Orthogonal Discrimination among Functional Groups in Ullmann-Type C-O and C-N Couplings

Article abstract of DOI:10.1021/acs.joc.6b01035

The copper-catalyzed arylation of nucleophiles has been established as an efficient methodology for the formation of C-C and C-heteroatom bonds. Considering the advances during the last two decades, the ligand choice plays a key role in such transformations and can strongly influence the catalytic efficiency. The applicability of these Ullmann-type coupling reactions regarding the orthogonal selectivity of different functional groups constitutes a challenging subject for current synthetic strategies. Herein, we report a useful toolkit of Cu-based catalysts for the chemoselective arylation of a wide-range of nucleophiles in competitive reactions using aryl iodides and bromides. We show in this work that the arylation of all kinds of amides can be orthogonal to that of amines (aliphatic or aromatic) and phenol derivatives. This high chemoselectivity can be governed by the use of different ligands, yielding the desired coupling products under mild conditions. The selectivity trends are maintained for electronically biased iodobenzene and bromobenzene electrophiles. Radical clock experiments discard the occurrence of radical-based mechanisms.

Full text of DOI:10.1021/acs.joc.6b01035

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pubs.acs.org/joc
Orthogonal Discrimination among Functional Groups in Ullmann-
Type C−O and C−N Couplings
Mireia Rovira,† Marta Soler,† Imma Guell,† Ming-Zheng Wang,† Laura Gomez,†,‡ and Xavi Ribas*,†
́
̈
†Institut de Química Computacional i Catal
E-17003 Girona, Catalonia, Spain
‡Serveis Tec
̀
nics de Recerca (STR), Universitat de Girona, Parc Científic i Tecnologic de la UdG, Pic de Peguera 15, E17003 Girona,
̀
isi (IQCC) and Departament de Química, Universitat de Girona, Campus de Montilivi,
̀
Catalonia, Spain
S
* Supporting Information
ABSTRACT: The copper-catalyzed arylation of nucleophiles
has been established as an efficient methodology for the
formation of C−C and C−heteroatom bonds. Considering the
advances during the last two decades, the ligand choice plays a
key role in such transformations and can strongly influence the
catalytic efficiency. The applicability of these Ullmann-type
coupling reactions regarding the orthogonal selectivity of
different functional groups constitutes a challenging subject for
current synthetic strategies. Herein, we report a useful toolkit
of Cu-based catalysts for the chemoselective arylation of a wide-range of nucleophiles in competitive reactions using aryl iodides
and bromides. We show in this work that the arylation of all kinds of amides can be orthogonal to that of amines (aliphatic or
aromatic) and phenol derivatives. This high chemoselectivity can be governed by the use of different ligands, yielding the desired
coupling products under mild conditions. The selectivity trends are maintained for electronically biased iodobenzene and
bromobenzene electrophiles. Radical clock experiments discard the occurrence of radical-based mechanisms.
temperature conditions.11−20 On the other hand, since the late
INTRODUCTION
■
1990s, much effort has been devoted to the use of chelating
ligands such as diamines, amino acids, phenanthroline
derivatives, and β-diketones to perform coupling reactions
under milder conditions while achieving enhanced yields.3,7,21
Moreover, the employment of auxiliary ligands not only
accelerates the reactions but also affords more reproducible
and safer reactions in terms of operating conditions and
residual toxicity.
Modern copper-catalyzed cross-coupling reactions have re-
cently evolved into reliable and efficient methods for the
formation of C−C and C−heteroatom bonds, which are
present in a large number of natural and pharmaceutical
products. Recent progress in modern catalytic Ullmann
coupling reactions has led to the emergence of numerous
methods to combine aryl halides (mainly iodides and
bromides) with aliphatic amines, amino alcohols, amides,
anilines, phenols, and other derivatives (Scheme 1).1−7
In thermal-based Ullmann couplings the detection of
intermediate species after the activation of the aryl halide,
which is usually rate-limiting, is very limited, and most
mechanistic proposals are derived from kinetic and computa-
tional studies.22−26 The most invoked mechanism for Ullmann
couplings is based on two-electron redox processes via a CuI/
CuIII catalytic cycle,6 although some computational reports
point toward one-electron redox processes through radical
intermediates (Scheme 2)22 and some MS studies suggest
competing mechanisms.27−30 On the other hand, Peters, Fu,
and co-workers recently reported a photoinduced, nonthermal
process involving a copper−carbazolide complex for promoting
the radical-based C−N bond forming reaction.31−36
Scheme 1. Copper-Catalyzed Ullmann-Type C−Heteroatom
Couplings
The first reports on Ullmann−Goldberg reactions originally
required relatively harsh conditions such as high temperatures
and sometimes the use of stoichiometric amounts of copper
salts.8−10 Interestingly, several “ligand-free” procedures have
also been reported as effective catalytic systems for Ullmann-
type reactions, taking advantage of the coordinating abilities of
solvents such as DMF, DMP, and TEOS, albeit under high
The ligand choice could play a determinant role in the
selectivity of the arylation reaction as well as in the operative
mechanism for such a transformation. Indeed, Buchwald and
Received: May 3, 2016
© XXXX American Chemical Society
A
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Scheme 2. Two Main Mechanistic Proposals for Ullmann-
Type Couplings
Figure 1. Bidentate and tridentate auxiliary ligands used in this work.
co-workers reported the first example of chemoselective
arylation of amino alcohols by using different auxiliary
ligands.37,38 While the β-diketone ligand promoted the
formation of N-arylated product in DMF at room temperature,
tetramethylphenanthroline ligand promoted selective O-
arylation in toluene at 90 °C (Scheme 3).
Scheme 4. Screening of Amides for N-Arylation with
Iodobenzene
Scheme 3. First Selective Ligand-Dependent Cu-Catalyzed
Arylation of a Bifunctional Nucleophile Reported by
Buchwald
triamine ligands (L1−L3). The use of L-proline (L7) was found
to be the most suitable ligand for the arylation of the primary
aliphatic amide 2g in excellent yield at 80 °C (Table S1, entry
7). Due to the low reactivity of secondary amides, the use of
1,10-phenanthroline (L4) as a ligand at 130 °C was necessary to
reach good performance in the arylation of aliphatic secondary
amides (3h and 3j; Table S1, entries 8 and 10). However, an
exception was found for pyrrolidin-2-one (2b), a cyclic
secondary amide, which afforded the N-arylated product 3b
in 80−91% using di- or triamine ligands (L1−L3) or 1,10-
phenantholine (L4) under mild conditions (Table S1, entry 2).
Next, we explored the arylation of alcohols under the same
reaction conditions (Scheme 5 and Table S2). As expected
Bearing in mind the importance of achieving selective
reactivity among functional groups in current synthetic
strategies, in this work we employed different well-known
and available ligands coordinating to CuI with the aim of
diverting the selective arylation of different nucleophiles at will.
As a result, herein we disclose a useful toolkit of Cu-based
catalytic systems for the highly chemoselective arylation of a
wide range of nucleophiles in competitive reactions using aryl
iodides and bromides.
Scheme 5. Mild O-Arylation of Alcohols with Iodobenzene
RESULTS AND DISCUSSION
■
We recently described a practical ligand-free protocol for the N-
and O-arylation of a wide range of amides, alcohols, and amines
under common optimized reaction conditions.20 Based on that
experimental protocol and employing the base/solvent
combination of K3PO4/DMSO with 10 mol % of CuI, in this
work we explored the arylation of N- and O-nucleophiles using
N,N-, N,O-, or O,O-bidentate or N,N,N-tridentate ligands
(L1−L10) with aryl halides under mild conditions (Figure 1).3,7
The K3PO4 base is substituted in selected cases by CsF or
K2CO3 to further improve the yield of the desired products. We
used this common experimental protocol for all kinds of
nucleophiles to visualize the impact of the ligand nature.
