Pd-PEPPSI-IPentAn Promoted Deactivated Amination of Aryl Chlorides with Amines under Aerobic Conditions

Article abstract of DOI:10.1021/acs.joc.8b01205

We report herein a highly efficient Pd-catalyzed amination by "bulky-yet-flexible" Pd-PEPPSI-IPent^An complexes. The relationship between the N-heterocyclic carbenes (NHCs) structure and catalytic properties was discussed. Sterically hindered (hetero)aryl chlorides and a variety of aliphatic and aromatic amines can be applied in this cross-coupling, which smoothly proceeded to provide desired products. The operationally simple protocol highlights the rapid access to C_Ar-N bond formation under mild conditions without the exclusion of air and moisture.

Full text of DOI:10.1021/acs.joc.8b01205

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Article
Pd-PEPPSI-IPentAn Promoted Deactivated Amination of
Aryl Chlorides with Amines under Aerobic Conditions
Fei-Dong Huang, Chang Xu, Dong-Dong Lu, Dong-Sheng Shen, Tian Li, and Feng-Shou Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01205 • Publication Date (Web): 10 Jul 2018
Downloaded from http://pubs.acs.org on July 10, 2018
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PdꢀPEPPSIꢀIPentAn Promoted Deactivated Amination of Aryl Chlorides with Amines under
Aerobic Conditions
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Fei-Dong Huang,† Chang Xu,† Dong-Dong Lu,† Dong-Sheng Shen,† Tian Li, † and Feng-Shou Liu*‡
† School of Chemistry and Chemical Engineering, Guangdong Cosmetics Engineering & Technology
Research Center, Guangdong Pharmaceutical University, Zhongshan, Guangdong, 528458, China
Correspondence authors: FengꢀShou Liu, Eꢀmail: fengshou2004@126.com.
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TOC
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ABSTRACT:
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We report herein
a
highly efficient Pdꢀcatalyzed amination by “bulkyꢀyetꢀflexible”
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PdꢀPEPPSIꢀIPentAn complexes. The relationship between the Nꢀheterocyclic carbenes (NHCs)
structure and catalytic properties was discussed. Sterically hindered (hetero)aryl chlorides and a
variety of aliphatic and aromatic amines can be applied in this crossꢀcoupling, which smoothly
proceeded to provide desired products. The operationally simple protocol highlights the rapid access
to CArꢀN bond formation under mild conditions without the exclusion of air and moisture.
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Introduction
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(Hetero)aryl amines presented important structural moieties in a large amount of
pharmaceuticals (eg. Sprycel, Rilpivirine, Brexpiprazole, Buspar, etc), bioactive molecules (eg.
R116010, RAF709, etc) and functional materials (eg. Hole transport for OLED in Figure 1).1 The
metalꢀcatalyzed crossꢀcoupling reactions have provided concise routes for constructing such target
molecular scaffolds.2ꢀ4 Among them, the Pdꢀcatalyzed BuchwaldꢀHartwig amination reaction has
been well established as the generally employed process with wide substrate scopes under mild
reaction conditions.4, 5
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Figure 1. Heteroarylated amines in pharmaceuticals, bioactive compounds and hole transport
materials.
In the past two decades, the classes of privileged ligands including sterically demanding and
electronꢀrich phosphines have been well developed and remarkable progress has been achieved in
these catalytic systems.4ꢀ6 Nevertheless, the search for phosphineꢀfree ligands is highly desirable
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from the environmental and economical viewpoint.7 Alternatively, Nꢀheterocyclic carbenes (NHCs)
have emerged as one of the most powerful phosphineꢀfree ligands in the Pdꢀcatalyzed crossꢀcoupling
reactions.8 The group of Nolan firstly demonstrated the wellꢀdefined PdꢀNHC complexes to generate
the aryl amines when aryl chlorides were used as electrophlic substrates.9 Subsequently, Organ
developed a new type of PdꢀPEPPSIꢀNHCs (PEPPSI: pyridineꢀenhanced precatalyst preparation,
stabilization, and initiation), which could mediate CꢀN bond formation at a low palladium loading,
even under room temperature.10 Afterward, numerous versatile PdꢀNHCs have been disclosed to be
effective in the arylation of amines with aryl chlorides. 11
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Despite these compelling advances in phosphineꢀfree catalyst design, several drawbacks still
limit their utility. First, the transformation is highly challenging when hindered aryl chlorides and
sterically demanding anilines or heterocyclic amines were selected as coupling partners in air
conditions.8, 12 The catalytic processes generally need strict oxygenꢀ and moistureꢀfree operation,
whereas trace of oxygen would trap the LPd(0) to form the unreactive LPd(O2).13 To ensure the
stabilization of the lowꢀvalent active species in aerobic conditions, the ligand with bulky substituted
groups is required.14 On the contrary, the placement of bulky steirc ligand would retard the oxidative
addition and subsequent amine coordination. Second, the fiveꢀmembered heterocyclic aryl chlorides
(especially with sulfide unit), represented the most difficult coupling substrates and there have only
been a few examples of catalyst systems that have successfully coupled this type of substrates to
date.15 Presumably, it can be ascribed to the feasible coordination of heteroatoms to the palladium
center and also reluctantly undergo reductive elimination of the Pd(II) amido complexes.16 In order
to prevent catalyst poisoning process, the introduction of NHCs with strong σꢀdonation group is of
great interest and importance.11c, 11e Very recently, we have reported a series of PdꢀPEPPSI complexes
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with ancenaphthyl as backbones.14e, 17 These palladium complexes showed promise for coupling of
sterically demanding coupling partners in the SuzukiꢀMiyaura crossꢀcoupling and BuchwaldꢀHartwig
amination in air. Considering the strong σꢀdonation and the conformational flexibility of the
PdꢀPEPPSI complexes, we envisioned that the “bulkyꢀyetꢀflexible” palladium complexes would act
as practical and modular precatalysts to extend the utility in amination reaction.18, 19 Herein, we
report a new strategy for the challenging CArꢀN bond formation by this approach.
