Modular Synthesis of Biaryl-Substituted Phosphine Ligands: Application in Microwave-Assisted Palladium-Catalyzed C-N Cross-Coupling Reactions

Article abstract of DOI:10.1002/ejoc.201500962

Biaryl-substituted monophosphine-based ligands have been synthesized by transition-metal-free "ARYNE" cross-coupling reaction of aryllithiums with 1,2-dibromobenzene and subsequent regioselective functionalization through bromine-lithium interconversion. These ligands were employed in palladium-catalyzed C-N bond-forming reactions. The reaction was found to be general with wide substrate applicability. A wide variety of both primary and secondary amines were successfully coupled with an array of differently substituted halobenzenes under microwave irradiation to give the expected products in good to excellent yields. A number of biaryl-substituted phosphine ligands screened for the coupling reaction showed that steric bulk and the electronic properties of substituents on phosphorus play a crucial role in governing the catalytic activity of C-N cross-coupling reactions. Biaryl-substituted monophosphines have been synthesized by transition metal free ARYNE cross-coupling reactions and subsequent regioselective functionalization through bromine-lithium interconversion. These ligands were employed in palladium-catalyzed C-N bond-forming reactions.

Full text of DOI:10.1002/ejoc.201500962

FULL PAPER
DOI: 10.1002/ejoc.201500962
Modular Synthesis of Biaryl-Substituted Phosphine Ligands: Application in
Microwave-Assisted Palladium-Catalyzed C–N Cross-Coupling Reactions
Chandani Singh,[a] Jayant Rathod,[a] Vishwajeet Jha,[b] Armen Panossian,[b]
Pradeep Kumar,*[a] and Frédéric R. Leroux*[b]
Keywords: Synthetic methods / Homogeneous catalysis / Palladium / Cross-coupling / Microwave chemistry / Biaryls /
Phosphines
Biaryl-substituted monophosphine-based ligands have been
were successfully coupled with an array of differently substi-
synthesized by transition-metal-free “ARYNE” cross-cou- tuted halobenzenes under microwave irradiation to give the
pling reaction of aryllithiums with 1,2-dibromobenzene and
subsequent regioselective functionalization through brom-
ine–lithium interconversion. These ligands were employed
expected products in good to excellent yields. A number of
biaryl-substituted phosphine ligands screened for the cou-
pling reaction showed that steric bulk and the electronic
in palladium-catalyzed C–N bond-forming reactions. The re- properties of substituents on phosphorus play a crucial role
action was found to be general with wide substrate applica-
bility. A wide variety of both primary and secondary amines
in governing the catalytic activity of C–N cross-coupling re-
actions.
tions.[1–8] Among other methods reported, several new and
bulky ligands,[9–13] which include electron-rich phos-
phines[14–20] and N-heterocyclic carbenes,[21–30] have been
reported for Pd-catalyzed amination reactions. Buchwald
and co-workers developed a new class of biaryl monophos-
phine ligands that were found to be useful in many cross-
coupling reactions.[31] To find a catalytic system that incor-
porates improved and better features, various strategies that
use catalysts based on multiple Pd sources and ligands have
been developed by various research groups.[32–39] In ad-
dition, a more comprehensive approach to catalyst design
that uses a multi-ligand system has also been employed for
cross-coupling methodologies.[40–43]
As a part of our ongoing research program on C1-sym-
metric biaryl-based phosphine ligands[44–48] and their appli-
cation for various catalytic reactions, we report here the
concise synthesis of biaryl-based phosphine ligands and
demonstrate their application in Pd-catalyzed C–N bond-
forming reactions.
Introduction
In last few years there has been tremendous upsurge of
interest among the synthetic chemists in developing diverse
methods for palladium-catalyzed C–N bond-forming reac-
tions. Consequently, this synthetic transformation has
gained utmost importance with its widespread use across
various disciplines, such as the synthesis of key intermedi-
ates for fine chemicals, building blocks for pharmaceuticals,
conducting polymers, and photographic materials. Despite
significant advances in palladium-catalyzed C–N coupling
reactions, many reported methods have limitations and suf-
fer from drawbacks, such as generality of methods, tedious
steps, expensive catalytic system, compatibility with various
functional groups, selectivity, and rather long reaction time.
In view of these issues, it is highly desirable to develop a
general catalytic system, which could be readily accessible
with a wide substrate scope in Pd-catalyzed amination reac-
tions.
Monodentate phosphines that possess a binaphthyl skel-
eton – MOP-type ligands – have been extensively employed
in asymmetric catalysis, including C–N bond forming reac-
Results and Discussion
Synthesis of Biaryl Monophosphines
[a] Organic Chemistry Division, CSIR – National Chemical
Laboratory,
Dialkylbiaryl-substituted phosphine ligands have been
efficiently used in palladium-catalyzed amination reactions.
It has been shown that they can favorably influence the re-
action time, catalyst loading and reaction conditions. Ac-
cording to the reaction mechanism, steric bulk and elec-
tron-donor ability of the dialkylbiaryl-substituted phos-
phine ligands facilitate the formation of an active L2Pd0
and thus oxidative addition under mild conditions. Another
Homi Bhabha Road, Pune 411008, India
E-mail: pk.tripathi@ncl.res.in
http://www.ncl-india.org/
[b] CNRS-University of Strasbourg (ECPM), UMR CNRS 7509,
COHA,
25 Rue Becquerel, 67087 Strasbourg, France
E-mail: frederic.leroux@unistra.fr
http://www.coha-lab.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500962.
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FULL PAPER
important aspect is the possibility of dialkylbiaryl-substi- bromobiphenyl (1) serves as powerful platform to access bi-
tuted phosphine ligands to engage Pd-arene π interactions phenyls with various ortho substituents like OMe, NMe2,
between the metal and the lower ring of the ligand, which Ph, and so on, because one bromine atom after the other
leads to increased electron density at the metal center and can be replaced in a regioselective manner.
thus increased catalyst stability.[20] Buchwald and co-
Regioselective bromine/lithium interconversions can be
workers have shown that the nature of the arene substituent performed on this substrate by lithiation in tetrahydrofuran
is critical to the performance of the ligands.[49]
(THF) with exactly 1 equiv. of BuLi. Under these condi-
After Buchwald’s first generation ligands (obtained in 4 tions only the bromine atom located in the most electron-
steps by Suzuki–Miyaura coupling),[31] he reported in 2000 poor ring is selectively displaced.[60] In addition, ortho,or-
on the preparation of a second generation of biaryl dialk- thoЈ-dibromobiphenyls obtained directly by the transition
ylphosphine family by the addition of an aryl Grignard rea- metal-free ARYNE coupling methodology can be function-
gent to benzyne (generated in situ), followed by trapping of alized to give new dissymmetric biphenyl ligands. To dem-
the newly formed organomagnesium species in the presence onstrate this modular approach, we targeted the synthesis
of a copper catalyst, with ClPR2.[50] However, the presence of the ligands depicted in Figure 1.
of excess magnesium metal from the Grignard formation in
the first step and the copper salts added to facilitate C–P
bond formation were serious drawbacks that complicated
the reaction workup. At that time, our group reported on
the coupling of an aryllithium reagent and an ortho-di-
haloarene (to afford in situ benzyne), which led to ortho-
bromobiphenyls.[51] Buchwald nicely applied then this
Figure 1. Targeted biaryl monophosphine ligands.
methodology to the preparation of his third generation li-
gands like S-Phos.[52] This approach has the advantage of
The whole range of biaryl-substituted phosphine ligands
being faster and cleaner, eliminates the need for CuI salts, developed by Buchwald found numerous applications in ca-
and avoids an additional step to prepare an aryl halide as talysis, and subtle changes in structure may have a tremen-
the precursor.