First, iodobenzene (1) was subjected to N-arylation with
different primary and secondary amides (2) (see Scheme 4 and
Table S1). Aromatic primary amides (2a and 2f; Table S1,
entries 1 and 6) rendered good-to-excellent yields using di- or
from previous studies, the O-arylation of phenols using
dimethylglycine (L6) as a Cu-chelating ligand gave excellent
coupling yields (82−97% 5a, 5b, 5c, 5d; Table S2, entries 1−
4).39,40 Phenols with electron-withdrawing groups and aliphatic
alcohols gave poor yields irrespective of the auxiliary ligand
used.
After screening the O-arylation of different alcohols, we were
also interested in exploring the reactivity of amines as
nucleophiles (Scheme 6 and Table S3). In line with the
literature, the N,O-bidentate ligands such as proline (L7) or
pyrrole-2-carboxylic acid (L8) were found to be the most
suitable chelating moieties when the arylation of amines is
targeted.7,40−42,7,39−41 In addition, the employment of CsF as a
B
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aromatic amides when L1 or L4 are used (Scheme 7, I, M, and
Scheme 8, A). Moreover, the arylation of phenols is especially
favored in competition with amines and amides when L6 is used
(Scheme 7, A, J−M and Scheme S1). Finally, anilines are
arylated selectively before phenols and amides (Scheme 7, B, F,
G, J) when L8 is used. The product ratios are in general higher
than 7 and in many cases above 20, showing an orthogonal
selectivity in most of the competitions explored. The
nonarylated nucleophile remained unconverted and could be
recovered at the end of the reaction. Due to the low reactivity
of aliphatic alcohols, no competition studies have been
undertaken since those nucleophiles are clearly more
challenging than the studied above (entries 6 and 7, Table S2).
Some nucleophiles present a strong preference toward
arylation irrespective of the competing nucleophile or the
auxiliary ligand used. Specifically, only minor changes in the
selectivity could be achieved when the same family of
nucleophiles is used, for example, the competitive reaction
between two types of amides, benzamide (2a) and the cyclic
amide pyrrolidin-2-one (2b) (Scheme 8, A). In this reaction, we
were only able to set out conditions to render the N-arylation
of 2b in excellent yield and conversion using L4 at 50 °C (76%
3b; 3b/3a ratio = 8). Despite performing the reaction with
other type of ligands such as L8, a very low yield of 3a was
obtained. Similarly, a competitive reaction of two types of
amines (6c and 6d) afforded the N-arylated cyclohexylamine
7d as the major product in all cases tested (Scheme 8, B). Best
results were observed by submitting proline ligand L7 as a
ligand (78% 7d; 7d/7c ratio = 44). Along the same line, when
the competition is performed between N-methylacetamide
(2h) and p-methoxyphenol (4c) (Scheme 8, C, and Scheme
S1), the O-arylated 5c was successfully formed employing the
glycine derivative L6 and K2CO3 in high yield and conversion at
50 °C (98% 5c; 5c/3h ratio >100). Additionally, the O,O-
bidentate ligand L10 also led to the selective formation of 5c
under the same conditions. However, we were unable to find
the appropriate conditions to tilt the balance in favor of the
arylation of the secondary amide 2h. Despite using the most
suitable ligand for the formation of 3h (L4), we found a very
high selectivity for the O-arylated coupling product in all cases
tested. The use of L1 with K3PO4 or CsF or L8 with K2CO3 at
50 °C significantly reduced the yield of the O-arylated product
(37% and 57% yield, respectively); however, the reaction
likewise proceeded in low yields for the formation N-
arylacetamide 3h. We rationalize that the facile arylation of
phenol and the high temperatures that are required for
achieving reactivity toward secondary amides prevent us from
establishing suitable conditions for such competition reactions.
Ligand-Dependent Selectivities in Competition Re-
actions Using Para-Substituted Iodobenzenes. Addition-
ally, in order to broaden the aryl iodide scope, we checked the
effect of electron-donating and electron-withdrawing substitu-
ents at the para position. Thus, p-iodotoluene and p-
nitroiodobenzene were selected as aryl halides in competition
reactions analogous to Scheme 7, C (Scheme S2 and S3 in the
SI). Regarding p-iodotoluene (Scheme S2), the arylation of
benzamide 2a was significantly suppressed using pincer ligand
L3. On the contrary, the arylation of the same nucleophile using
pyrrole derivative L8 was successfully improved up to 92% yield
of 3n as a single arylated product in complete conversion (3n/
7o ratio = 92). On the other hand, the formation of the
coupling product 7o was also a bit suppressed when proline L7
was used; however, it was effectively formed as a unique
Scheme 6. Mild N-Arylation of Amines with Iodobenzene
base instead of K3PO4 rendered better results for these coupling
reactions. In particular, the use of L8 for the N-arylation of
aromatic amines afforded moderate to good yields (62−76%,
7a and 7c; Table S3, entries 1 and 3), while the N-arylated p-
nitro-substituted aniline (7b) was obtained only in 22% yield
(Table S3, entry 2). On the contrary, the N-arylation of
primary aliphatic amines (6d and 6e) was very effective using
ligand L7, and excellent yields and conversions were observed
(89−95%; Table S3, entries 4 and 5). Regarding secondary
aliphatic amines, cyclic piperidine (6g) afforded the desired
product 7g in excellent yield (86% yield, Table S3, entry 7),
while under the same reaction conditions, a very poor yield of
the arylated product 7f was observed (Table S3, entry 6). In
contrast, conjugated N-heterocyclic secondary amine 6h
rendered the N-arylated product 7h in excellent yield using
L1 (96%; Table S3, entry 8). In particular, this latter product
was also formed in excellent yields and conversions employing
other ligands such as L2, L3, L4, or L6 or even working at rt with
L1.
Eventually, we also examined the arylation of different N-
and O-nucleophiles employing the aryl bromide as a substrate
(Table S4). Excellent yields (88−100%) were obtained for
aromatic alcohols (5a and 5c; Table S4, entries 6 and 7), and
moderate-to-good yields (50−80%) were found for aromatic
and aliphatic amines (7a, 7c and 7d; Table S4, entries 8−10).
Nevertheless, very poor reactivity was observed for the arylation
of amides and only the use of pyrrole derivative L8 afforded the
arylation of the cyclic amide pyrrolidin-2-one (2b) in 26% yield
(Table S4, entries 1−5).
Ligand-Dependent Selectivities in Competition Re-
actions Using Iodobenzene. Considering the trends
observed from the different ligands previously tested, we
focused our attention on the study of the selective arylation of a
wide-range of nucleophiles in competition reactions under mild
conditions (50 °C). Thus, we performed competitive experi-
ments combining amides, amines, and phenols under standard
conditions (1 equiv of iodobenzene, 2 equiv of each
nucleophile), aiming to find out the most suitable ligand for
the arylation of each nucleophile in high selectivity and yield
(Scheme 7).
In general trends, we have found that the arylation of
aromatic amides is favored over that of phenols and amines
when tridentated N-based auxiliary ligands and mild temper-
atures are used, with L1 and L3 being the best ones (Scheme 7,
A−D). Owing to its well-known poor reactivity, the arylation of
noncyclic aliphatic amides requires higher temperatures and is
favored in front of the arylation of amines when L4 is used
(Scheme 7, E−H). Moreover, noncyclic primary aliphatic
amides can be slightly favored in front of the arylation of
phenols with L4 (Scheme 7, L), but noncyclic secondary
aliphatic amides cannot compete with phenols (Scheme 8, C).