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RESULTS AND DISCUSSION
Synthesis and Characterization of PdꢀPEPPSI complex
The synthesis of the PdꢀPEPPSIꢀIPentAn complex of C1 was followed by the previously
reported procedure.18 An oneꢀpot reaction of imidazolium chloride salt with PdCl2 was heated in the
presence of pyridine and K2CO3, affording the PdꢀPEPPSIꢀIPentAn complex in a high yield of 85%.
The palladium complex is moistureꢀ and airꢀstable either in the solid or in solution state and thus can
be stored on benchtop for several months at r.t. The chemical structure of C1 was characterized by
high resolution mass spectrometer (HRMS) and NMR spectroscopy, for which the peak at
m/z=880.3351 being evidence to the cationic species of [M+H]+. Moreover, the formation of
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PdꢀCcarbene bond was confirmed by the disappearance of the imidazolium proton signal in the H
NMR spectrum and the observed resonance of 159.5 ppm in the 13C NMR spectrum.
Xꢀray diffraction analysis was conducted on single crystal of C1 obtained by slow diffusion of
hexane into their concentrated solution in CH2Cl2. As shown in Figure 2, it revealed a slightly
distorted square planar geometry for the palladium complex, in which the carbene ligand was
positioned trans to pyridine. The bond length of PdꢀC(6) and PdꢀN(1) bond lengths are 1.966 (5) and
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2.107 (4) Å, respectively, which are comparable to that of the reported PdꢀPEPPSI complex (Table
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1).11b, 13, 17bꢀd, 18 It is noteworthy that the Nꢀaryl moieties derived from carbene ligand are oriented
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nearly perpendicularly to the coordination plane with dihedral angles of 79.41 and 84.15 ,
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respectively. These results suggest that the bulky alkyl chain would effectively protect the palladium
center. In order to further examine the steric property of the synthesized complex, the percent buried
volume (%Vbur) was then calculated using the application of SambVca.20, 21 As illustrated in Table 1,
the PdꢀPEPPSIꢀIPentAn complex of C1 with pyridine as “throw away” ligand presents a moderate
value of 36.1, which is notably higher than that of the PdꢀPEPPSIꢀIPr (34.3) and PdꢀPEPPSIꢀIPrAn
(34.7). Out of our expectation, the %Vbur value of the PdꢀPEPPSIꢀIPentAn complex C2 with
3ꢀchloropyridine ligand turned out to be 38.2, which is much larger than the value of C1
.
Considering bearing the same carbene ligand, the remarkable difference between the percent buried
volume computed for C1 and C2 highlights the flexibility of the IPentAn ligand, which would play
profound effect on the catalytic performance.
Table 1. Comparison of structural parameters in classical Pd–PEPPSI complexes.a
b
Pd–PEPPSI complexes PdꢀC (Å)
PdꢀN (Å)
1.966 (5) 2.107 (4)
1.965(2) 3.0926(17) 2041.6
TEP (cmꢀ1) %Vbur
IPentAn (Py) C1
IPentAn (3ꢀClPy) C2
IPent C3
2041.6
36.1
38.2
37.9
43.1
34.3
34.7
35.7
41.1
1.974 (3) 2.097 (3)
1.974 (6) 2.132 (6)
1.969 (3) 2.109 (2)
1.960 (6) 2.113 (6)
2049.6
2052.7
2050.2
2041.8
NR
IPr* C4
IPr C5
IPrAn C6
(IPr(OMe)*IPr)An C7
(IPr**)An C8
1.963(2)
1.953(6)
2.162(2)
2.076(6)
2047.4
aAll bond distances and %VBur have been calculated using cif files obtained from the CCDC.
bThe %VBur calculated for PdꢀC=2.00 Å. Mesh spacing 0.05 Å. Sphere radius 3.5Å. Bondi radii
scaled by 1.17.
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Figure 2. Molecular structure of C1 depicted in 30% thermal ellipsoids with the hydrogen atoms
omitted for clarity. Selected bond distances (Å) and angles (o): Pd(1)ꢀC(6) 1.966(5), Pd(1)ꢀN(1)
2.107(4), Pd(1)ꢀCl(1) 2.3049(14), Pd(1)ꢀCl(2) 2.2782(14), N(1)ꢀPd(1)ꢀC(6) 177.97(19),
N(1)ꢀPd(1)ꢀCl(1)
91.30(12),
C(6)ꢀPd(1)ꢀCl(1)
90.70(15),
N(1)ꢀPd(1)ꢀCl(2)
88.66(12),
C(6)ꢀPd(1)ꢀCl(2) 89.34(15), Cl(1)ꢀPd(1)ꢀCl(2) 178.84(6).
Application in the Pdꢀcatalyzed amination of aryl chlorides
In an effort to demonstrate the catalytic properties of the “bulkyꢀyetꢀflexible” palladium
complexes, the crossꢀcoupling were carried out in air and the solvents were used as received without
any further purification. Our investigation began by treating 2ꢀchloroꢀ1,3ꢀdimethylbenzene (1a) with
2,6ꢀdiisopropylaniline (2a). After the reaction condition evaluation (see SI, Table S2 for details), we
were delighted to find that the optimized conditions was 0.5 mol% palladium loading, KOtBu as base
and 1,4ꢀdioxane as solvent at 100 °C for 2 h. Under these conditions, the expected
Nꢀ(2,6ꢀdiisopropylphenyl)ꢀ2,6ꢀdimethylaniline (3a) was obtained in a satisfied isolated yield of 92%
by PdꢀPEPPSIꢀIPentAn (C1). Nevertheless, it is deserved to note that the current reaction conditions
without anhydrous solvents and the protection of inert gas, requires high temperature and moderate
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high palladium loading. Moreover, the effect of the “throw away” ligands was also investigated. In
the current study, C2 bearing 3ꢀchloropyridine was slightly less effective than that of C1 with
pyridine. Presumably, the pyridine might remain attached to the NHCꢀPd(0), which could stabilized
the Pd(0) active species.