dous impact on reactivity. Therefore, we will underline here,
In parallel, we developed further this so-called “ARYNE that the ability to generate new ligands of this type will be
coupling” methodology, in particular for the synthesis of useful because it allows for fine-tuning of the ligand back-
dissymmetric biphenyls that bear at least one exchangeable bone and may lead to important enhancements of reactivity
halogen (Scheme 1).[53,54,51,55] We could show that highly re- in various metal-catalyzed reactions.
gioselective[53,56,57,51,55] halogen–metal interconversions al-
The synthesis of biaryl monophosphine ligands 2–4 was
low for subsequent functionalization. More recently, an based on 2,2Ј,6-tribromobiphenyl (1)[53] obtained by
atropo-diastereoselective version and access to enantioen- ARYNE coupling of 1,3-dibromo-2-iodobenzene[55] with
riched biphenyls has been documented.[58,59]
1,2-dibromobenzene in 86% yield (Scheme 2).[44] Regio-
In this paper, we will not add further ligands to the nu- selective bromine–lithium interconversion on 1 followed by
merous already present in literature. We will outline here trapping with FB(OMe)2·OEt2,[61,62] oxidation with H2O2/
that 2,2Ј,6-tribromobiphenyl (1; obtained in 97% yield on NaOH, and methylation with MeI led to biaryl 6 in 67%
multi-gram scale by ARYNE coupling)[53] and sequential global yield. Another regioselective bromine–lithium in-
lithiation/functionalization is a complementary strategy to terconversion allowed for the introduction of the methyl
Buchwald’s route, and allows for the preparation of deriva- substituent in position 6 in 74% yield. Compound 7 was
tives in which the aryl bromide precursors for the ARYNE then used as a common precursor for the synthesis of li-
coupling are not readily available. We illustrate this ap- gands 2 (PCy2) and 3 (PPh2) by means of a final bromine–
proach on the synthesis of biaryls in which the lower and lithium exchange and trapping with ClPCy2 and ClPPh2,
upper phenyl rings are diversely functionalized. 2,2Ј,6-Tri- respectively.
Scheme 1. Mechanism of the “ARYNE” coupling reaction.
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Modular Synthesis of Biaryl-Substituted Phosphine Ligands
Scheme 2. Synthesis of phosphine ligands 2 and 3 from 2,2Ј,6-tribromobiphenyl (1).
Scheme 3. Synthesis of phosphine ligand 4.
Similarly, ligand 4 can be accessed from biaryl com- ation allowed for functionalization of the 6 position. After
pound 1. After the first bromine–lithium exchange, the in- final bromine–lithium exchange, monophosphine 5 was ob-
termediate aryllithium was trapped with iodine to give iodo tained in 63% yield (Scheme 4).
biaryl 8 that readily underwent chemoselective Suzuki–Mi-
yaura coupling with phenyl boronic acid to give compound
9 in 95% yield (Scheme 3).
Pd-Catalyzed Amination Studies
Regioselective bromine–lithium interconversion followed
by trapping with MeI resulted in formation of compound
10 in 93% yield. Finally, the phosphorus substituent was
introduced as previously shown to afford biaryl-substituted
phosphine ligand 4 in 65% yield.
In contrast to the approach based on the use of tribro-
mobiphenyl 1, ligand 5 was prepared from 2,2Ј-dibromobi-
phenyl 11 obtained directly by ARYNE coupling.[44] Re-
gioselective bromine–lithium interconversion and methyl-
With the desired biaryl monophosphine ligands in hand,
we studied their efficiency in C–N coupling reactions of
both primary and secondary amines with various halides.
As illustrated in Table 1, the reaction of bromobenzene
with dibutylamine was chosen as a model reaction to study
the influence of solvent and base. The C–N coupling reac-
tion was performed in 1,2-dimethoxyethane at reflux tem-
peratures for 18 h with the different ligands, which led to
only low yields (10–16%) of product (Table 1, Entries 1–4).
By changing the solvent to THF, and the base to potassium
tert-butoxide the yield increased modestly to 40% (Table 1,
Entry 5). However, when the reaction was carried out in
toluene, 90% yield of the desired product was obtained
(Table 1, Entry 6). To reduce the reaction time, we further
performed the coupling reaction in high-boiling solvents
such as m- or p-xylene or mesitylene at elevated tempera-
tures in the presence of ligand 2; however only moderate
yields were obtained (Table 1, Entries 7, 8, and 9, with 68,
60, and 48% yield, respectively). Interestingly, the use of
1,4-dioxane as solvent and ligand 2 afforded the highest
yield of coupling product (Table 1, Entry 10). Ligand 5 was
also effective in toluene with a similar yield of product
(Table 1, Entry 11). In contrast, ligand 3 gave only 8% yield
Scheme 4. Synthesis of phosphine ligand 5.
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(Table 1, Entry 13). A blind reaction in the absence of li- Table 2. Arylation of secondary amines with aryl halides catalyzed
by Pd(OAc)2/2 with KOtBu as base.[a]
gand gave no reaction (Table 1, Entry 12). The screening of
different bases and ligands for this C–N coupling reaction
showed that the combination of potassium tert-butoxide
and ligand 2 in 1,4-dioxane and Pd(OAc)2 as a source for
palladium were the best reaction conditions. Ligand 2 cor-
responds to the best requirements in terms of electron den-
sity of the upper phenyl ring, steric hindrance, and electron
density of the phosphorus substituent.
Table 1. The effect of base and solvent on the Pd(OAc)2-ligand-
catalyzed amination reaction between bromobenzene and dibut-
ylamine.[a]
Entry
Ligand Solvent
Temp. Base
[°C]
t
Yield
[h] [%][b]
1
2
3
4
5
6
7
8
2
3
4
5
2
2
2
2
2
2
5
–
3
DME
DME
DME
DME
85
85
85
85
66
110
139
140
145
110
110
110
110
Cs2CO3
18
18
18
18
16
14
24
24
8
12%
12%
10%
16%
40%
90%
68%
60%
48%
90%
85%
n.r.
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
THF
toluene
m-xylene
p-xylene
mesitylene
dioxane
toluene
toluene
toluene
9
10
11
12
13
6
14
24
14
8%
[a] Reaction conditions: bromobenzene (1 equiv.), nBu2NH
(1.2 equiv.), base (1.5 equiv.), Pd(OAc)2 (2 mol-%), ligand (3 mol-
%); DME = 1,2-dimethoxyethane. [b] Isolated yield after column
chromatography; n.r.: no reaction.
Next, we decided to perform the coupling reaction under
microwave irradiation (Anton Parr Monowave-400, Glass
vial-G10, 160 °C) to reduce the reaction time. Luckily, the
reaction between bromobenzene and dibutylamine per-
formed very well in 10 min to afford 90% yield of coupling
product.
Encouraged by the above findings, we carried out a sys-
tematic study of the C–N coupling reaction by employing
various primary and secondary amines and halo com-
pounds under the optimal reaction conditions. The mono-
dentate
biaryl-substituted
phosphine-based
ligand
BrettPhos developed by Buchwald et al.[49] was found to be
applicable only in the monoarylation of primary amines,
whereas RuPhos, developed by the same group,[63] was ef-
fective only in the arylation of secondary amines. In view
of this, a multi-ligand-based Pd catalyst for C–N coupling
reactions was reported for both primary and secondary
amines.[64] In this context, we became particularly interested
in examining the efficacy of our biaryl monodentate phos-
phine ligand 2 for the C–N coupling reaction of both pri-
mary and secondary amines with various halo compounds.
[a] Reaction conditions: aryl halide (1 equiv.), R2NH (1.2 equiv.),
KOtBu (1.5 equiv.), Pd(OAc)2 (2 mol-%), 2 (3 mol-%). [b] Isolated
yield after column chromatography; n.r.: no reaction.