On the other hand, the arylation of cyclic aliphatic amides is
sharply chemoselective in front of aliphatic amines, phenols and
C
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a
Scheme 7. Competition Reactions among Nucleophiles Using Iodobenzene with a Sharp Switch of Chemoselectivity
a
Conversions are given in parentheses; standard experimental conditions used.
D
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Scheme 8. Competition Reactions among Nucleophiles with
Strong Arylation Preference for One Nucleophile
Irrespective of the Auxiliary Ligand Used
Scheme 9. Competition Reactions Using Bifunctional
a
Nucleophiles 8a−8c
a
a
Conversions are given in parentheses; standard experimental
conditions used.
ratio >100). On the contrary, this trend successfully switched to
the formation of the N-arylated product 9b in the presence of
L3, even though the yield was modest (29% 9b; 9b/10b ratio =
6). In the arylation reaction of 4-amino-N-phenylbenzamide
(8c) with iodobenzene (Scheme 9, C), only the N-arylation of
the amino group was observed as the major product,
irrespective of the auxiliary ligand used. Compound 10c was
obtained as a single product in moderate yield and high
selectivity when the pyrrole derivative ligand L8 using CsF as a
base (40% 10c; 10c/9c ratio >100) was used. Presumably, the
arylation of the secondary amide was hampered by steric
effects, and even when high temperatures (130 °C) together
with L1 or L4 as ligands were used, the formation of 10c was
unavoidable in both cases tested.
Ligand-Dependent Selectivities in Competition Re-
actions Using Bromobenzene. With these good results in
hand, we decided to conduct most of the competition reactions
described above using bromobenzene. Because of the low
reactivity of bromobenzene, reactions were undertaken at 110
or 130 °C. Among them and as shown in Scheme 10,
competitions B′, H′, and I′ were those in which excellent
selectivities and yields were observed. First, when the
competitive reaction was run between benzamide (2a) and
anisidine (6c) (Scheme 10, competition B′, equivalent to
Scheme 7, B), we were very pleased to observe the single
formation of N-arylamide 3a in good yield using phenanthro-
line ligand L4 at 130 °C (52% 3a; 3a/7c ratio >100).
Remarkably, the selectivity was effectively turned to the unique
arylation of 6c in excellent yield when the pyrrole derivative L8
(73% 7c; 7c/3a ratio >100) was employed. On the other hand,
when the competitive reaction was run between N-methyl-
acetamide (2h) and cyclohexylamine (6d) (Scheme 10,
competition H′, equivalent to Scheme 7, H), the presence of
DMEDA (L1) at 110 °C yielded 3h almost exclusively in
remarkable yield and selectivity (68%, 3h/7d ratio = 23).
Surprisingly, all of the attempts using phenanthroline-type
ligands (L4 and L5) aiming to promote the same coupling
product failed. However, using proline as chelating ligand (L7)
a
Conversions are given in parentheses; standard experimental
conditions used.
product (55% 7o, 7o/3n ratio >100). When p-nitroiodoben-
zene was used as a substrate (Scheme S3), we observed a
reactivity similar to that of the iodobenzene. It is noteworthy
that pincer-type ligand L3 improved the formation of 3l, which
was obtained almost as a single product in good yield (64% 3l,
3l/7m ratio = 32). Additionally, the employment of proline L7
also gave rise to the coupling product 7m as single product
(66% 7m, 7m/3l ratio = 66). Therefore, both electron-rich and
electron-deficient aryl iodides underwent arylation with
excellent selectivities.
Ligand-Dependent Selectivities in Competition Re-
actions Using Bifunctional Nucleophiles and Iodoben-
zene. To further probe the orthogonality of our Cu-based
catalytic systems, we next evaluated the selective arylation of
different bifunctional nucleophiles (8a, 8b, and 8c) (Scheme
9). First, the aminophenol 8a could be selectively O-arylated
with dimethylglycine L6 (Scheme 9, A) to give the coupling
product 9a in excellent yield and with high chemoselectivity
(88% 9a; 9a/10a ratio = 7). On the other hand, the N-arylation
of 8a was highly favored when L7 was used as a ligand and CsF
as a base (10a, 51%). Very notably, running the same reaction
with N,O-bidentate ligand L9 (20 mol %) in combination with
K2CO3 improved the formation of 10a as a unique product up
to 68% yield (10a/9a ratio >100). We also succeeded in the
competition reaction between the bifunctional nucleophile 8b
(bearing aromatic amide and phenol functional groups) and
iodobenzene (Scheme 9, B). Not surprisingly, the presence of
the dimethylglycine L6 at 70 °C led to the O-arylation of 8b,
yielding 10b as a sole coupling product (75% 10b; 10b/9b
E
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a
Scheme 10. Competition Reactions among Nucleophiles Using Bromobenzene with a Sharp Switch of Chemoselectivity
a
Conversions are given in parentheses.
at 110 °C successfully led to the almost exclusive formation of
7d in 70% yield (7d/3h ratio = 70). In line with these results,
we observed similar reactivity when facing the cyclic amide
pyrrolidin-2-one (2b) and cyclohexylamine (6d) (Scheme 10,
competition I′, equivalent to Scheme 7, I). While L7 provided
the arylation of the aliphatic amine to yield 7d in good yields
(67% 7d; 7d/3b ratio = 17), the pyrrole derivative L8 using
K2CO3 as a base favored the arylation of the cyclic amide in
good yield and moderate selectivity (76% 3b, 3b/7d ratio = 5).
We noticed an important base effect in the latter case, since the
use of CsF as a base instead of K2CO3 prevented the
chemoselectivity between both nucleophiles. Furthermore,
competitive reactions A′, C′, D′, G′, and J′ and bifunctional
8a employing bromobenzene also led to the selective arylation
one of the nucleophiles, although most of them were in lower
yields and moderate to good selectivities (Scheme S4, SI).
Some unexpected effects were found, such as the fact that all
reactions combining bromobenzene and aromatic amides 2a
and 2f with L1 ligand completely failed in any competition
tested (Scheme 10, competition B′, and Scheme S4,
competitions A′, C′, and D′). Moreover, 1,10-phenathroline
(L4) showed a chemoselective behavior with bromobenzene
different from that with iodobenzene when facing primary
amides and aliphatic or aromatic amines with other
nucleophiles (competitions B/B′ and H/H′, Schemes 7 and
10).
conditions in the presence of another nucleophile, provided
careful selection of the auxiliary ligand and experimental
conditions is made. Therefore, Table 1 is a practical recipe for
mild and chemoselective C−O and C−N Ullmann-type
couplings. Note that this high selectivity has also been
successfully translated into bifunctional substrates (Scheme
10). However, the limitations of the methodology in terms of
selectivity are shown in Table 2. The nonpreferred nucleophile
in these competitions is arylated as a mixture with the arylation
of the preferred nucleophile, so the corresponding reaction
conditions are not included in Table 2.