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Table 2. Catalyst Screening for the Pdꢀcatalyzed Amination Reactiona
aReaction conditions: 2ꢀchloroꢀ1,3ꢀdimethylbenzene (1.0 mmol), 2,6ꢀdiisopropylaniline (1.2
mmol), KOtBu (1.5 mmol), 1,4ꢀdioxane (4.0 mL), in air. GC yields. bIsolated yields.
To get further information on the relationship between the catalyst structure and activities, a
series of palladium complexes, such as the PdꢀPEPPSIꢀIPent (C3),18b PdꢀPEPPSIꢀIPr*(C4),13a
PdꢀPEPPSIꢀIPr (C5),18a PdꢀPEPPSIꢀIPrAn(C6),11b PdꢀPEPPSIꢀ(IPrOMe*IPr)An (C7),14e and
PdꢀPEPPSIꢀ(IPr**)An (C8),17d were screened for comparison. As illustrated in Table 2, the
precatalysts of PdꢀPEPPSIꢀIPent (C3) and PdꢀPEPPSIꢀIPr (C5), which were highly efficient under
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inert atmosphere (Table S3), however, afforded the desired amination product 3a in 60% and 33%
yield, respectively. Even more, the PdꢀPEPPSIꢀIPr* (C4) was much less efficient to give the cross
coupling product in 9% yield under the current reaction conditions. Obviously, the steric and the
electronic effect of NHCs ligand would play a crucial role. The C4 bearing 2,6ꢀdibenzhydryl group
on Nꢀaryl moieties exhibited largest %Vbur value of 43.3, implying less flexibility of the ligands
around to the palladium center would retard the oxidative addition and subsequent amine
coordination. In contrast, the introduction of bulky steric of IPentAn in C1 and C2 would stabilize the
axial site of LPd(0) species to avoid the capture of oxygen. Meanwhile, the maintained configuration
flexibility of the alkyl group on Nꢀaryl moieties would allow the room adjustment toward the
incoming substrates.17b Moreover, in our previous report, we found that the Tolman electronic
parameter (TEP) for IPentAn is 2041.6 cmꢀ1, which indicates higher electronꢀdonating ability than
that of other classical PdꢀNHCs, such as PdꢀPEPPSIꢀIPent (C3) and PdꢀPEPPSIꢀIPr (C5).10b
Therefore, the rate of oxidative addition would be much faster than oxidative addition of O2 by
PdꢀPEPPSIꢀIPentAn in this study. Then the palladium complexes of C6ꢀC8 with the same acenaphthyl
backbones were evaluated. The palladium complexes C6 and C7 showed moderate activity of 41 and
56% yield, whereras their Vbur% value turned out to be 34.7 and 35.7, respectively. Again, the bulky
sterically C8 (Vbur% = 41.1) gave the product of 3a in a low yield of 8%. These results suggest that
the catalytic activity toward deactivated substrates under aerobic conditions is mainly controlled by
the supporting backbones as well as Nꢀmoieties on the NHCs ligand, which demonstrated that the
“bulkyꢀyetꢀflexible” PdꢀPEPPSIꢀIPentAn would significantly promote the transformation process.
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Having established the promising results of the PdꢀPEPPSIꢀIPentAn (C1), we then examined the
reaction of 2ꢀchloroꢀ1,3ꢀdimethylbenzene (1a) with other primary amines. As shown in Table 3, a
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range of sterically hindered aliphatic and aromatic amines, such as 2,6ꢀdiisopropylaniline,
2,6ꢀdiethylaniline, 2,6ꢀdimethylaniline and 1ꢀadamantylamine, were exclusively affording the
corresponding products (3aꢀd) in high yields by using only 0.1ꢀ0.5 mol% palladium. It is significant
that the electronꢀdeficient 2,6ꢀdifluoroaniline and 2,4,6ꢀtrifluoroaniline, which are considered to be
the most challenging coupling partners,10c can be installed in moderate yields. Other primary alkyl
amines containing hexyl, benzylic, octyl, 2ꢀfurylmethyl and iophenethyl were all converted to
desired products (3gꢀ3k) in high to quantitative yields. Moreover, other electronꢀrich electrophilic
reagents, such as 2ꢀchloroꢀ1,3,5ꢀtrimethylbenzene and 2ꢀchloroꢀ5ꢀmethoxyꢀ1,3ꢀdimethylbenzene,
which are sluggish toward oxidative addition, were smoothly coupled with sterically demanding
anilines. To our delight, the undesired byproduct of diarylated amines weren’t observed in our
catalytic systems.22
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Table 3. CꢀN CrossꢀCoupling Reaction of Stercially Hindered Aryl Chlorides with
amines.a
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aReaction conditions: aryl chloride (1.0 mmol), amine (1.2 mmol), KOtBu (1.5 mmol), 1,4ꢀdioxane
(4.0 mL), in air. Isolated yields.