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Modular Synthesis of Biaryl-Substituted Phosphine Ligands
As illustrated in Table 2, a variety of secondary amines also Table 3. Optimization of the reaction conditions for C–N cross-
coupling reaction of aniline with iodobenzene.
proved to be excellent substrates for the coupling reac-
tion.
For example, the reaction of dibutylamine with various
halo compounds, such as chloro-, bromo- and iodobenzene,
led to the coupling products in excellent yields. The same
reaction when performed under microwave irradiation was
complete within 10 min to afford the desired products in
similar yields (Table 2, Entries 1–3). The aminated product
was formed in excellent yield under both conventional and
microwave conditions and the fluorine atom remained in-
tact (Table 2, Entries 4 and 5). Pyrrolidine was successfully
coupled with bromobenzene (Table 2, Entry 6). However,
no reaction occurred with 2-bromoanisole under conven-
tional conditions but the microwave assisted reaction led to
the desired product in 85% yield (Table 2, Entry 7). Several
other secondary amines were arylated smoothly both under
microwave and reflux conditions to afford good to excellent
Entry Catalyst
Solvent
Base
Reaction
time
Yield
1[a]
2[b]
3[c]
Pd(OAc)2 1,4-dioxane KOtBu
Pd(OAc)2 1,4-dioxane KOtBu
Pd(OAc)2 1,4-dioxane KOtBu
2 h
1 h
2 h
18%[d]
15%[d]
75%
[a] Reaction at room temperature. [b] Reaction at 100 °C. [c] Reac-
tion at 100 °C; before heating, the medium was purged with argon
gas for 10 min. [d] Low yield of the desired product as a result of
formation of azobenzene as the major product when the reaction
was carried out under aerobic conditions.
yields of the products (Table 2, Entries 8, 9, 12, and 13). conditions, it was decided to carry out the amination reac-
Even p-nitro-chlorobenzene reacted smoothly with N-meth- tion under an argon atmosphere.
ylaniline to afford the desired product in excellent yields
We then investigated the scope of this catalytic system
under both conventional and microwave conditions for a variety of other primary anilines. As depicted in
(Table 2, Entry 14). We also used a variety of substituted Table 4, aniline was coupled with various aryl halides under
halo compounds for the coupling with amines to examine both conventional and microwave conditions to afford cou-
the influence of steric and electronic properties of the sub- pled products in excellent yields (Table 4, Entries 1–3). As
stituents during the amination reaction. The reaction of anticipated, the time was drastically reduced for the cou-
phenyl methylamine with 2-bromoanisole was unsuccessful pling reactions that were carried out with microwave heat-
under conventional heating; however, under microwave irra- ing. We then examined the effect of both electronic and
diation, 80% of coupling product were obtained (Table 2, steric factors by employing substituted anilines or substi-
Entry 10). Similarly, p-bromoanisole and dibutylamine at tuted aryl halides. For example, when p-aminoanisole was
reflux temperatures led only to decomposition. However, treated with bromobenzene (Table 4, Entry 4) or p-bromo-
when the reaction was performed under microwave irradia- anisole (Table 4, Entry 5), it furnished the expected prod-
tion, 85% yield of the desired product was obtained after ucts in 90% yield under both the conditions. Interestingly,
10 min (Table 2, Entry 11). In contrast, the reaction of di- when the bulky isopropyl group was placed ortho to the
phenylamine with either o- or p-bromoanisole did not af- amine function, the coupling with bromobenzene or substi-
ford the desired products (Table 2, Entries 15 and 16). This tuted aryl halides afforded the desired coupling products in
is probably a result of strong steric hindrance caused by the excellent yields (Table 4, Entries 6–8).
two phenyl groups.
Surprisingly, in all these reactions, only the mono-aryl-
Next, we decided to study the scope of this reaction in ated product was obtained under microwave conditions. Pd-
the arylation of primary amines, which are less-reactive sub- catalyzed C–N coupling reactions with Ph3P as ligand are
strates for C–N coupling reactions. Reductive dehalogena- known to give mainly a mixture of both mono- and di-
tion of aryl halides is frequently encountered with primary arylated products.[65] In general, it is quite difficult to tune
amines in Pd-catalyzed C–N coupling reactions. Therefore, the mono- and diarylation of a primary amine in palla-
in the case of primary amines, bidentate biphosphine li- dium-catalyzed arylation reactions. To achieve selective
gands are commonly employed and the products are often monoarylation, fine-tuning of the catalyst with bulky li-
contaminated with tertiary amines that result from the com- gands is required.[11,13] However, it was observed that when
peting diarylation reaction.
aniline (1 equiv.) was treated with aryl halides (1.2 equiv.),
We first examined the Pd-catalyzed reaction of aniline it afforded a mixture of both mono- and diarylated prod-
with iodobenzene (Table 3). Reactions performed at room ucts. In contrast, when primary amines were used in small
temperature or by heating at 100 °C for 1–2 h in the pres- excess (1.2 equiv.) relative to the aryl halide (1 equiv.), only
ence of potassium tert-butoxide in 1,4-dioxane gave only mono-arylation was observed. The reaction of aniline with
low yields (Table 3, Entries 1 and 2). A significant amount p-bromo-chlorobenzene either under normal heating or mi-
of azobenzene as side product was formed as a result of crowave conditions led to a mixture of fully aminated prod-
oxidation of aniline under aerobic conditions. To prevent uct and N-(p-chlorophenyl)aniline in a 6:4 ratio (Table 4,
the formation of side products and increase the yield the Entry 10). Prolonged reaction times for both conventional
reaction medium was initially purged with argon for 10 min heating and microwave conditions furnished the bis-amin-
before heating. To our delight, the desired product was ob- ated product only, in good yield (Table 4, Entry 11). Inter-
tained in 75% yield (Table 3, Entry 3). Thus, for optimal estingly the reaction of aniline with 2-fluoro-4-iodotoluene
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FULL PAPER
Table 4. Arylation reaction of primary amines with aryl halides catalyzed by Pd(OAc)2/2 with KOtBu as base.[a]
[a] Reaction conditions: aryl halide (1 equiv.), R2NH (1.2 equiv.), KOtBu (1.5 equiv.), Pd(OAc)2 (2 mol-%), 2 (3 mol-%). [b] Isolated yield
after column chromatography. [c] Combined yield of the mixture of products. [d] Aniline (2 equiv.) and aryl halide (1 equiv.).
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Modular Synthesis of Biaryl-Substituted Phosphine Ligands
tion with 1,2-dibromoethane)]. 1H NMR and solution-phase 13C
NMR spectra were recorded with Bruker AC-200, AC-400, AC-
500 or AM-300 instruments and deuterated solvents. Chemical
shifts are calibrated with respect to the residual solvent signal. 13C
NMR chemical shifts are reported relative to the central line of the
given deuterated solvent. Column chromatography was performed
with silica gel. MS experiments were performed with a TOF spec-
trometer equipped with an orthogonal electrospray (ESI) interface.
Gas chromatography analysis was performed with a Varian-CP-
3800 instrument with a FID detector and HP-5 capillary column
produced the selective mono-aminated product (Table 4,
Entry 12). It was found that an aliphatic amine, such as
hexylamine, was also a suitable substrate and the reaction
with bromobenzene took place smoothly under both condi-
tions to give the mono-arylated product in 76% yield under
microwave conditions and gave a moderate 50% yield under
normal heating (Table 4, Entry 13). It should be mentioned
here that the Pd-catalyzed coupling of chlorobenzene with
n-octylamine in the presence of a N-heterocyclic carbene is
known to produce a mixture of both mono- and diarylated (5% phenyl-95% methylsiloxane 30 m, 0.25 mm i.d., 0.25 μm film
products.[5]
thickness) and nitrogen as the carrier gas. Gas chromatography-
mass analysis was carried out with an Agilent 7890B instrument
A sterically hindered substrate, such as 2,4,6-trimethyl
with an Agilent 5977A Mass Selective Detector (EI) and HP-5 20
aniline, was well tolerated in the coupling reaction with bro-
capillary column (5% phenyl-95% methylsiloxane 30 m, 0.25 mm
mobenzene and gave the desired product in 92% yield
i.d., 0.25 μm film thickness) and helium as the carrier gas. Micro-
(Table 4, Entry 9). In contrast, no reaction occurred be-
wave reactions were performed with an Anton Parr Monowave-400
tween sterically hindered anilines and p-bromo- or p-
chloro-nitrobenzene (Table 4, Entries 14–16).
in 10 mL sealed glasses tubes (G10).