Finally, to gain insight into the mechanism of the cross-
coupling reactions with different auxiliary ligands, we have
selected the most successful combinations of nucleophiles and
ligands and used the radical clock 1-allyloxy-2-iodobenzene (rc)
as substrate in the coupling reactions (Scheme 11). In all
reactions, a significant amount of rc-H was observed, suggesting
a protodecupration side reaction as previously observed by
Cohen,43 Hartwig,25 and in the reactivity of well-defined model
aryl-CuIII complexes.44 No traces were found of the cyclized
coupling product, thus pointing toward a prototypical CuI/CuIII
mechanism for thermal-based Ullmann couplings and discard-
ing a radical pathway. Given the fact that protodecupration
product rc-H was found in important amounts when rc was
used as a substrate, we wondered if this mechanism has also
some contribution when iodobenzene is used. If so, benzene
should be found as the product of a putative protodecupration.
As suspected, low but significant amounts of benzene (from 4
to 8%) were found in several coupling reactions of anilines 6a,
6b, 6c, and methylacetamide 2h, indicating that the
protodecupration pathway is generally spread as a side reaction
in Ullmann couplings (see Scheme S6).
Ligand-Dependent Selectivities in Competition Re-
actions Using Chlorobenzene. Several reactions were also
attempted using chlorobenzene as arylating agent and several
nucleophiles and auxiliary ligands; however, the reactivity was
almost suppressed for all nucleophiles tested at 130 °C
(Scheme S5, SI).
Practical Orthogonal Nucleophile Discrimination
Summary. Table 1 summarizes the most important results
of all tested competition reactions, and the best conditions
found to achieve the arylation of a given nucleophile in the
presence of another are highlighted. In general, highly selective
arylation of any nucleophile can be performed under mild
CONCLUSION
■
In light of the tremendous interest in finding a practical Cu-
catalyzed methodology that allows orthogonal discrimination
among N- or O-based functional groups, we have demonstrated
that this is now possible with multiple combinations of
F
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Table 1. Optimized Conditions for Ligand-Dependent Arylation of Nucleophiles (A or B) with Iodobenzene in Competition
a
Reactions with Orthogonal Selectivity
a
Standard reaction conditions: iodobenzene (0.88 mmol, 0.9 M), A and B (1.79 mmol), 24 h, DMSO under an inert atmosphere (yields given in
parentheses).
nucleophiles using a common experimental methodology and a
preferred auxiliary ligand for each nucleophile. The exact role of
each auxiliary ligand in switching the selectivity requires already
ongoing in-depth computational studies. So far, the precise,
simple methodologies to be used for the arylation of any of the
nucleophiles tested should be a precious practical guide in
organic synthesis laboratories. Indeed, by means of using a
radical clock substrate (rc), no signs of radical-mediated
mechanism were found in any of the coupling reactions tested
in this work, reinforcing the occurrence of a nonradical
mechanism in the thermal-based copper-catalyzed cross-
coupling reactions.
EXPERIMENTAL SECTION
■
General Methods. The reagents and solvents used were
commercially available unless indicated otherwise. Solvents were
purchased and were purified and dried by passing them through an
activated alumina purification system. The preparation and handling of
air-sensitive materials were performed in a N2 drybox with O2 and
H2O concentrations of <1 ppm. 4′-Hydroxy(1,1′-biphenyl)-3-carbox-
amide (8b) was synthesized following the published procedures.45
General Procedure for Catalytic Experiments. A vial was
loaded with the base (1.8 mmol), the solid nucleophile (1.8 mmol),
and the corresponding auxiliary ligand (10 mol %). Then, in an inert-
atmosphere glovebox, copper(I) (10 mol %) in DMSO and the aryl
iodide (0.9 mmol) were added. Liquid nucleophiles were added after
G
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1,3,5-trimethoxybenzene (200 μL, 1.5 M in DMSO) as internal
standard was added. Subsequently, the reaction was quenched by the
addition of AcOEt (5 mL). The workup consisted of the filtration of
400 μL of the crude product through silica gel using AcOEt as eluent.
All samples were analyzed by gas chromatography. The GC yields
were obtained through calibration curves obtained with authentic
sample of all products with 1,3,5-trimethoxybenzene as an internal
standard.
Table 2. Optimized Conditions for Ligand-Dependent
Arylation of Nucleophiles with Iodobenzene in Competitive
Reactions with High Selectivity for One of the Competing
a
Nucleophiles (Column A)
Benzanilide (3a).46,47 1H NMR (300 MHz, DMSO-d6, 25 °C) δ
(ppm): 7.17−7.23 (m, 1H), 7.43−7.48 (m, 2H), 7.60−7.72 (m, 3H),
7.86−7.89 (m, 2H), 8.03−8.07 (m, 2H), 10.34 (s, 1H, NH). 13C{1H}
NMR (75 MHz, DMSO-d6, 25 °C) δ (ppm): 120.3, 123.7, 127.6,
128.4, 128.6, 131.6, 134.9, 139.2, 165.5. HRMS (ESI-TOF (m/z)):
calcd for C13H11NONa 220.0733, found 220.0725, calcd for
(C13H11NO)2Na 417.1573, found 417.1571.
1-Phenyl-2-pyrrolidone (3b).46,47 1H NMR (300 MHz, CDCl3, 25
°C) δ (ppm): 2.14−2.22 (m, 2H), 2.59−2.65 (m, 2H), 3.87 (t, 2H,
2JHH = 6.9 Hz), 7.59−7.63 (m, 2H), 7.34−7.40 (m, 2H), 7.12−7.17
(m, 1H). 13C{1H} NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 18.0,
32.7, 48.8, 119.9, 124.5, 128.8, 139.4, 174.2. HRMS (ESI-TOF (m/z)):
calcd for C10H11NONa 184.0733, found 184.0720, calcd
(C10H11NO)2Na 345.1573, found 345.1559.
N-phenoxindole (3c).48 1H NMR (300 MHz, DMSO-d6, 25 °C) δ
2
(ppm): 3.86 (s, 2H), 6.79−6.81 (m, 1H), 7.16 (td, 1H, JHH = 7.43
Hz, 4JHH = 1 Hz), 7.31 (td, 1H, 2JHH = 7.8 Hz, 4JHH = 1.5 Hz), 7.44−
7.46 (m, 1H), 7.50−7.58 (m, 3H), 7.64−7.70 (m, 2H). 13C{1H} NMR
(75 MHz, DMSO-d6, 25 °C) δ (ppm): 35.9, 108.6, 122.4, 124.7, 124.8,
126.8, 127.5, 127.9, 129.6, 134.5, 144.8, 173.9. HRMS (ESI-TOF (m/
z)): calcd for C14H11NONa 232.0733, found 232.0726, calcd for
(C14H11NO)2Na 441.1573, found 441.1577.
Salicylanilide (3d).47 1H NMR (400 MHz, DMSO-d6, 25 °C) δ
(ppm): 7.04−7.09 (m, 2H), 7.22−7.26 (m, 1H), 7.45−7.50 (m, 2H)
7.52−7.56 (m, 1H), 7.79−7.82 (m, 2H), 8.06 (dd, 1H, 2JHH = 7.8 Hz,
4JHH = 1.4 Hz), 10.50 (s, 1H, NH), 11.90 (br s, 1H, OH). 13C{1H}
NMR (100 MHz, DMSO-d6, 25 °C) δ (ppm): 117.2, 117.5, 119.0,
120.9, 124.2, 128.7, 129.0, 133.6, 138.1, 158.5, 166.6. HRMS (ESI-
TOF (m/z)): calcd for C13H11NO2Na 236.0682, found 236.0679,
calcd for (C13H11NO2)2Na 419.1472, found 419.1471.
a
Standard reaction conditions: iodobenzene (0.88 mmol, 0.9 M), A
and B (1.79 mmol), 24 h, DMSO under an inert atmosphere (yields
are given in parentheses).