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Fiveꢀmembered heteroaryl chlorides, especially with multiple heteroatoms have been
recognized as the most challenging substrates in the CꢀN crossꢀcoupling for a long time.7a Inspired by
the aforementioned encouraging results, we extended our protocol to the synthesis of sulfideꢀbased
arylated amines because of the increased prevalence of such motifs in biologically active molecules
and functional materials. As can be seen in Table 4, in the presence of relative high palladium
loading of 0.2ꢀ2 mol%, the sulfide containing aryl chlorides, such as 2ꢀchlorobenzo[d]thiazole and
3ꢀchlorothiophene could be incorporated into the amine substrates to give the corresponding products
(such as 4aꢀ4d) in high yields. Importantly, the most deactivated 2ꢀchlorothiazole exhibited excellent
reactivity toward a wide range of substituted amines. For example, the aryl anilines with 2ꢀmethyl
and 4ꢀflroroꢀsubstitutents were successfully converted (4e and 4f). It is noteworthy that
2ꢀ(4ꢀaminophenyl)ethanꢀ1ꢀol with protic functional group, was successfully coupled and nearly
quantitative yield was afforded in product of 4g, which would enable the opportunity to be used in
further transformations. Moreover, other primary and secondary amines bearing functional groups,
such as hexyl, benzylic, piperidinyl, dibutyl, 4ꢀphenylpiperazinyl, Nꢀmethylcyclohexyl, and
Nꢀmethylphenyl were suitable crossꢀcoupling partners, giving the desired products (4hꢀ4n) in high
yields. Then, we investigated the reactivity of the heteroarylamine (such as 2ꢀaminopyridine) with
2ꢀchlorothiazole, unfortunately, no reaction was performed even in the presence of 5 mol%
palladium loading after 24 hours. Probably, 2ꢀaminopyridine would act as a competing ligand and
inhibits the catalyst activity.16b
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To further highlight the robust palladium complex of C1, other heteroaryl chlorides, such as
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5ꢀchlorobenzo[b]thiophene,
2ꢀchlorobenzo[d]oxazole,
5ꢀchlorobenzo[d][1,3]dioxole,
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2ꢀchloropyridine, 3ꢀchloropyridine, 2ꢀchloroquinoline, 2ꢀchloroꢀ1,3,5ꢀtriazine, 2ꢀchloroquinoxaline,
2ꢀchloropyrimidine were evaluated (Table 4). To our delight, at a low palladium loading of 0.1ꢀ0.2
mol %, the desired products of 4pꢀ4ac were obtained in high to excellent yields. Remarkably, the
application of this protocol was further featured by the rapid access to network prescription drug of
Piribedil (4ad), which is received as an important antiparkinsonian agent and α2ꢀadrenergic
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antagonist.
Table 4. CꢀN CrossꢀCoupling Reaction of Heteroryl Chlorides with amines.a
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Reaction conditions: Heterocyclic Chloride (1.0 mmol), amine (1.2 mmol), KOtBu (1.5
mmol), 1,4ꢀdioxane (4.0 mL). Isolated yields, in air.
CONCLUSION
In summary, we have developed an efficient protocol for versatile CꢀN cross coupling by
bulkyꢀyetꢀflexible PdꢀPEPPSIꢀIPentAn complex. This methodology can circumvent the classic
problem emerged limited substrate scopes as well as the requirement of strict oxygenꢀ and
moistureꢀfree reaction operation. Under the developed reaction conditions, a wide range of sterically
hindered (hetero)aryl chlorides could be coupled with various aliphatic and aromatic amines with
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different electronic and steric groups, which enable the reaction to proceed in high yields.
Considering the potential toxicology and environmental problem arised from 1,4ꢀdioxane, further
studies exploring the environmental, health and safety solvents for CꢀN crossꢀcouplings are
undergoing.
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EXPERIMENTAL SECTION
1. Physical Measurements and Materials
The NMR spectra were recorded on a Bruker DMX 400 MHz instrument at room temperature
with the decoupled nucleus, employing TMS as an internal standard and CDCl3 as solvent. Elemental
analysis was carried out using a Flash EA1112 microanalyzer. High resolution mass spectrometric
(HRMS) data were obtained using a LTQ Orbitrap Elite instrument, using a sample concentration of
approximately 1 ppm. The Xꢀray diffraction data of single crystals were obtained with the ωꢀ2θ scan
mode on a Bruker SMART 1000 CCD diffractionmeter with graphiteꢀmonochromated Mo Kα
radiation (λ=0.71073Å) at 100 K for C1. Cell parameters were obtained by global refinement of the
positions of all collected reflections. Intensities were corrected for Lorentz and polarization effects
and empirical absorption. The structures were solved by direct methods and refined by fullꢀmatrix
least squares on F2. All hydrogen atoms were placed in calculated positions. Structure solution and
refinement were performed by using the SHELXLꢀ97 package. All nonꢀhydrogen atoms were refined
anisotropically. Hydrogen atoms were introduced in calculated positions with the displacement
factors of the host carbon atoms. Wattecs Parallel Reactor (WPꢀTECꢀ1020H) was equipped with 10
o
tubes × 10 (mL); Power: 650 w; Temperature range: rtꢀ220 C; Polytetrafluoroethylene (PTFE) as
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sealed material.
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2. The Procedures for the Synthesis of PdꢀPEPPSI complex of C1.