Ligand Synthesis
Dicyclohexyl(2-methoxy-6-methylbiphenyl-2Ј-yl)phosphine (2) and
(2-Methoxy-6-methylbiphenyl-2Ј-yl)diphenylphosphine (3)
Conclusions
2,2Ј-Dibromo-6-methoxybiphenyl (6): At –78 °C, BuLi (45.5 mmol,
In summary, we have presented the synthesis of new non-
symmetric Buchwald-type biaryl-substituted phosphine li-
gands. They have been prepared by using the ARYNE cou-
pling methodology to access 2,2Ј-dibromo- and 2,2Ј,6-tri-
bromobiphenyl, which have been used as common scaffolds
to allow modular ligand synthesis through highly regiose-
lective bromine–lithium interconversions. The ligands have
been tested successfully in Pd-catalyzed C–N coupling reac-
tions that employed both conventional and microwave heat-
ing methods. Although the ligands did not show superior
activity relative to Buchwald’s ligands, the approach is com-
plementary to the Buchwald route and allows for the prepa-
ration of derivatives in which the aryl bromide precursor for
the ARYNE approach is not readily available. Buchwald’s
biaryl-substituted phosphines have numerous applications
in catalysis however, through this approach, subtle changes
in structure and the introduction of sophisticated substitu-
ents might be useful for various catalytic systems with im-
proved properties.
1 equiv.) in hexanes (30.0 mL) was added to a solution of 2,2Ј,6-
tribromobiphenyl[53,44] (1; 17.8 g, 45.5 mmol, 1 equiv.) in THF
(95.0 mL). Immediately after the addition was completed,
fluorodimethoxyborane·Et2O[61,62] (10.0 mL, 52.0 mmol, 1.2 equiv.)
was added and the reaction mixture was then allowed to reach 0 °C.
After 30 min, an aqueous solution of sodium hydroxide (3.0 m;
18.0 mL) and hydrogen peroxide (30%; 5.00 mL) were added drop-
wise. The reaction mixture was then allowed to reach 25 °C over-
night. After addition of water (100 mL), the organic phase was sep-
arated and the aqueous layer was extracted with dichloromethane
(3ϫ50.0 mL). The combined organic layers were dried with so-
dium sulfate before being evaporated. Purification on column
chromatography afforded 2Ј,6-dibromobiphenyl-2-ol (10.6 g,
32.3 mmol, 71%) as a slightly yellow oil. 1H NMR (CDCl3,
400 MHz): δ = 7.77 (dd, J = 8.3, 1.3 Hz, 1 H), 7.47 (dt, J = 7.7,
1.4 Hz, 1 H), 7.36 (dt, J = 8.0, 1.7 Hz, 1 H), 7.29 (dd, J = 7.5,
1.7 Hz, 1 H), 7.28 (dd, J = 7.7, 1.3 Hz, 1 H), 7.19 (t, J = 8.3 Hz, 1
H), 6.97 (dd, J = 8.3, 1.1 Hz, 1 H), 4.59 (s, 1 H) ppm. 13C NMR
(CDCl3, 101 MHz): δ = 156.4, 142.0, 136.1, 131.2, 130.8, 129.9,
129.5, 127.0, 122.7, 117.5, 116.8 ppm. C12H8Br2O (328.00): calcd.
C 43.94, H 2.46; found C 44.19, H 2.57.
2Ј,6-Dibromobiphenyl-2-ol was then dissolved in acetone
(100 mL). Potassium carbonate (6.00 g, 45.0 mmol, 1 equiv.) and
MeI (7.76 g, 3.40 mL, 1.2 equiv.) were successively added. The mix-
ture was heated at reflux overnight. After cooling to 25 °C, water
(50.0 mL) was added and the organic layer was extracted with
dichloromethane (4ϫ100 mL). The combined organic layers were
dried, filtered and the solvents evaporated. The crude product was
purified by chromatography which afforded pure 2Ј,6-dibromo-2-
methoxy-1,1Ј-biphenyl (6; 11.6 g, 34.0 mmol, 95%) as a light-yel-
Experimental Section
Materials and Analysis: Starting materials were purchased and used
as received, after adequate checks (melting ranges, refractive in-
dices, and gas chromatography) had confirmed the claimed purity.
Air- and moisture-sensitive materials were stored in Schlenk tubes
or Schlenk burettes, and protected by and handled under an atmo-
sphere of argon with appropriate glassware. Et2O and THF were
dried by distillation from sodium after the characteristic blue color
of sodium diphenyl ketyl (benzophenone–sodium “radical-anion”)
persisted. Melting ranges given were found to be reproducible after
recrystallization, unless stated otherwise (“decomp.”). Thin-layer
chromatography was carried out with 0.25 mm Merck silica-gel
(60-F254). Column chromatography was carried out on a column
packed with silica-gel 60N spherical neutral size 63-210 μm. nBuLi
and tBuLi were used as solutions in hexanes or pentane and their
concentrations were determined following the Wittig–Harborth
Double Titration method [(total base) – (residual base after reac-
1
low crystalline solid. Overall yield: 68%, m.p. 93–95 °C. H NMR
(CDCl3, 300 MHz): δ = 7.60 (dd, J = 7.9, 1.0 Hz, 1 H), 7.38 (td, J
= 7.4, 1.2 Hz, 1 H), 7.2 (m, 4 H), 6.86 (dd, J = 7.9, 1.3 Hz, 1 H),
3.66 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.0, 138.9,
132.5, 131.5, 131.3, 130.0, 129.2, 127.2, 124.7, 124.6, 124.4, 109.9,
56.2 ppm. C13H10Br2O (342.03): calcd. C 45.32, H 2.95; found C
45.32, H 2.85.
2Ј-Bromo-6-methoxy-2-methylbiphenyl (7): At –78 °C, butyllithium
(33.0 mmol, 1 equiv.) in hexanes was added dropwise to a solution
of 2,2Ј-dibromo-6-methoxybiphenyl (6; 11.3 g, 33.0 mmol) in THF
Eur. J. Org. Chem. 2015, 6515–6525
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6521

C. Singh, J. Rathod, V. Jha, A. Panossian, P. Kumar, F. R. Leroux
FULL PAPER
(150 mL). After the addition was completed, iodomethane (5.2 g,
2.3 mL, 36.3 mmol) was added dropwise and the reaction mixture
was then allowed to reach 25 °C. Water (80.0 mL) was added, fol-
lowed by extraction with ethyl acetate (3ϫ80.0 mL). The combined
organic layers were dried with sodium sulfate, filtered, and the sol-
vents evaporated. Purification by filtration through silica gel, fol-
lowed by crystallization from methanol, afforded 2Ј-bromo-6-meth-
oxy-2-methylbiphenyl (7; 74%) as colorless cubic crystals, m.p. 58–
with a mixture of hexane and ethyl acetate as eluent. 2,2Ј-Dibromo-
6-iodobiphenyl (8; 83%) was obtained as a yellow solid, m.p. 100–
103 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.83 (td, J = 8.2, 1.1 Hz,
1 H), 7.61 (td, J = 7.5, 1.2 Hz, 2 H), 7.19–7.35 (m, 2 H), 7.08 (dd,
J = 7.51, 1.66 Hz, 1 H), 6.86 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 145.7, 145.2, 138.1, 132.8, 132.6, 130.7,
130.6, 129.9, 127.6, 123.4, 123.1, 100.1 ppm. C12H7Br2I (437.90):
calcd. C 32.91, H 1.61; found C 33.03, H 1.72.