Scheme 11. Selected Coupling Reactions Using Radical
Clock rc as Substrate
N-phenyl-4-hydroxybenzamide (3e).47 1H NMR (300 MHz,
DMSO-d6, 25 °C) δ (ppm): 6.93−6.98 (m, 2H), 7.13−7.19 (m,
1H), 7.40−7.46 (m, 2H), 7.82.7.86 (m, 2H), 7.92−7.97 (m, 2H),
10.07 (s, 1H, NH). 13C{1H} NMR (75 MHz, DMSO-d6, 25 °C) δ
(ppm): 115.3, 120.6, 123.6, 125.7, 128.9, 130.1, 139.9, 160.9, 165.5.
HRMS (ESI-TOF (m/z)): calcd for C13H11NO2Na 236.0682, found
236.0679, calcd for (C13H11NO2)2Na 449.1472, found 449.1479.
Nicotinanilide (3f).47 1H NMR (300 MHz, DMSO-d6, 25 °C) δ
(ppm): 7.20−7.26 (m, 1H), 7.44−7.50 (m, 2H), 7.67 (ddd, 1H, 2JHH
7.8 Hz, 3JHH = 4.8 Hz, 4JHH = 0.9 Hz), 7.85−7.89 (m, 2H), 8.39 (ddd,
=
2
3
4
1H, JHH = 8.03 Hz, JHH = 2.33 Hz, JHH = 1.73 Hz), 8.86 (dd, 1H,
3JHH = 4.8 Hz, JHH = 1.8 Hz), 9.20 (dd, 1H, JHH = 2.25 Hz, JHH
=
4
3
4
0.75 Hz), 10.54 (s, 1H, NH). 13C{1H} NMR (75 MHz, DMSO-d6, 25
°C) δ (ppm): 120.4, 123.5, 124.0, 128.7, 130.6, 135.5, 138.8, 148.7,
152.1, 164.1. HRMS (ESI-TOF (m/z)): calcd for C12H10N2ONa
221.0685, found 221.0674, calcd for (C12H10N2O)2Na 419.1478,
found 419.1464.
Acetanilide (3g).46,47 1H NMR (300 MHz, DMSO-d6, 25 °C) δ
(ppm): 2.13 (s, 3H), 7.08−7.14 (m, 1H), 7.34−7.41 (m, 2H), 7.65−
7.68 (m, 2H), 10.01 (s, 1H, NH). 13C{1H} NMR (75 MHz, DMSO-
d6, 25 °C) δ (ppm): 29.0, 118.9, 123.0, 128.7, 139.3, 168.3. HRMS
(ESI-TOF (m/z)): calcd for C8H9NONa 158.0576, found 158.0566.
N-Methylacetanilide (3h).49 1H NMR (300 MHz, CDCl3, 25 °C) δ
(ppm): 1.87 (s, 3H), 3.27 (s, 3H), 7.18−7−21 (m, 2H), 7.31−7.36
(m, 1H), 7.39−7.45 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, 25
°C) δ (ppm): 22.4, 37.2, 127.1, 127.7, 129.7, 144.6, 170.6. HRMS
(ESI-TOF (m/z)): calcd for C9H11NONa 172.0733, found 172.0722,
calcd for (C9H11NO)2Na 321.1573, found 321.1572.
N,N-Diphenylbenzamide (3i).50 1H NMR (300 MHz, CDCl3, 25
°C) δ (ppm): 7.14−7.32 (m, 13H), 7.44−7.47 (m, 2H). 13C{1H}
NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 126.6, 127.7, 128.1, 129.4,
129.4, 130.4, 136.3, 144.3. HRMS (ESI-TOF (m/z)): calcd for
the aryl iodide. The vial was sealed, and the reaction mixture was kept
under an inert atmosphere and placed in a preheated oil bath at the
required temperature. After the reaction mixture was stirred for 24 h,
H
DOI: 10.1021/acs.joc.6b01035
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
C19H16NO 274.1226, found 274.1234, calcd for C19H15NONa
296.1046, found 296.1064, calcd for (C19H15NO)2Na 569.2199;
found 569.2221.
7.24 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm):
11.7, 22.8, 45.9, 112.7, 117.1, 129.2, 148.6. HRMS (ESI-TOF (m/z)):
calcd for C9H14N 136.1121, found 136.1126.
N,N-Ethylphenylacetamide (3j).51 1H NMR (300 MHz, CDCl3, 25
°C) δ (ppm): 1.10 (t, 3H, 2JHH = 7.2 MHz), 1,82 (s, 3H), 3.75 (q, 3H,
2JHH = 7.2 MHz), 7.13−7.17 (m, 2H), 7.31−7.45 (m, 3H). 13C{1H}
NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 13.3, 23.1, 44.1, 128.1,
128.5, 129.9, 143.2, 170.2. HRMS (ESI-TOF (m/z)): calcd for
C10H14NO 164.1070, found 164.1067, calcd for C10H13NONa
186.0889, found 186.0889, calcd for (C10H13NO)2Na 349.1886,
found 349.1869.
N,N-Diethylaniline (7f).60 This compound was obtained in a low
yield. It was detected by GCMS: tR 6.834. MS (C10H15N): 149.1.
1-Phenylpiperidine (7g).58 1H NMR (300 MHz, CDCl3, 25 °C) δ
(ppm): 1.55−1.62 (m, 2H), 1.68−1.75 (m, 4H), 3.14−3.17 (m, 4 H),
6.79−6.85 (m, 1H), 6.92−6.97 (m, 2H), 7.21−7.28 (m, 2H). 13C{1H}
NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 24.3, 25.9, 50.7, 116.5,
119.2, 129.0, 152.3. HRMS (ESI-TOF (m/z)): calcd for C11H16N
162.1277, found 162.1265.
Diphenyl Ether (5a).52 1H NMR (300 MHz, CDCl3, 25 °C) δ
(ppm): 7.03−7.07 (m, 4H), 7.10−7.16 (m, 2H), 7.33−7.40 (m, 4H).
13C{1H} NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 119.2, 123.5, 130.1,
157.6. GCMS: tR 9.220. MS (C12H10O): 170.0.
1-Phenyl-1H-imidazole (7h).61 1H NMR (400 MHz, CDCl3, 25
°C) δ (ppm): 7.21 (s, 1H), 7.29 (s, 1H), 7.35−7.41 (m, 3H), 7.47−
7.52 (m, 2H), 7.86 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C)
δ (ppm): 118.1, 121.2, 127.3, 129.6, 130.1, 135.3, 137.1. HRMS (ESI-
TOF (m/z)): calcd for C9H9N2 145.0760, found 145.0771, calcd for
C9H8N2Na 167.0580, found 167.0580, calcd for (C9H8N2)2Na
311.1267, found 311.1262.
1-Methyl-4-phenoxybenzene (5b).52 1H NMR (400 MHz, CDCl3,
25 °C) δ (ppm): 2.40 (s, 3H), 6.97−6.99 (m, 2H), 7.04−7.08 (m,
2H), 7.10−7.15 (m, 1H), 7.18−7.21 (m, 2H), 7.35−7−39 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 20.9, 118.5, 119.3,
122.9, 129.8, 130.5, 133.1, 154.9, 158.0. GCMS: tR 10.584. MS
(C12H12O): 184.0.