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Imidazolium chloride salt of L1 and PdꢀPEPPSI compound C2 were reported by our group.17b,
23 A mixture of imidazolium salt L1 (1 mmol), palladium dichloride (0.177 g, 1.1 mmol), and K2CO3
(1.38 g, 10 mmol) in pyridine (4 mL) was added to a vial under a nitrogen atmosphere. The reaction
was refluxed at 90°C for 24 h. When the solution was cooled to room temperature, 20 mL of
dichloromethane was added, and then the reaction mixture was passed through a short silica gel
column using substantial dichloromethane as elute. Evaporation of the filtrate furnished a
yellowꢀbrown solid. The yellowꢀbrown solid was dissolved completely with suitable
dichloromethane, and dropped into a large amount of stirring hexane, causing the formation of a
yellow precipitate. The suspension was filtered through a sintered funnel. Drying the solid in vacuo
1
produced the desired palladium complex of C1 as yellow powders in 86% yield (758.8 mg). H
NMR (400 MHz, CDCl3) δ 8.60 – 8.53 (m, 2H), 7.62 (d, J = 8.2 Hz, 2 H), 7.50 (dd, J = 13.5, 5.8 Hz,
3 H), 7.32 (d, J = 7.8 Hz, 4 H), 7.23 (dd, J = 11.1, 4.0 Hz, 2 H), 7.06 (dd, J = 7.6, 6.5 Hz, 2 H), 6.62
(d, J = 7.0 Hz, 2 H), 3.23 (td, J = 9.0, 5.5 Hz, 4 H), 2.00 – 1.76 (m, 8 H), 1.33 (ddd, J = 14.1, 7.5, 3.6
Hz, 4 H), 1.22 – 1.10 (m, 4 H), 1.06 (d, J = 7.2 Hz, 12 H), 0.45 (t, J = 7.4 Hz, 12 H). 13C NMR (101
MHz, CDCl3) δ 159.5, 151.5, 144.6, 140.6, 137.2, 135.5, 129.4, 128.9, 128.8, 127.9, 126.9, 126.8,
126.5, 124.0, 121.6, 40.7, 26.4, 26.2, 12.4, 9.8. Anal.calcd for C50H61N3Cl2Pd: C, 68.14; H, 6.98; N,
4.77. Found: C, 67.95; H, 7.04; N, 4.72. HRMS calcd for C50H62N3Cl2Pd [M + H]+ 880.3350, found
880.3351.
3. General Procedure for Buchwald−Hartwig Amination
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Unless otherwise noted, the amination reactions were carried out in air. All solvents were used
as received without further purification. A parallel reactor containing a stirred bar was charged with
PdꢀPEPPSI complexes (0.001−0.02 mmol), amine (1.2 mmol), aryl chloride (1.0 mmol), base (1.5
mmol), and 4 mL of solvent. The reaction mixture was conducted at 100 °C for 2 h. After completion
of the reaction, the reaction mixture was cooled to room temperature, and 20 mL of water was added.
The mixture was diluted with dichloromethane (5 mL) and extracted three times (3 × 5 mL) with
dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered, and
evaporated under reduce pressure. The crude crossꢀcoupling products were purified by silicaꢀgel
column chromatography using petroleum etherꢀdichloromethane (20/1) as the eluent
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4. NMR data of the crossꢀcoupling products.
Nꢀ(2,6ꢀdiisopropylphenyl)ꢀ2,6ꢀdimethylaniline (3a).24a The crossꢀcoupling product was isolated in
92% yield (258.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.19 – 7.11 (m, ArꢀH, 3 H), 6.96 (d, J = 7.5 Hz,
ArꢀH, 2 H), 6.75 (t, J = 7.4 Hz, ArꢀH, 1 H), 4.82 (s, NH, 1 H), 3.18 (dt, J = 13.7, 6.9 Hz, CH, 2 H),
2.00 (s, CH3, 6 H), 1.14 (d, J = 6.9 Hz, CH3, 12 H). 13C NMR (101 MHz, CDCl3) δ 144.1, 143.1,
138.8, 129.5, 125.6, 124.8, 123.2, 119.6, 28.0, 23.4, 19.3.
Nꢀ(2,6ꢀdiethylphenyl)ꢀ2,6ꢀdimethylaniline (3b).24b The crossꢀcoupling product was isolated in 98%
yield (248.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.12 – 6.99 (m, ArꢀH, 5H), 6.83 (t, J = 7.4 Hz, ArꢀH,
1 H), 4.93 (s, NH, 1 H), 2.48 (q, J = 7.5 Hz, CH2, 4 H), 2.03 (s, CH3, 6 H), 1.17 (t, J = 7.5 Hz, CH3, 6
H). 13C NMR (101 MHz, CDCl3) δ 142.1, 140.4, 136.9, 129.0, 127.6, 126.1, 123.0, 120.6, 24.8, 19.2,
13.8.
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Bis(2,6ꢀdimethylphenyl)amine (3c).17c The crossꢀcoupling product was isolated in 95% yield (214.1
mg). 1H NMR (400 MHz, CDCl3) δ 7.04 – 7.00 (m, ArꢀH, 4 H), 6.91 – 6.86 (m, ArꢀH, 2 H), 4.84 (s,
NH, 1 H), 2.05 (s, CH3, 12 H). 13C NMR (101 MHz, CDCl3) δ 141.7, 129.5, 128.7, 121.7, 19.1.
(3s,5s,7s)ꢀNꢀ(2,6ꢀdimethylphenyl)adamantanꢀ1ꢀamine (3d).24c The crossꢀcoupling product was
isolated in 95% yield (242.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.4 Hz, ArꢀH, 2 H),
6.93 – 6.85 (m, ArꢀH, 1 H), 2.37 (s, CH3, 6 H), 2.05 (s, CH, 3 H), 1.78 (d, J = 2.7 Hz, CH2, 6 H),
1.67 – 1.56 (m, CH2, 6 H). 13C NMR (101 MHz, CDCl3) δ 143.0, 134.7, 128.3, 122.9, 55.5, 44.3,
36.4, 30.1, 20.6.