1
59 °C. H NMR (CDCl3, 300 MHz): δ = 7.61 (dd, J = 7.7, 0.9 Hz,
2,6Ј-Dibromo-1,1Ј:2Ј,1ЈЈ-terphenyl (9): To a solution of 2,2Ј-di-
bromo-6-iodobiphenyl (8; 3.88 g, 8.86 mmol, 1 equiv.), sodium
carbonate (5.63 g, 53.2 mmol, 6 equiv.), phenylboronic acid (2.16 g,
17.7 mmol, 2 equiv.), in MeCN (130 mL) and water (130 mL) was
added Pd(PPh3)4 (0.51 g, 0.44 mmol, 5 mol-%). The mixture was
heated at 90 °C for 3 h and was then allowed to reach 25 °C. Water
(100 mL) was added, followed by extraction with ethyl acetate
(4ϫ100 mL). The combined organic layers were dried with sodium
sulfate, filtered and the solvents evaporated. The dark brown oil
was purified by filtration through silica gel with cyclohexane as
eluent to afford a colorless oil (9; 3.33 g, 8.58 mmol, 95%). 1H
NMR (CDCl3, 300 MHz): δ = 7.61 (dd, J = 7.5, 1.7 Hz, 1 H), 7.44
(dd, J = 7.7, 1.1 Hz, 1 H), 7.30–7.20 (m, 2 H), 7.10–7.00 (m, 6 H),
7.0–6.9 (m, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 143.6,
141.2, 140.5, 140.3, 132.3, 131.9, 131.6, 129.6, 129.3 (2 C), 129.1,
129.0, 127.6, 127.4, 127.0, 126.9, 124.8, 124.7 ppm. MS (EI): m/z
(%) = 388 (7) [M]+, 308 [M – Br]+, 228 [M – 2 Br]+. C18H12Br2
(388.10): calcd. C 55.71, H 3.12; found C 55.13, H 3.47.
1 H), 7.31 (td, J = 7.4, 1.2 Hz, 1 H), 7.22 (t, J = 7.9 Hz, 1 H), 7.2–
7.1 (m, 2 H), 6.85 (d, J = 7.5 Hz, 1 H), 6.77 (d, J = 8.2 Hz, 1 H),
3.66 (s, 3 H), 1.95 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
156.8, 139.0, 137.7, 132.5, 131.4, 130.1, 128.7, 128.6, 127.3, 124.6,
122.2, 108.4, 55.9, 19.9 ppm. C14H13BrO (276.01): calcd. C 60.67,
H 4.73; found C 61.18, H 4.61.
Dicyclohexyl(2-methoxy-6-methylbiphenyl-2Ј-yl)phosphine (2): At
0 °C, butyllithium (7.70 mmol, 1.1 equiv.) in hexanes was added
dropwise to a solution of 2Ј-bromo-6-methoxy-2-methylbiphenyl
(7; 1.93 g, 7.0 mmol) in toluene (14.0 mL). After 15 min the reac-
tion mixture was cooled to –78 °C. A solution of chlorodicyclohex-
ylphosphine (1.63 g, 1.55 mL, 7.70 mmol, 1.1 equiv.) in toluene
(7.00 mL) was added dropwise. After 1 h, the mixture was allowed
to reach 25 °C and filtered through silica gel with diethyl ether. The
organic layer was evaporated. The crude product was triturated
with methanol to afford dicyclohexyl(2-methoxy-6-methylbiphenyl-
1
2Ј-yl)phosphine (2; 76%) as a white powder, m.p. 103–105 °C. H
NMR (CDCl3, 300 MHz): δ = 7.49 (d, J = 7.1 Hz, 1 H), 7.3–7.2
(m, 2 H), 7.2–7.1 (m, 1 H), 7.1–7.0 (m, 1 H), 6.79 (d, J = 7.5 Hz,
1 H), 6.67 (d, J = 8.2 Hz, 1 H), 3.58 (s, 3 H), 1.91 (s, 3 H), 1.7–1.4
(m, 11 H), 1.2–0.9 (m, 11 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 156.8, 145.6 (d, J = 33.8 Hz), 137.4, 135.8 (d, J = 1.6 Hz), 132.5
(d, J = 18.7 Hz), 131.1 (d, J = 6.6 Hz), 130.6 (d, J = 6.0 Hz), 128.4,
128.1, 126.2, 121.9, 107.2, 54.9, 34.8 (d, J = 14.8 Hz), 33.3 (d, J =
13.7 Hz), 30.3, 30.1, 29.9, 29.8, 29.6, 29.6, 29.4, 27.8, 27.7, 27.4,
27.3, 27.2, 26.5, 20.8 (d, J = 4.4 Hz) ppm. 31P NMR (CDCl3,
161 MHz): δ = –8.1 ppm. C26H35OP (394.53): calcd. C 79.15, H
8.94; found C 79.12, H 8.96.
2ЈЈ-Bromo-3Ј-methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl (10): In a similar way as
for 7 but by starting from 2,2Ј-dibromo-6-phenylbiphenyl (9). The
brown oil was purified by filtration through silica gel to afford 2ЈЈ-
bromo-3Ј-methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl (10; 93%) as white crystals.
1H NMR (CDCl3, 300 MHz): δ = 7.46 (dd, J = 7.9, 0.9 Hz, 1 H),
7.31 (d, J = 7.5 Hz, 1 H), 7.3–7.2 (m, 2 H), 7.1–7.0 (m, 6 H), 7.0–
6.9 (m, 2 H), 2.06 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
141.6, 141.5, 141.4, 139.4, 136.7, 132.3, 131.9, 129.3 (2 C), 128.9,
128.4, 127.8, 127.5, 127.4 (2 C), 127.0, 126.4, 124.9 ppm. C19H15Br
(323.22): calcd. C 70.60, H 4.68; found C 70.48, H 4.90.
(3Ј-Methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl-2ЈЈ-yl)diphenylphosphine (4): At
–78 °C, butyllithium (2.00 mmol, 1 equiv.) in hexanes was added
dropwise to a solution of 2ЈЈ-bromo-3Ј-methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl
(10; 0.65 g, 2.00 mmol) in THF (4.00 mL). After 1 h, a solution of
chlorodiphenylphosphine (0.49 g, 0.41 mL, 2.2 mmol, 1.1 equiv.) in
toluene (2.00 mL) was added dropwise. After 1 h, the mixture was
allowed to reach 25 °C and filtered through silica gel with diethyl
ether. The organic layer was evaporated and the crude product was
purified by chromatography on silica gel. Trituration with meth-
anol afforded (3Ј-methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl-2ЈЈ-yl)diphenylphos-
(2-Methoxy-6-methylbiphenyl-2Ј-yl)diphenylphosphine (3): Prepared
in
a similar way but with chlorodiphenylphosphine (1.54 g,
1.29 mL, 7.70 mmol, 1.1 equiv.) in toluene (7.00 mL for 7 mmol)
to afford (2-methoxy-6-methylbiphenyl-2Ј-yl)diphenylphosphine (3;
68%) as a white powder, m.p. 105–106 °C. 1H NMR (CDCl3,
300 MHz): δ = 7.35 (td, J = 7.4, 1.1 Hz, 1 H), 7.2–7.0 (m, 14 H),
6.78 (d, J = 7.6 Hz, 1 H), 6.54 (d, J = 8.2 Hz, 1 H), 3.17 (s, 3 H),
1.87 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 157.1, 144.3
(d, J = 33.5 Hz), 138.2, 138.1, 137.6, 137.5, 137.4 (d, J = 2.8 Hz),
137.3, 134.1 (d, J = 2.2 Hz), 133.9, 133.8, 133.7, 133.5, 130.3, 130.1
(d, J = 6.0 Hz), 129.1, 128.4, 128.3, 128.2, 128.0, 127.9, 127.2,
122.0, 107.5, 54.8, 20.4 ppm. 31P NMR (CDCl3, 161 MHz): δ =
–12.3 ppm. C26H23OP (382.15): calcd. C 81.66, H 6.06; found C
81.82, H 6.15.