7-Phenoxy-1,2,3,4-tetrahydronaphthalen-2-amine (9a). 1H
NMR (400 MHz, CDCl3, 25 °C) δ (ppm): 1.56 (s, 2H, NH),
1.60−1.66 (m, 1H, Hi or Hj), 1.97−2.04 (m, 1H, Hi or Hj), 2.53 (dd,
2JHH = 16.22 Hz, 3JHH= 9.41 Hz, 1H, Hf or Hg), 2.80−2.85 (m, 2H, Hk
1-Methoxy-4-phenoxybenzene (5c):53 1H NMR (400 MHz,
CDCl3, 25 °C) δ (ppm): 3.81 (s, 3H), 6.87−6.91 (m, 2H), 6.93−
7.01 (m, 4H), 7.05 (t, 1H, J = 7.4 Hz), 7.28−7.33 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 55.9, 115.1, 117.8, 121.0,
122.6, 129.8, 150.3, 156.1, 158.7. GCMS: tR 12.359. MS (C13H12O2):
200.1.
2
3
and Hl), 2.94 (dd, JHH = 16.41 Hz, JHH = 5.14 Hz, 1H, Hf or Hg),
3.15−3.24 (m, 1H, Hh), 6.73 (d, JHH = 2.54 Hz, 1H, Hd), 6.78 (dd,
4
3JHH = 8.29 Hz, JHH = 2.63 Hz, 1H, He), 6.99 (dt, JHH = 7.64, 1.12
4
4
Hz, 2H, Ha), 7.05 (dt, JHH = 7.69 Hz, JHH = 1.12 Hz, 2H, Hc and
3
4
Hd), 7.31 (dd, JHH = 7.52 Hz, JHH = 1.28 Hz, 2H, Hb). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 27.4 (C8), 29.7 (C11), 31.0
(C10), 52.9 (C9), 117.1 (C13), 118.4 (C1), 119.4 (C6), 122.9 (C3),
129.6 (C2), 19.8 (C14), 131.0 (C12), 136.0 (C7), 155.1 (C5) and 157.8
(C4). HRMS (ESI-TOF (m/z)): calcd for C16H18NO 240.1383, found
240.1395, calcd for (C16H17NO)2H 479.2693, found 479.2708.
7-(Phenylamino)-5,6,7,8-tetrahydronaphthalen-2-ol (10a). 1H
NMR (400 MHz, CDCl3, 25 °C) δ (ppm): 1.77 (m, 1H, He or Hf),
3
4
1,3-Dimethyl-5-phenoxybenzene (5d).54 1H NMR (300 MHz,
CDCl3, 25 °C) δ (ppm): 2.29 (s, 6H), 6.64−6.65 (m, 2H), 6.76 (sept,
1H, 4JHH = 0.7 MHz), 6.99−7.03 (m, 2H), 7.07−7.12 (m, 1H), 7.30−
7.37 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, 25 °C) δ (ppm):
21.6, 116.8, 119.1, 123.2, 124.2, 129.9, 139.8, 157.4, 157.7. GCMS: tR
11.596. MS (C12H12O): 198.1.
1-(4-Nitrophenoxy)benzene (5e).53 1H NMR (300 MHz, CDCl3,
25 °C) δ (ppm): 7.00−7.06 (m, 2H), 7.09−7.14 (m, 2H), 7.22−7.32
(m, 1H), 7.43−7.51 (m, 2H), 8.20−8.25 (m, 2H). 13C{1H} NMR (75
MHz, CDCl3, 25 °C) δ (ppm): 117.3, 120.8, 125.7, 126.2, 130.6,
154.9, 163.6. GCMS: tR 14.180. MS (C12H12O): 215.0.
2.16 (m, 1H, He or Hf), 2.64 (ddd, JHH = 16.58 Hz, JHH = 8.34 Hz,
2
3
1H, Hh or Hi), 2.83 (m, 2H, Hd), 3.15 (ddd, JHH = 16.54 Hz, JHH
=
2
3
4.86 Hz, 1H, Hi or Hh), 3.75 (m, 1H, Hg), 4.58 (m, 1H, NH), 6.55 (d,
4JHH = 2.62 Hz, 1H, Ha), 6.64 (dd, 3JHH = 8.66 Hz, 4JHH = 1.06 Hz, 3H,
Hb and Hj), 6.70 (tt, 3JHH = 7.93 Hz, 4JHH = 1.07 Hz, 1H, Hl), 6.98 (d,
3JHH = 8.41 Hz, 1H, Hc), 7.18 (dd, 3JHH = 7.39 Hz, 4JHH = 1.2 Hz, 2H,
Hk). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 26.6 (C6),
29.3 (C7), 36.6 (C9), 48.5 (C8), 113.5 (C3 and C12), 115.6 (C1), 117.8
(C14), 128.4 (C5 or C10), 129.3 (C13), 129.9 (C4), 136.0 (C5 or C10),
147.1 (C11) and 153.6 (C2). HRMS (ESI-TOF (m/z)): calcd for
C16H18NO 240.1383, found 240.1378, calcd for (C16H17NO)2Na
501.2515, found 501.2507.
Ethoxybenzene (5f).55 1H NMR (400 MHz, CDCl3, 25 °C) δ
(ppm): 1.4 (t, 3H), 4.02 (q, 2H), 6.87−6.93 (m, 3H), 7.30−7.34 (m,
2H). GCMS: tR 3.76. MS (C8H10O): 122.0.
N,N-Diphenylamine (7a).41,56 1H NMR (400 MHz, CDCl3, 25 °C)
δ (ppm): 5.71 (s, 1H, NH), 6.96 (tt, 2H), 7.08−7.12 (m, 4H), 7.27−
7.32 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm):
117.9, 121.0, 129.4, 143.2. HRMS (ESI-TOF (m/z)): calcd for
C12H12N 170.0964, found 170.0948.
p-Nitro-N-phenylaniline (7b).57 1H NMR (300 MHz, CDCl3, 25
°C) δ (ppm): 6.33 (s, 1H, NH), 6.92−6.97 (m, 2H), 7.14−7.26 (m,
3H), 7.35−7.42 (m, 2H), 8.09−8.11 (m, 2H). 13C{1H} NMR (75
MHz, DMSO-d6, 25 °C) δ (ppm): 113.9, 122.2, 124.9, 126.5, 130.0,
139.7, 140.0, 150.4. HRMS (ESI-TOF (m/z)): calcd for C12H11N2O2
215.0815, found 215.0813.
4′-Hydroxy-N-phenyl(1,1′-biphenyl)-3-carboxamide (9b). 1H
3
NMR (400 MHz, DMSO-d6, 25 °C) δ (ppm): 6.90 (d, JHH = 8.61
Hz, 2H, Hi), 7.12 (t, 3JHH = 7.40 Hz, 4JHH = 1.12 Hz, 1H, Ha), 7.37 (t,
3
3JHH = 7.40 Hz, 2H, Hb), 7.57 (t, JHH = 7.68 Hz, 1H, Hf), 7.61 (dd,
3JHH = 8.70 Hz, 2H, Hh), 7.79 (d, 3JHH = 8.61 Hz, 4JHH = 1.17 Hz, 3H,
Hc and Hg), 7.85 (dt, 3JHH = 7.68 Hz, 4JHH = 1.49 Hz, 1H, He), 8.14 (t,
J = 3.32, 4JHH = 1.67 Hz, 1H, Hd), 9.66 (s, 1H, OH) and 10.31 (s, 1H,
NH). 13C{1H} NMR (100 MHz, DMSO-d6, 25 °C) δ (ppm): 116.3
(C14), 120.9 (C3), 124.2 (C1), 125.5 (C7), 126.2 (C8), 128.5 (C13),
129.1 (C2), 129.4 (C9 and C10), 130.7 (C12), 136 (C6), 139.6 (C4),
140.8 (C11), 157.9 (C15) and 166.1 (C5). HRMS (ESI-TOF (m/z)):
Positive mode (+): calcd for C19H15NO2Na 312.0995, found
312.0994; Negative mode (−): calcd for C19H14NO2 288.1025,
found 288.1002, calcd for (C19H14NO2)(C19H15NO2) 577.2127, found
577.2110.
p-Methoxy-N-phenylaniline (7c).57,58 1H NMR (400 MHz, CDCl3,
25 °C) δ (ppm): 3.80 (s, 3H), 5.46 (s, 1H, NH) 6.81−6.92 (m, 5H),
7.05−7.09 (m, 2H), 7.18−7.23 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3, 25 °C) δ (ppm): 55.8, 114.9, 115.9, 119.8, 122.5, 129.5, 139.7,
140.0, 150.4. HRMS (ESI-TOF (m/z)): calcd for C13H14NO
200.1070, found 200.1059.
