.73-6.69 (m, 2H), 6.02-5.89 (m,
1H), 5.20 (s, 2H), 5.13-5.04 (m, 2H), 3.87 (s, 3H), 3.51 (s, 3H), 3.35-3.33 (m, 2H). – 13C NMR
(75 MHz, CDCl3): δ = 149.6, 144.7, 137.4, 134.4, 120.5, 116.5, 115.6, 112.2, 95.6, 56.0,
55.7, 39.8. – LRMS (DCI, positive mode) m/z (rel intensity) 226 ([M+NH4]+, 100), 209
([M+H]+, 25).
5-Allyl-1-iodo-3-methoxy-2-(methoxymethoxy)benzene (9). To a stirred solution of 9a
(1.385 g, 6.65 mmol, 1.0 equiv.) in anhydrous THF (18 mL) was added dropwise nBuLi (1.6 M
in hexanes, 5 mL, 7.98 mmol, 1.2 equiv.) at –30°C. The solution was slowly warmed to –
10°C over 30 min and stirred at this temperature for 75 min. The resulting orange mixture
was then cooled to –30°C and a solution of I2 (2.535 g, 9.98 mmol, 1.5 equiv.) in dry THF (17
mL) was added dropwise until the dark orange coloration remained (i.e. 12.5 mL). The
reaction mixture was then warmed to 0°C over 4 h and stirred for an additional 2 h at 0°C.
Saturated aq. NH4Cl (20 mL) was added at 0°C and the resulting mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with 1 M aq. Na2S2O3 (40
mL), brine (40 mL), dried over Na2SO4, filtered and evaporated. Purification of the crude
materials by column chromatography, eluting with cyclohexane/EtOAc (10:0 to 98:2),
furnished 9 (1.45 g, 65%) in pure forms as a pale yellow oil. – Rf = 0.40 (90:10 cyclohexane/
EtOAc). – FTIR-ATR (neat) 2960, 2935, 2838, 1591, 1561, 1463, 1266, 1159, 1043, 955,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4
4
845, 677 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 1.8 Hz, 1H), 6.70 (d, J = 1.8
Hz, 1H), 5.98-5.84 (m, 1H), 5.13-5.07 (m, 4H), 3.82 (s, 3H), 3.67 (s, 3H), 3.30-3.28 (m, 2H).
– 13C NMR (75 MHz, CDCl3): δ = 152.0, 144.0, 138.1, 136.5, 130.6, 116.4, 113.2, 98.6, 92.5,
58.3, 55.9, 39.3. – HRMS (DCI, positive mode) m/z: calcd for C12H15O3I 334.0066, found
334.0072 [M]+.
5-allyl-1-(4-allylphenoxy)-3-methoxy-2-(methoxy methoxy)benzene (10).21 In a 2-5 mL
Biotage microwave reaction vial were successively added CuI-USY (ca. 15 mg, 10 mol% of
copper species), toluene as solvent (0.5 mL), the aryl halide 9 (167 mg, 0.5 mmol, 1.0
equiv.), 4-allylphenol as O-nucleophile (101 mg, 0.75 mmol, 1.5 equiv.) and cesium
carbonate (326 mg, 1.0 mmol, 2.0 equiv.). The vial was sealed and after 4 days stirring at
90°C (unless otherwise stated), the reaction was complete as revealed by either TLC or
LCMS analysis. After cooling to room temperature, the solid materials were removed by
filtration over a Millipore membrane and further washed with diethyl ether (1 × 20 mL). The
resulting organic phase was washed with 1M aqueous NaOH solution (3 × 10 mL), water (3 ×
10 mL), brine (1 × 10 mL), dried over Na2SO4, filtered and evaporated. Purification of the
crude materials by column chromatography, eluting with cyclohexane/toluene (50:50 to
0:100), furnished 10 (87 mg, 51%) in pure forms as a pale yellow oil. – Rf = 0.15 (toluene). –
1
FTIR-ATR (neat) 3000, 2932, 2839, 1586, 1505, 1426, 1235, 1218, 1095, 968 cm-1. – H
4
NMR (300 MHz, CDCl3): δ = 7.13-7.08 (m, 2H), 6.92-6.87 (m, 2H), 6.54 (d, J = 1.8 Hz, 1H),
4
6.41 (d, J = 1.8 Hz, 1H), 6.03-5.83 (m, 2H), 5.10-5.02 (m, 6H), 3.86 (s, 3H), 3.51 (s, 3H),
3.36-3.34 (m, 2H), 3.28-3.26 (m, 2H). – 13C NMR (75 MHz, CDCl3): δ = 155.9, 153.7, 149.8,
137.5, 136.9, 136.4, 135.4, 134.2, 129.6, 117.5, 116.1, 115.6, 113.1, 107.9, 98.2, 57.0, 56.0,
40.0, 39.4. – LRMS (DCI, positive mode) m/z (rel intensity) 341 ([M+H]+, 50), 340 ([M]+, 45),
309 ([M–OCH3]+, 100).
3-Methylobovatol (11). In a 2-5 mL Biotage microwave reaction vial was dissolved the
diaryl ether 10 (35 mg, 103 µmol, 1.0 equiv.) in 3 mL of a 9:1 MeOH/H2O mixture. To the
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
solution was added freshly prepared H-USY (ca. 27 mg, 1.0 equiv. of acidic sites number).
The vial was sealed and after 24 h stirring at 100 °C, the reaction was complete as revealed
by either TLC or LCMS analysis. The solid materials were removed by filtration over PTFE
Millipore membrane, rinced with MeOH and the filtrate was concentrated. Filtration of the
crude over silica gel, eluting with MeOH, furnished the desired natural compound 11 as a
pale yellow oil (31 mg, quantitative yield). – Rf = 0.30 (90:10 cyclohexane/ EtOAc). – FTIR-
ATR (neat) 3512, 2976, 2902, 2841, 1600, 1505, 1453, 1433, 1313, 1222, 1087, 994, 914,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
833 cm-1. – H NMR (300 MHz, CDCl3): δ = 7.14-7.10 (m, 2H), 6.94-6.90 (m, 2H), 6.53 (d, 4J
= 1.8 Hz, 1H), 6.44 (d, 4J = 1.8 Hz, 1H), 6.03-5.84 (m, 2H), 5.41 (brs, 1H), 5.11-5.01 (m, 4H),
3.91 (s, 3H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H). – 13C NMR (75 MHz, CDCl3): δ = 155.7,
147.8, 143.0, 137.5, 137.2, 135.6, 134.4, 131.4, 129.6, 117.3, 115.8, 115.7, 112.9, 107.3,
56.2, 39.9, 39.4. – LRMS (DCI, positive mode) m/z (rel intensity) 314 ([M+NH4]+, 100), 297
([M+H]+, 65).
Recycling procedure. At the end of a run, the mixture was filtered and the recovered
solid materials (i.e., mixture of CuI-USY and salts) was successively washed with DMF, water
and acetone. After drying at 100°C under reduced pressure for 3 h, the so-obtained solid was
used as catalyst in the next run.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: …
1
Compilation of NMR spectra – H, 13C and DEPT – of most reported
compounds.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ppale@unistra.fr
*E-mail: chassaing@unistra.fr
ORCID
Patrick Pale: 0000-0002-3924-530X
Stefan Chassaing: 0000-0001-5842-5288
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Agence Nationale de la Recherche (ANR-13-BS07-0017-02
ChOZe) and the CNRS. TG thanks the Agence Nationale de la Recherche for a post-doc
fellowship.
ACS Paragon Plus Environment