1
phine (4; 65%) as a colorless powder, m.p. 120–122 °C. H NMR
(CDCl3, 300 MHz): δ = 7.3–7.2 (m, 3 H), 7.2–7.1 (m, 4 H), 7.1–7.0
(m, 12 H), 7.0–6.9 (m, 1 H), 6.6–6.4 (m, 2 H), 1.61 (s, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 146.58 (d, J = 33.5 Hz, 3 C),
142.1 (d, J = 1.7 Hz), 141.8 (d, J = 2.2 Hz), 139.7 (d, J = 6.6 Hz),
138.3 (d, J = 13.7 Hz),137.0 (d, J = 5.5 Hz), 134.6 (2 C), 134.3,
132.6 (d, J = 18.1 Hz), 131.5 (d, J = 6.6 Hz), 130.5 (2 C), 128.9,
128.7, 128.4–128.0 (6 C), 127.7, 127.6, 127.5, 127.3 (3 C), 126.0,
20.8 ppm. 31P NMR (CDCl3, 161 MHz): δ = –13.7 ppm. HRMS:
calcd. for C31H25P [M + H] 429.1767; found 429.1742.
(3Ј-Methyl-[1,1Ј;2Ј,1ЈЈ]terphenyl-2ЈЈ-yl)diphenylphosphine (4)
2,2Ј-Dibromo-6-iodobiphenyl (8): At –78 °C, BuLi (47.2 mmol,
1 equiv.) in hexanes (30.5 mL) was added to a solution of 2,2Ј,6-
tribromo-1,1Ј-biphenyl[53,44] (1; 47.2 mmol, 18.4 g, 1 equiv.) in THF
(94.0 mL). The mixture was consecutively treated with iodine
(47.2 mL, 12.0 g, 1 equiv.) in THF (50.0 mL) and allowed to reach
25 °C. Then, the mixture was treated with a saturated aqueous
solution of ammonium chloride (50.0 mL). The mixture was ex-
tracted with ethyl acetate (3ϫ100 mL), and the combined organic
layers were dried with sodium sulfate. After concentration of the
solvent, the residue was purified by chromatography on silica gel
Dicyclohexyl[2-(5-methylbenzo[1,3]dioxol-4-yl)phenyl]phosphine (5)
4-(2-Bromophenyl)-5-methylbenzo[1,3]dioxole (12): At –78 °C, but-
yllithium (33.0 mmol, 1 equiv.) in hexanes was added dropwise to
a solution of 5-bromo-4-(2-bromophenyl)benzo[1,3]dioxole[44] (11;
11.8 g, 33.0 mmol) in THF (150 mL). After the addition was com-
pleted, iodomethane (5.2 g, 2.3 mL, 36.3 mmol) was added drop-
6522
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6515–6525

Modular Synthesis of Biaryl-Substituted Phosphine Ligands
wise and the reaction mixture was then allowed to reach 25 °C.
Water (80.0 mL) was added, followed by extraction with ethyl acet-
ate (3ϫ80.0 mL). The combined organic layers were dried with
sodium sulfate, filtered, and the solvents evaporated. Purification
by flash chromatography afforded 4-(2-bromophenyl)-5-meth-
(c) C–N Coupling Reaction by Microwave Irradiation: A flame-dried
microwave reaction vial was charged with Pd(OAc)2 (2 mol-%), li-
gand (3 mol-%), base (1.5 equiv.), aryl halide (1 equiv.), amine
(1.2 equiv.), and solvent (2 mL). The reaction mixture was degassed
with argon and the vial heated to 160 °C for the given time in a
microwave reactor. After completion of the reaction, diethyl ether
(5 mL) was added and the reaction mixture filtered through a pad
of Celite. The filtrate was concentrated under vacuum. Purification
1
ylbenzo[1,3]dioxole (12; 95%) as a colorless oil. H NMR (CDCl3,
300 MHz): δ = 7.61 (dd, J = 7.5, 1.0 Hz, 1 H), 7.31 (td, J = 7.0,
8.1 Hz, 1 H), 7.3–7.1 (m, 2 H), 6.7–6.6 (m, 2 H), 5.9–5.7 (m, 2 H),
1.95 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 145.6, 137.0, by column chromatography gave pure compounds.
133.3, 131.7, 130.1, 130.3, 129.8, 127.8, 124.6, 123.3, 122.5, 108.2,
101.5, 19.5 ppm. HRMS: calcd. for C14H11BrO2 [M + Na]
312.9835; found 312.9846.
Characterization Data for the C–N Coupling Products
N,N-Dibutylaniline: (Table 2, Entries 1, 2, and 3)[66] Colorless oil.
1H NMR (CDCl3, 200 MHz): δ = 7.08–7.27 (m, 2 H), 6.51–6.73
Dicyclohexyl[2-(5-methylbenzo[1,3]dioxol-4-yl)phenyl]phosphine (5):
(m, 3 H), 3.10–3.39 (m, 4 H), 1.46–1.68 (m, 4 H), 1.20–1.46 (m, 4
At –78 °C, butyllithium (2.00 mmol, 1 equiv.) in hexanes was added
dropwise to a solution of 4-(2-bromophenyl)-5-methylbenzo[1,3]di-
oxole (12; 2.00 mmol, 0.58 g) in THF (4.00 mL). After 1 h, a solu-
tion of chlorodicyclohexylphosphine (0.51 g, 0.49 mL, 2.20 mmol,
1.1 equiv.) in toluene (2.00 mL) was added dropwise. After 1 h, the
mixture was allowed to reach 25 °C and filtered through silica gel
with diethyl ether. The organic layer was evaporated and the crude
product was purified by chromatography on silica gel. Trituration
from methanol afforded dicyclohexyl[2-(5-methyl-benzo[1,3]dioxol-
4-yl)phenyl]phosphine (5; 63%) as a colorless powder, m.p. 128–
130 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.6–7.4 (m, 1 H), 7.4–
7.2 (m, 2 H), 7.2–7.0 (m, 1 H), 6.7–6.5 (m, 2 H), 5.82 (d, J = 1.5 Hz,
1 H), 5.71 (s, 1 H), 1.93 (s, 3 H), 1.7–1.4 (m, 12 H), 1.3–0.8 (m, 10
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 144.3, 144.3, 143.7,
142.4, 142.0, 131.9 (d, J = 3.3 Hz), 129.3 (d, J = 6 Hz), 128.8, 127.7,
126.1, 120.9, 106.3, 99.5, 33.6 (d, J = 12.1 Hz), 32.0 (d, J =
12.6 Hz), 29.0 (d, J = 8.8 Hz), 29.1, 29.0, 28.9, 28.8, 28.7, 28.5,
28.1, 28.0, 26.7, 26.6, 26.5, 26.5, 26.3, 26.2, 26.1, 25.4, 18.9 (d, J =
5.5 Hz) ppm. 31P NMR (CDCl3, 161 MHz): δ = –8.0 ppm. HRMS:
calcd. for C26H33O2P [M + H] 409.2291; found 409.2272.
H), 0.81–1.07 ppm (m, 6 H). 13C NMR (CDCl3, 50 MHz): δ =
148.2, 129.1, 115.1, 111.7, 77.6, 76.4, 50.8, 29.4, 20.4, 14.0 ppm.
GC–MS: m/z = 05.18 [M]+.