N-Cyclohexylaniline (7d).57 1H NMR (400 MHz, CDCl3, 25 °C) δ
(ppm): 1.16−1.50 (m, 5Haliphatic), 1.68−1.75 (m, 1Haliphatic), 1.80−1.85
(m, 2Haliphatic), 2.10−2.14 (m, 2Haliphatic), 3.28−3.35 (m, 1H), 3.55 (m,
1H, NH), 6.63−6.66 (m, 2H), 6.72 (t, 1H, 2JHH = 7.2 Hz 4JHH = 0.93
Hz), 7.19−7.24 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ
(ppm): 25.2, 26.1, 33.7, 51.8, 113.3, 117.0, 129.4, 147.6. HRMS (ESI-
TOF (m/z)): calcd for C12H18N 176.1434, found 176.1406, calcd for
C12H17NNa 198.1253, found 198.1226.
1
4′-Phenoxy(1,1′-biphenyl)-3-carboxamide (10b). H NMR (400
MHz, CDCl3, 25 °C) δ (ppm): 5.73 (s, 1H, NH), 6.17 (s, 1H, NH),
3
4
7.07−7.13 (m, 4H, Hf and Hg), 7.16 (tt, JHH = 7.42, JHH = 1.15 Hz,
3
4
1H, Hi), 7.37−7.42 (m, 2H, Hh), 7.54 (t, JHH = 8.00 Hz, JHH = 0.61
N-Propylaniline (7e).59 1H NMR (400 MHz, CDCl3, 25 °C) δ
Hz 1H, Hc), 7.60 (dt, JHH = 8.85 Hz, JHH = 2.18 Hz, 2H, He), 7.76
3
4
(dt, 3JHH = 7.77 Hz, 4JHH = 1.80 Hz, 2H, Ha and Hd) and 8.06 (t, 3JHH
2
2
(ppm): 1.03 (t, 3H, JHH = 7.39 Hz), 1.67 (q, 2H, JHH = 7.28 Hz),
3.11 (t, 2H, JHH = 7.01 Hz), 3.64 (s, 1H, NH), 6.61−6.65 (m, 2H),
= 3.75 Hz, JHH = 1.92 Hz, 1H, Hb). 13C{1H} NMR (100 MHz,
2
4
6.72 (tt, 1H, 2JHH = 14.71 Hz, 3JHH = 7.24 Hz, 4JHH = 1.07 Hz,), 7.17−
CDCl3, 25 °C) δ (ppm): 119.1 (C10), 119.2 (C13), 123.6 (C15), 125.7
I
DOI: 10.1021/acs.joc.6b01035
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
4
3
(C6), 126.1 (C4), 128.5 (C9), 129.1 (C5), 129.9 (C14), 130.4 (C1),
133.9 (C2), 135.1 (C8), 141.2 (C7), 156.9 (C12), 157.4 (C11) and
169.2 (C3). HRMS (ESI-TOF (m/z)): calcd for C19H15NO2Na
312.1000, found 312.0993, calcd for (C19H15NO2)2Na 601.2103,
found 601.2078, calcd for (C19H15NO2)3Na 890.3206, found
890.3186.
7.69 Hz, JHH = 1.73 Hz, 2H), 6.82−6.92 (m, 3H), 7.07 (dd, JHH
=
4
3
7.79 Hz, JHH = 1.74 Hz, 2H) 7.17 (d, JHH = 8.91 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 55.6, 69.5, 111.8, 112.8,
114.6, 117.8, 118.4, 121.3, 123.0, 133.4, 135.4, 146.3, 155.4. HRMS
(ESI-TOF (m/z)): calcd for C16H17NO2Na 278.1151, found
278.1161.
N-(2-(Allyloxy)phenyl)-N-methylacetamide (rc-3h). 1H NMR
(300 MHz, CDCl3, 25 °C) δ (ppm): 1.84 (s, 3H), 3.21 (s, 3H),
4.60 (dt, 3JHH = 4.98 Hz, 4JHH = 1.65 Hz, 2H), 5.30 (ddd, 2JHH = 10.57
Hz, 3JHH = 4.36 Hz, 4JHH = 1.50 Hz, 1H), 5.41 (ddd, 2JHH = 17.27 Hz,
4-Amino-N,N-diphenylbenzamide (9c). 1H NMR (400 MHz,
3
CDCl3, 25 °C) δ (ppm): 3.78−3.92 (m, 2H, NH), 6.44 (d, JHH
=
8.71 Hz, 2H, Hb), 7.11−7.19 (m, 6H, Hc or Hd and He), 7.23−7.33
(dd, JHH = 7.87 Hz, 4JHH = 2.05 Hz, 6H, Ha and Hc or Hd). 13C{1H}
3
3JHH = 4.90 Hz, JHH = 1.68 Hz, 1H), 5.96- 6.08 (m, 1H), 6.96- 7.02
4
NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 113.6 (C4), 125.2 (C2),
125.9 (C9), 127.4 (C7 or C8), 129.1 (C7 or C8), 131.8 (C3), 144.7
(C6), 148.6 (C5), 170.7 (C1). (ESI-TOF (m/z)): calcd for C19H17N2O
289.1335, found 289.1335, calcd for C19H16N2ONa 311.1155, found
311.1163, calcd for (C19H16N2O)2Na 599.2417, found 599.2420.
N-Phenyl-4-(phenylamino)benzamide (10c). 1H NMR (400 MHz,
CDCl3, 25 °C) δ (ppm): 6.07 (s, 1H, NHamine), 7.04 (d, 3JHH = 8.65
Hz, 2H, Hb), 7.07 (d, 3JHH = 7.20 Hz, 1H, He), 7.13 (t, 3JHH = 7.46 Hz,
4JHH = 1.04 Hz, 1H, Hh), 7.16 (d, 3JHH = 7.72 Hz, 4JHH = 1.18 Hz, 2H,
(m, 2H), 7.19 (dd, 3JHH = 7.68 Hz, 4JHH = 1.68 Hz, 1H) 7.85 (td, 3JHH
= 8.91 Hz, JHH = 1.79 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3, 25
4
°C) δ (ppm): 21.6, 35.8, 68.6, 113.2, 117.6, 121.2, 129.0, 129.2, 132.5,
154.0, 171.4. (ESI-TOF (m/z)): calcd for C12H15NO2Na 228.0995,
found 228.0993, calcd for (C12H15NO2)2Na 433.2098, found
433.2095.