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Nꢀ(2,6ꢀdifluorophenyl)ꢀ2,6ꢀdimethylaniline (3e). The crossꢀcoupling product was isolated in 81%
yield (188.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.08 (s, ArꢀH, 3 H), 6.87 – 6.79 (m, ArꢀH, 2 H),
6.71 – 6.64 (m, ArꢀH, 1 H), 5.08 (s, NH, 1 H), 2.26 (s, CH3, 6 H). 13C NMR (101 MHz, CDCl3) δ
152.8 (dd, J = 242.6, 7.0 Hz), 139.0, 135.2, 128.0, 125.55, 124.2 (t, J = 12.5 Hz), 117.1 (t, J = 9.2
Hz), 112.0 – 110.8(m), 18.5. HRMS calcd for C14 H14 N F2 [M + H]+ 234.1089, found 234.1084 .
Nꢀ(2,6ꢀdimethylphenyl)ꢀ2,4,6ꢀtrifluoroaniline (3f). The crossꢀcoupling product was isolated in 77%
yield (193.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.10 – 7.00 (m, ArꢀH, 3H), 6.71 – 6.57 (m, ArꢀH, 2
H), 4.86 (s, NH, 1 H), 2.23 (s, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ 154.3 (dt, J = 240.9, 14.7
Hz), 152.8 (ddd, J = 244.8, 14.2, 9.1 Hz), 139.1, 134.5, 128.2, 125.3, 120.8 (td, J = 12.9, 4.5 Hz),
100.2 (ddd, J = 26.2, 18.7, 9.7 Hz), 18.4. HRMS calcd for C14 H13 N F3 [M + H]+ 252.0995, found
252.0989 .
Nꢀcyclohexylꢀ2,6ꢀdimethylaniline (3g).25a The crossꢀcoupling product was isolated in 98% yield
(199.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.4 Hz, ArꢀH, 2 H), 6.81 (t, J = 7.4 Hz, ArꢀH,
1 H), 2.98 (t, J = 3.7 Hz, CH, 1 H), 2.29 (s, CH3, 6 H), 1.99 (dd, J = 12.3, 2.0 Hz, CH2, 2 H), 1.76
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(dd, J = 9.6, 3.3 Hz, CH2, 2 H), 1.65 (d, J = 11.0 Hz, CH2, 1 H), 1.34 – 1.20 (m, CH2, 3 H), 1.14 (dd,
J = 15.5, 6.5 Hz, CH2, 2 H). 13C NMR (101 MHz, CDCl3) δ 145.1, 128.9, 128.7, 121.1, 56.1, 34.9,
25.9, 25.5, 19.0
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Nꢀbenzylꢀ2,6ꢀdimethylaniline (3h).25b The crossꢀcoupling product was isolated in 99% yield (209.2
mg). 1H NMR (400 MHz, CDCl3) δ 7.44 – 7.38 (m, ArꢀH, 4 H), 7.37 – 7.32 (m, ArꢀH, 1 H), 7.08 (d,
J = 7.2 Hz, ArꢀH, 2 H), 6.95 – 6.88 (m, ArꢀH, 1 H), 4.17 (d, J = 1.8 Hz, CH2, 2 H), 2.34 (d, J = 1.9
Hz, CH3, 6 H). 13C NMR (101 MHz, CDCl3) δ 145.8, 140.4, 129.8, 128.8, 128.5, 127.9, 127.2, 122.1,
52.8, 18.4.
2,6ꢀDimethylꢀNꢀoctylaniline (3i).25c The crossꢀcoupling product was isolated in 90% yield (210.1
mg). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 7.5 Hz, ArꢀH, 2 H), 6.83 (t, J = 7.5 Hz, ArꢀH, 1 H),
3.01 – 2.97 (m, CH2, 2 H), 2.31 (s, CH3, 6 H), 1.59 (dd, J = 14.7, 7.7 Hz, CH2, 2 H), 1.35 (dd, J =
17.1, 9.5 Hz, CH2, 10 H), 0.91 (t, J = 6.9 Hz, CH3, 3 H).13C NMR (101 MHz, CDCl3) δ 146.4, 129.0,
128.7, 121.5, 48.7, 31.8, 31.2, 29.5, 29.3, 27.2, 22.6, 18.5, 14.1.
Nꢀ(furanꢀ2ꢀylmethyl)ꢀ2,6ꢀdimethylaniline (3j).26a The crossꢀcoupling product was isolated in 71%
yield (142.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.37 (m, ArꢀH, 1 H), 7.02 (d, J = 7.4 Hz,
ArꢀH, 2 H), 6.87 (t, J = 7.5 Hz, ArꢀH, 1 H), 6.32 (dd, J = 3.1, 1.9 Hz, ArꢀH, 1 H), 6.12 (d, J = 3.1 Hz,
ArꢀH, 1 H), 4.15 (s, CH2, 2 H), 2.29 (s, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ 153.7, 145.1,
141.8, 130.0, 128.7, 122.4, 110.3, 106.8, 45.1, 18.2.
2,6ꢀDimethylꢀNꢀ(2ꢀ(thiophenꢀ2ꢀyl)ethyl)aniline (3k).26b The crossꢀcoupling product was isolated in
89% yield (205.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 5.1, 1.2 Hz, ArꢀH, 1 H), 7.03
(ddd, J = 7.7, 6.0, 1.8 Hz, ArꢀH, 3 H), 6.94 (dd, J = 3.4, 1.0 Hz, ArꢀH, 1 H), 6.90 – 6.85 (m, ArꢀH, 1
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H), 3.35 (t, J = 6.7 Hz, CH2, 2 H), 3.15 (t, J = 6.7 Hz, CH2, 2 H), 2.24 (s, CH3, 6 H). 13C NMR (101
MHz, CDCl3) δ 145.5, 142.0, 129.2, 128.8, 126.9, 125.4, 123.8, 121.8, 49.4, 31.1, 18.3.