N,N-Dibutyl-3-fluoro-4-methylaniline: (Table 2, Entry 4) Colorless
1
liquid. H NMR [(CD3)2SO, 400 MHz]: δ = 6.98 (t, J = 8.9 Hz, 1
H), 6.27–6.40 (m, 2 H), 3.16–3.25 (m, 4 H), 2.07 (s, 3 H), 1.46
(quin, J = 7.5 Hz, 4 H), 1.26–1.36 (m, 4 H), 0.91 ppm (t, J = 7.3 Hz,
6 H) 13C NMR [(CD3)2SO, 101 MHz]: δ = 131.6, 131.6, 107.4, 98.3,
98.0, 49.9, 28.9, 19.6, 13.9, 13.1 ppm. HRMS: m/z calcd. for
C15H25NF [M]+ 238.1967; found 238.1966.
3-Fluoro-4-methyl-N,N-diphenylaniline: (Table 2, Entry 5) Colorless
1
solid, m.p. 93–94 °C. H NMR (CDCl3, 500 MHz): δ = 7.26–7.22
(m, 4 H), 7.07 (d, J = 7.6 Hz, 4 H), 7.04–6.99 (m, 3 H), 6.77–6.71
(m, 2 H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 162.6, 160.6,
147.5, 131.5, 131.5, 129.3, 124.3, 123.0, 119.2, 118.8, 118.6, 110.7,
110.5, 14.0 ppm. HRMS: m/z calcd. for C19H17NF [M]+ 278.1340;
found 278.1310.
1-Phenylpyrrolidine: (Table 2, Entry 6)[66] Colorless liquid. 1H
NMR (C6D6, 400 MHz): δ = 7.25–7.38 (m, 2 H), 6.76–6.87 (m, 1
H), 6.48–6.59 (m, 2 H), 2.82–2.98 (m, 4 H), 1.47 ppm. (dt, J = 6.6,
3.3 Hz, 4 H) ppm. 13C NMR (C6D6, 101 MHz): δ = 148.5, 129.6,
128.2, 127.9, 116.1, 112.3, 47.6, 25.6 ppm. GC–MS: m/z = 47.10
[M]+.
C–N Coupling Reactions
General Procedure for the Palladium-Catalyzed C–N Coupling Re-
actions
(a) Coupling Reaction of Secondary Amines and Aryl Halides by
Conventional Heating: In an oven-dried two-neck round-bottomed
flask Pd(OAc)2 (2 mol-%), ligand (3 mol-%), and base (1.5 equiv.)
were purged by high vacuum/backfilling with argon 3 times. Sub-
sequently, the aryl halide (1 equiv.), secondary amine (1.2 equiv.),
and solvent were added by syringe through a septum and the reac-
tion mixture heated to reflux in a preheated oil bath. Completion
of the reaction was monitored by thin layer chromatography by
using a mixture of ethyl acetate and petroleum ether as eluent. Af-
ter completion of the reaction, diethyl ether (5 mL) was added and
the reaction mixture filtered through a pad of Celite. The filtrate
was concentrated under vacuum. Purification by column
chromatography gave pure compounds.
1-(2-Methoxyphenyl)pyrrolidine: (Table 2, Entry 7)[67] Colorless li-
quid. 1H NMR (CD3OD, 500 MHz): δ = 6.93 (d, J = 4.9 Hz, 1 H),
6.81–6.90 (m, 3 H), 3.84 (s, 3 H), 3.24 (ddd, J = 6.6, 4.1, 2.7 Hz, 4
H), 1.94 ppm (dt, J = 6.7, 3.4 Hz, 4 H). 13C NMR (CD3OD,
126 MHz): δ = 152.5, 141.1, 122.3, 122.0, 117.3, 113.3, 56.2, 51.9,
25.5 ppm. GC–MS: m/z = 77.11 [M]+.
1-Phenylindoline: (Table 2, Entry 8)[68] Colorless solid, m.p. 50–
52 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.46–7.60 (m, 1 H), 7.30–
7.46 (m, 2 H), 6.91–7.25 (m, 5 H), 6.67–6.84 (m, 1 H), 3.97 (t, J =
8.5 Hz,
2 H), 3.14 ppm (t, J = 8.4 Hz, 2
H). 13C NMR
(CD3OD,126 MHz): δ = 156.0, 153.2, 140.8, 138.7, 136.5, 134.6,
130.2, 128.3, 126.8, 117.2, 61.1, 37.0 ppm. GC–MS: m/z = 95.10
[M]+.
(b) Coupling Reaction of Primary Amines and Aryl Halides by Con-
ventional Heating: In an oven-dried two-neck round-bottomed flask
Pd(OAc)2 (2 mol-%), ligand (3 mol-%), base (1.5 equiv.), aryl halide
(1 equiv.), primary amine (1.2 equiv.), and the solvent were de-
gassed with argon. The reaction mixture was heated to reflux in a
preheated oil bath for the given time. Completion of the reaction
was monitored by thin layer chromatography by using a mixture of
ethyl acetate and petroleum ether as eluent. After completion of the
reaction, diethyl ether (5 mL) was added and the reaction mixture
filtered through a pad of Celite. The filtrate was concentrated under
vacuum. Purification by column chromatography gave pure com-
pounds.
4-Phenylmorpholine: (Table 2, Entry 9)[24] Colorless solid, m.p. 53–
54 °C. 1H NMR (CD3OD, 500 MHz): δ = 7.25 (t, J = 7.0 Hz, 2
H), 6.97 (d, J = 7.9 Hz, 2 H), 6.86 (t, J = 6.7 Hz, 1 H), 3.83 (br.
s., 4 H), 3.12 ppm (br. s., 4 H). 13C NMR (CD3OD, 126 MHz): δ
= 153.0, 130.2, 121.4, 117.2, 68.1, 49.3 ppm. GC–MS: m/z = 63.09
[M]+.
2-Methoxy-N-methyl-N-phenylaniline: (Table 2, Entry 10)[69] Color-
1
less liquid. H NMR (CDCl3, 500 MHz): δ = 7.25–7.43 (m, 5 H),
7.02–7.12 (m, 2 H), 6.82 (t, J = 7.3 Hz, 1 H), 6.76 (d, J = 8.2 Hz,
2 H), 3.88 (s, 3 H), 3.33 ppm (s, 3 H). 13C NMR (CDCl3,126 MHz):
δ = 156.0, 149.4, 136.8, 129.1, 128.7, 126.9, 121.3, 117.1, 113.4,
Eur. J. Org. Chem. 2015, 6515–6525
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C. Singh, J. Rathod, V. Jha, A. Panossian, P. Kumar, F. R. Leroux
FULL PAPER
112.6, 77.3, 76.7, 55.6, 55.6, 39.0 ppm. GC–MS: m/z = 13.11 [M]+.
2,4,6-Trimethyl-N-phenylaniline: (Table 4, Entry 9) Brown crystal-
line solid, m.p. 48–50 °C. 1H NMR (CDCl3, 400 MHz): δ = 7.17
(t, J = 7.5 Hz, 2 H), 6.97 (s, 2 H), 6.75 (t, J = 7.0 Hz, 1 H), 6.52
(d, J = 8.3 Hz, 2 H), 5.13 (br. s., 1 H), 2.34 (s, 3 H), 2.21 ppm (s,
6 H). 13C NMR (CDCl3, 101 MHz): δ = 146.6, 135.9, 135.5, 135.4,
129.2, 117.8, 113.2, 20.9, 18.2 ppm. GC–MS: m/z = 11.13 [M]+.