Synthesis of Auxiliary Ligand L3. N,N′-Dimethyl-2,6-bis-
(aminomethyl)pyridine as HCl Salt (L3·(HCl)2). 2,6-Bis-
(chloromethyl)pyridine (1 g, 5.6 mmol) was added to aqueous
methylamine (40%) (30 mL, 350 mmol) in a round-bottom flask, and
the mixture was stirred at room temperature for 2−3 days. The
3
3
Hc), 7.35 (dt, JHH = 7.74 Hz, 4H, Hd and Hg), 7.63 (d, JHH = 8.60
Hz, 2H, Hf), 7.77 (d, 3JHH = 8.54 Hz, 2H, Ha), 7.80 (s, 1H, NHamide).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 115.2 (C4), 120.1
(C7 and C11), 122.9 (C9), 124.2 (C13), 125.7 (C2), 128.8 (C8 or C12),
129.0 (C3), 129.5 (C8 or C12), 138.2 (C10), 141.1 (C6), 147.2 (C5),
165.5 (C1). HRMS (ESI-TOF (m/z)): calcd for C19H16N2ONa
311.1155, found 311.1149, calcd for (C19H16N2O)2Na 599.2417,
found 599.2407.
1
reaction was monitored by H NMR. Next, NaOH (0.470 g) was
added, and the mixture was concentrated under reduced pressure. The
crude was extracted with CH2Cl2, and the combined organic layers
were dried with anhydrous MgSO4. Finally, the solvent was evaporated
under reduced pressure, obtaining L3 as a yellow oil (0.920 g, 90%
yield). Since the product is highly hygroscopic, the hydrochloric salt
L3·(HCl)2 was prepared by dissolving the oil in CHCl3 (1 mL) and
hydrochloric acid 36.5% (0.85 mL). The aqueous phase was dried
under vacuum to dryness, and the crystallization was performed with a
1-(Allyloxy)-2-iodobenzene (rc). rc was synthesized following
published procedures.36 The characterization of rc-H was performed
by comparison to a commercially available sample.
1-(Allyloxy)-2-(4-methoxyphenoxy)benzene (rc-5c). 1H NMR
1
mixture of MeOH and Et2O (0.660 g, 55% yield). L3·(HCl)2 salt: H
3
(300 MHz, CDCl3, 25 °C) δ (ppm): 3.81 (s, 3H), 4.62 (dt, JHH
=
NMR (400 MHz, D2O, 25 °C) δ (ppm): 2.83 (s, 6 H), 4.43 (s, 4 H),
7.46 (d, 2 H), 7.93 (t, 1 H). HRMS (ESI-TOF (m/z)): calcd for
C9H16N3 166.1339, found 166.1345. Anal. Calcd for (C9H17N3Cl2·1.15
H2O): C, 41.76; H, 7.51; N, 16.23. Found: C, 41.78; H, 7.37; N, 16.10.
5.23 Hz, 4JHH = 1.55 Hz, 2H), 5.24 (ddd, 2JHH = 10.50 Hz, 3JHH = 3.21
Hz, 4JHH = 1.64 Hz, 1H), 5.34 (ddd, 2JHH = 17.25 Hz, 3JHH = 3.65 Hz,
4JHH = 1.72 Hz, 1H), 5.94- 6.08 (m, 1H), 6.84- 6.97 (m, 6H), 7.01-
7.09 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3, 25 °C) δ (ppm):
55.6, 69.9, 114.6, 114.9, 117.5, 119.1, 119.9, 121.4, 123.8, 133.2, 146.9,
149.8, 151.3, 155.2. HRMS (ESI-TOF (m/z)): calcd for C16H16O3Na
279.0992, found 279.0999, calcd for (C16H16O3)2Na 535.2091, found
535.2084.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01035.
■
S
N-(2-(Allyloxy)phenyl)benzamide (rc-3a). 1H NMR (300 MHz,
3
4
CDCl3, 25 °C) δ (ppm): 4.68 (dt, JHH = 5.28 Hz, JHH = 1.44 Hz,
2H), 5.37 (ddd, 2JHH = 10.50 Hz, 3JHH = 3.17 Hz, 4JHH = 1.32 Hz, 1H),
5.46 (ddd, 2JHH = 17.29 Hz, 3JHH = 3.47 Hz, 4JHH = 1.61 Hz, 1H),6.05-
Experimental details; full characterization of chemical
compounds; supplementary methods; supplementary
schemes, figures, and tables (PDF)
3
4
6.12 (m, 1H), 6.95 (dd, JHH = 7.25 Hz, JHH = 2.37 Hz, 1H), 7.05-
3
4
7.09 (m, 2H), 7.50- 7.58 (m, 3H), 7.92 (dd, JHH = 8.28 Hz, JHH
=
1.76 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3, 25 °C) δ (ppm): 69.6,
111.5, 118.2, 119.9, 121.5, 123.8, 127.0, 128.1, 128.8, 131.7, 132.8,
135.7, 147.1, 165.2. HRMS (ESI-TOF (m/z)): calcd for
C1 6 H1 5 NO2 Na 276.0995, found 276.0991, calcd for
(C16H15NO2)2Na 529.2098, found 529.2083.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xavi.ribas@udg.edu.
■
Notes
2-(Allyloxy)-N-cyclohexylaniline (rc-7d). 1H NMR (400 MHz,
CDCl3, 25 °C) δ (ppm): 1.15−1.31 (m, 3H), 1.31- 1.48 (m, 3H),
The authors declare no competing financial interest.
3
1.61−1.73 (m, 1H), 1.73- 1.86 (m, 2H), 2.09 (d, JHH = 12.18 Hz,
ACKNOWLEDGMENTS
3
■
2H), 3.22- 3.34 (m, 1H), 4.19 (s, 1H, NH), 4.57 (dt, JHH = 5.23 Hz,
4JHH = 1.51 Hz, 2H), 5.30 (ddd, 2JHH = 10.50 Hz, 3JHH = 3.21 Hz, 4JHH
This work was supported by grants from the European
Research Council (Starting Grant Project ERC-2011-StG-
277801), the Spanish MICINN (CTQ2013-43012-P, Con-
solider-Ingenio CSD2010-00065, INNPLANTA project INP-
2011-0059-PCT-420000-ACT1), and the Catalan DIUE of the
Generalitat de Catalunya (2014SGR862). X.R. thanks ICREA
for an ICREA-Academia award. We thank STR from UdG for
̀
technical support. We also thank Prof. J. Roithova
Luis for fruitful discussions.
2
3
4
= 1.64 Hz, 1H), 5.42 (ddd, JHH = 17.23 Hz, JHH = 3.55 Hz, JHH
1.58 Hz, 1H), 6.04- 6.18 (m, 1H), 6.63 (dd, JHH = 10.50 Hz, JHH
=
=
2
3
4
3
4
8.17 Hz, JHH = 1.44 Hz, 2H), 6.79 (dd, JHH = 8.04 Hz, JHH = 1.41
Hz, 1H), (ddt, 2JHH = 15.35 Hz, 3JHH = 7.69 Hz, 4JHH = 1.31 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3, 25 °C) δ (ppm): 25.1, 26.0, 33.5,
51.4, 69.3, 110.5, 111.3, 115.7, 117.3, 121.5, 133.7, 137.7, 145.7.
HRMS (ESI-TOF (m/z)): calcd for C15H22NO 232.1696, found
232.1705, calcd for C15H21NONa 254.1515, found 254.1514.
́
and Dr. JM.
2-(Allyloxy)-N-(4-methoxyphenyl)aniline (rc-7c). 1H NMR (400
MHz, CDCl3, 25 °C) δ (ppm): 3.83 (s, 3H), 4.64 (dt, 3JHH = 5.45 Hz,
4JHH = 1.34 Hz, 2H), 5.33 (ddd, 2JHH = 10.46 Hz, 3JHH = 3.33 Hz, 4JHH
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2
3
4
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=
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