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Nꢀ(2,6ꢀdimethylphenyl)ꢀ2,4,6ꢀtrimethylaniline (3l).24a The crossꢀcoupling product was isolated in
90% yield (215.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 7.4 Hz, ArꢀH, 2 H), 6.87 – 6.82 (m,
ArꢀH, 3 H), 4.76 (s, NH, 1 H), 2.30 (s, CH3, 3 H), 2.04 (d, J = 1.7 Hz, CH3, 12 H).13C NMR (101
MHz, CDCl3) δ 142.2, 139.0, 131.5, 130.5, 129.2, 128.8, 128.4, 120.9, 20.6, 19.1, 19.0.
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Dimesitylamine (3m).26c The crossꢀcoupling product was isolated in 97% yield (245.8 mg). H
NMR (400 MHz, CDCl3) δ 6.88 – 6.79 (m, ArꢀH, 4 H), 4.66 (s, NH, 1 H), 2.29 (s, CH3, 6 H), 2.02 (s,
CH3, 12 H).13C NMR (101 MHz, CDCl3) δ 139.4, 130.7, 129.4, 129.3, 20.5, 19.0.
Nꢀ(4ꢀmethoxyꢀ2,6ꢀdimethylphenyl)naphthalenꢀ1ꢀamine (3n). The crossꢀcoupling product was
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isolated in75% yield (208.0 mg). H NMR (400 MHz, CDCl3) δ 8.07 – 8.04 (m, ArꢀH, 1 H), 7.87 –
7.83 (m, ArꢀH, 1 H), 7.54 – 7.50 (m, ArꢀH, 2 H), 7.28 (d, J = 8.1 Hz, ArꢀH, 1 H), 7.23 – 7.19 (m,
ArꢀH, 1 H), 6.74 (s, ArꢀH, 2 H), 6.18 (dd, J = 7.5, 1.1 Hz, ArꢀH, 1 H), 5.64 (s, NH, 1 H), 3.84 (s,
CH3, 3 H), 2.20 (s, CH3, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ 157.3, 142.0, 137.4, 134.5, 131.3,
128.7, 126.6, 125.7, 124.8, 123.4, 120.1, 118.0, 113.7, 106.1, 55.3, 18.4. HRMS calcd for C19H20ON
[M + H]+ 278.1539, found 278.1538.
Nꢀ(2,6ꢀdiisopropylphenyl)ꢀ4ꢀmethoxyꢀ2,6ꢀdimethylaniline (3o).27a The crossꢀcoupling product
was isolated in 92% yield (286.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.12ꢀ7.09 (m, ArꢀH, 2 H), 7.05
(dd, J = 8.9, 5.9 Hz, ArꢀH, 1 H), 6.56 (s, ArꢀH, 2 H), 5.30 (s, NH, 1 H), 3.77 (s, OCH3, 3 H), 3.08 (dt,
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J = 13.7, 6.8 Hz, CH, 2 H), 2.01 (s, CH3, 6 H), 1.12 (d, J = 6.9 Hz, 12 H). C NMR (101 MHz,
CDCl3) δ 153.9, 141.5, 139.7, 136.5, 129.9, 123.4, 123.0, 114.4, 55.4, 27.8, 23.5 19.5.
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Nꢀ(2,6ꢀdiethylphenyl)ꢀ4ꢀmethoxyꢀ2,6ꢀdimethylaniline (3p). The crossꢀcoupling product was
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isolated in 99% yield (280.6 mg). H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 7.5 Hz, ArꢀH, 2 H),
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7.5 Hz, CH2, 4 H), 2.07 (s, CH3, 6 H), 1.17 (t, J = 7.5 Hz, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ
154.6, 141.4, 135.2, 133.9, 132.0, 126.3, 121.1, 113.8, 55.3, 24.7, 19.4, 13.7. HRMS calcd for
C19H26ON [M + H]+ 284.2009, found 284.2008.
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Nꢀ(2,6ꢀdimethylphenyl)ꢀ4ꢀmethoxyꢀ2,6ꢀdimethylaniline (3q). The crossꢀcoupling product was
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isolated in 98% yield (250.2 mg). H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 7.4 Hz, ArꢀH, 2 H),
6.80 (t, J = 7.4 Hz, ArꢀH, 1 H), 6.64 (s, ArꢀH, 2 H), 4.73 (s, NH, 1 H), 3.83 (s, OCH3, 3 H), 2.11 (s,
CH3, 6 H), 2.04 (s, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ 155.3, 142.7, 134.7, 133.8, 129.0,
126.6, 119.9, 113.4, 55.2, 19.3, 19.1. HRMS calcd for C17H22ON [M + H]+ 256.1696, found
256.1694.
Nꢀ(2,6ꢀdimethoxyphenyl)ꢀ4ꢀmethoxyꢀ2,6ꢀdimethylaniline (3r). The crossꢀcoupling product was
isolated in 89% yield (255.7 mg). 1H NMR (400 MHz, CDCl3) δ 6.72 (dd, J = 8.7, 7.7 Hz, ArꢀH, 1
H), 6.62 – 6.55 (m, ArꢀH, 4 H), 5.28 (s, NH, 1 H), 3.80 (s, OCH3, 3 H), 3.65 (s, OCH3, 6 H), 2.20 (s,
CH3, 6 H). 13C NMR (101 MHz, CDCl3) δ 156.1, 148.8, 136.8, 134.8, 127.1, 117.3, 112.4, 106.0,
56.5, 55.2, 19.08. HRMS calcd for C17H22O3N [M + H]+ 288.1594, found 288.1594.