N,N-Dibutyl-4-methoxyaniline: (Table 2, Entry 11)[70] Colorless li-
1
quid. H NMR (CD3OD, 400 MHz): δ = 6.65–6.84 (m, 4 H), 3.71
(s, 3 H), 3.07–3.19 (m, 4 H), 1.40–1.52 (m, 4 H), 1.21–1.39 (m, 8
H), 0.88–0.95 ppm (m, 6 H). 13C NMR (CD3OD, 101 MHz): δ =
117.7, 115.8, 56.3, 53.6, 30.7, 21.6, 14.5 ppm. GC–MS: m/z = 35.19
[M]+.
4-Chloro-N-phenylaniline: (Table 4, Entry 10)[63] Colorless solid,
1
m.p. 68–69 °C. H NMR (C6D6, 500 MHz): δ = 7.15 (br. s., 1 H),
1
N,N-Diethylaniline: (Table 2, Entry 12) Colorless liquid. H NMR
7.08 (t, J = 7.9 Hz, 2 H), 6.83 (t, J = 7.5 Hz, 1 H), 6.70–6.76 (m,
J = 8.5 Hz, 2 H), 6.39–6.48 (m, J = 8.5 Hz, 2 H), 4.78 ppm (br. s.,
1 H). 13C NMR (C6D6, 126 MHz): δ = 143.1, 143.0, 132.7, 129.9,
122.1, 119.7, 118.9, 113.1 ppm. GC–MS: m/z = 03.05 [M]+.
[(CD3)2SO, 400 MHz]: δ = 7.06–7.19 (m, 2 H), 6.64 (d, J = 8.1 Hz,
2 H), 6.54 (t, J = 7.2 Hz, 1 H), 3.31 (q, J = 7.0 Hz, 4 H), 1.07 ppm
(t, J = 7.0 Hz, 6 H). 13C NMR [(CD3)2SO, 101 MHz]: δ = 147.4,
129.1, 114.8, 111.5, 43.5, 12.4 ppm. GC–MS: m/z = 49.12 [M]+.
N,NЈ-Diphenylbenzene-1,4-diamine: (Table 4, Entry 11)[73] Colorless
1
1
N-Methyl-N-phenylaniline: (Table 2, Entry 13) Colorless liquid. H
solid, m.p. 144–146 °C. H NMR (C6D6, 400 MHz): δ = 7.09–7.15
(m, 4 H), 6.71–6.89 (m, 10 H), 4.92 ppm (br. s., 2 H). 13C NMR
(C6D6, 101 MHz): δ = 145.3, 137.9, 121.5, 120.5, 117.1 ppm. GC–
MS: m/z = 60.15 [M]+.
NMR (C6D6, 500 MHz): δ = 7.11 (t, J = 7.9 Hz, 4 H), 6.93 (d, J
= 7.9 Hz, 4 H), 6.85 (t, J = 7.3 Hz, 2 H), 2.91 ppm (s, 3 H). 13C
NMR (C6D6, 126 MHz): δ = 149.9, 129.8, 128.7, 128.6, 128.3,
128.2, 121.9, 121.2, 40.4 ppm. GC–MS: m/z = 83.10 [M]+.
3-Fluoro-4-methyl-N-phenylaniline: (Table 4, Entry 12) Colorless li-
1
quid. H NMR [(CD3)2SO, 500 MHz]: δ = 8.24 (s, 1 H), 7.20–7.28
N-Methyl-4-nitro-N-phenylaniline: (Table 2, Entry 14) Yellow solid,
1
(m, 2 H), 7.05–7.13 (m, 3 H), 6.75–6.89 (m, 3 H), 2.14 ppm (s, 3
H). 13C NMR [(CD3)2SO, 126 MHz]: δ = 162.5, 160.6, 143.9, 143.8,
143.7, 143.4, 132.3, 132.2, 129.7, 129.6, 120.6, 120.1, 117.6, 117.2,
114.8, 114.6, 112.8, 112.8, 103.4, 103.2, 13.9, 13.9 ppm. HRMS:
m/z calcd. for C13H13NF [M]+ 202.1027; found 202.1028.
m.p. 152–154 °C. H NMR [(CD3)2SO, 400 MHz]: δ = 8.53 (br. s.,
1 H), 8.41 (d, J = 9.0 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 1 H), 7.23–
7.45 (m, 2 H), 6.96–7.23 (m, 3 H), 3.47 ppm (s, 3 H). 13C NMR
(CDCl3, 50 MHz): δ = 147.3, 146.2, 130.0, 127.8, 126.1, 123.3,
123.1, 121.1, 42.5 ppm. GC–MS: m/z = 28.07 [M]+.
N-Hexylaniline: (Table 4, Entry 13) Colorless liquid. 1H NMR
(CDCl3,200 MHz): δ = 7.04–7.30 (m, 2 H), 6.37–6.87 (m, 3 H),
2.98–3.23 (m, 2 H), 1.52–1.73 (m, 2 H), 1.29–1.46 (m, 6 H), 0.87–
0.94 ppm (m, 3 H). 13C NMR (CDCl3, 50 MHz): δ = 147.9, 129.2,
117.6, 113.2, 44.4, 31.6, 29.3, 26.8, 22.6, 14.0 ppm. GC–MS: m/z =
77.29 [M]+.
Diphenylamine: (Table 4, Entries 1, 2, and 3) Colorless solid, m.p.
48–50 °C. 1H NMR (CDCl3, 200 MHz): δ = 7.25–7.43 (m, 4 H),
7.07–7.20 (m, 4 H), 6.93–7.04 (m, 2 H), 5.86 ppm (br. s., 1 H). 13C
NMR (CDCl3, 50 MHz): δ = 142.96, 129.25, 120.91, 117.13 ppm.
GC–MS: m/z = 69.08 [M]+.
4-Methoxy-N-phenylaniline: (Table 4, Entry 4) Colorless solid, m.p.
1
98–99 °C. H NMR [(CD3)2SO, 400 MHz]: δ = 7.82 (s, 1 H), 7.15
Acknowledgments
(t, J = 7.8 Hz, 2 H), 6.99–7.07 (m, 2 H), 6.82–6.94 (m, 4 H), 6.70
(t, J = 7.2 Hz, 1 H), 3.71 ppm (s, 3 H). 13C NMR [(CD3)2SO,
101 MHz]: δ = 153.8, 145.1, 136.1, 129.1, 120.4, 118.2, 114.8, 114.5,
55.2, ppm. HRMS: m/z calcd. for C13H14ON [M]+ 200.1070; found
200.1069.
C. S. and V. J. thank the Indo-French Centre for the Promotion of
Advanced Research (CEFIPRA/IFCPAR), New Delhi for financial
support in the form of fellowships and through project number
5005-2. J. R. thanks the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for a Junior Research Fellowship. The
French Centre National de la Recherche Scientifique (CNRS) is
acknowledged for financial support.
Bis(4-methoxyphenyl)amine: (Table 4, Entry 5)[71] Colorless solid,
1
m.p. 99–100 °C. H NMR [(CD3)2SO, 500 MHz]: δ = 7.51 (s, 1 H),
6.87–6.95 (m, 4 H), 6.77–6.84 (m, 4 H), 3.68 ppm (s, 6 H). 13C
NMR [(CD3)2SO, 126 MHz]: δ = 152.8, 138.0, 118.0, 114.5,
55.2 ppm. GC–MS: m/z = 29.11 [M]+.
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2-Isopropyl-N-phenylaniline: (Table 4, Entry 6)[72] Yellow liquid. H
NMR (CDCl3, 200 MHz): δ = 6.99–7.36 (m, 6 H), 6.79–6.90 (m, 3
H), 5.39 (br. s., 1 H), 3.15 (sept, J = 6.8 Hz, 1 H), 1.24 (d, J =
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1
line solid, m.p. 45–46 °C. H NMR (CDCl3, 200 MHz): δ = 7.02–
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6524
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Eur. J. Org. Chem. 2015, 6515–6525

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Received: July 22, 2015
Published Online: August 26, 2015
Eur. J. Org. Chem. 2015, 6515–6525
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