4ꢀ(Benzo[d]thiazolꢀ2ꢀyl)morpholine (4a).27b The crossꢀcoupling product was isolated in 97% yield
(213.7 mg). 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.55 (m, ArꢀH, 2 H), 7.31 (td, J = 7.8, 1.2 Hz,
ArꢀH, 1 H), 7.10 (td, J = 7.9, 1.1 Hz, ArꢀH, 1 H), 3.86 – 3.82 (m, CH2, 4 H), 3.65 – 3.60 (m, CH2, 4
H).13C NMR (101 MHz, CDCl3) δ 169.0, 152.5, 130.5, 126.1, 121.7, 120.8, 119.3, 66.2, 48.5.
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2ꢀThiomorpholinobenzo[d]thiazole (4b).27c The crossꢀcoupling product was isolated in 96% yield
(226.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 7.9, 0.8 Hz, ArꢀH, 1 H), 7.54 (dd, J = 8.1,
0.5 Hz, ArꢀH, 1 H), 7.30 (td, J = 7.8, 1.3 Hz, ArꢀH, 1 H), 7.08 (td, J = 7.8, 1.1 Hz, ArꢀH, 1 H), 4.02 –
3.91 (m, CH2, 4 H), 2.80 – 2.69 (m, CH2, 4 H). 13C NMR (101 MHz, CDCl3) δ 168.1, 152.6, 130.6,
126.0, 121.5, 120.7, 119.1, 51.2, 26.5.
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NꢀmethylꢀNꢀphenylbenzo[d]thiazolꢀ2ꢀamine (4c).27d The crossꢀcoupling product was isolated in 93%
yield (223.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, ArꢀH, 1 H), 7.53 – 7.41 (m,
ArꢀH, 5 H), 7.37 – 7.28 (m, ArꢀH, 2 H), 7.08 (t, J = 7.6 Hz, ArꢀH, 1 H), 3.65 (s, CH3, 3 H).13C NMR
(101 MHz, CDCl3) δ 168.2, 152.6, 145.7, 131.1, 129.9, 127.4, 125.9, 125.8, 121.7, 120.4, 119.1,
40.4.
4ꢀ(Thiophenꢀ3ꢀyl)morpholine (4d).28a The crossꢀcoupling product was isolated in 90% yield (152.3
mg). 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 5.2, 3.1 Hz, ArꢀH, 1 H), 6.85 (dd, J = 5.3, 1.6 Hz,
ArꢀH, 1 H), 6.19 (dd, J = 3.1, 1.6 Hz, ArꢀH, 1 H), 3.85 – 3.81 (m, CH2, 4 H), 3.10 – 3.05 (m, CH2, 4
H).13C NMR (101 MHz, CDCl3) δ 152.3, 125.5, 119.5, 100.3, 66.6, 50.6.
Nꢀ(oꢀtolyl)thiazolꢀ2ꢀamine (4e).28b The crossꢀcoupling product was isolated in 89% yield (169.3
mg). 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, ArꢀH, 1 H), 7.24 (dd, J = 7.8, 4.2 Hz, ArꢀH,
3 H), 7.08 (t, J = 7.4 Hz, ArꢀH, 1 H), 6.58 (d, J = 3.6 Hz, ArꢀH, 1 H), 2.32 (s, CH3, 3 H).13C NMR
(101 MHz, CDCl3) δ 167.5, 139.0, 138.8, 131.1, 129.3, 127.1, 124.5, 120.5, 107.5, 17.8.
Nꢀ(4ꢀfluorophenyl)thiazolꢀ2ꢀamine (4f).28c The crossꢀcoupling product was isolated in 98% yield
(190.3 mg). 1H NMR (400 MHz, CDCl3) δ 8.98 (s, ArꢀH, 1 H), 7.37 – 7.31 (m, ArꢀH, 2 H), 7.27 (d, J
= 3.5 Hz, ArꢀH, 1 H), 7.10 – 7.02 (m, ArꢀH, 2 H), 6.60 (d, J = 3.7 Hz, ArꢀH, 1 H).13C NMR (101
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MHz, CDCl3) δ 167.0, 158.8 (d, J = 242.7 Hz), 138.5, 136.9 (d, J = 2.5 Hz), 120.6 (d, J = 7.9 Hz),
116.2 (d, J = 22.7 Hz), 107.1.
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Nꢀ(4ꢀfluorophenyl)thiazolꢀ2ꢀamine (4g). The crossꢀcoupling product was isolated in 99% yield
(218.1 mg). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 3.8 Hz, ArꢀH, 1 H), 7.05 (d, J = 8.4 Hz, ArꢀH,
2 H), 6.64 (dt, J = 8.9, 2.2 Hz, ArꢀH, 3 H), 4.54 (t, J = 7.1 Hz, CH2, 2 H), 3.00 (t, J = 7.1 Hz, CH2, 2
H).13C NMR (101 MHz, CDCl3) δ 175.0, 144.9, 136.8, 129.8, 127.3, 115.2, 110.9, 72.4, 34.3.
HRMS calcd for C11H12ON2NaS [M + Na]+ 243.0562, found 243.0561.
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Nꢀcyclohexylthiazolꢀ2ꢀamine (4h).28d The crossꢀcoupling product was isolated in 98% yield (178.6
mg). 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 3.6 Hz, ArꢀH, 1 H), 6.45 (d, J = 3.6 Hz, ArꢀH, 1 H),
5.38 – 5.28 (m, NH, 1 H), 3.41 – 3.29 (m, CH, 1 H), 2.09 (dd, J = 12.5, 2.9 Hz, CH2, 2 H), 1.78 –
1.59 (m, CH2, 3 H), 1.37 (dd, J = 13.1, 11.6 Hz, CH2, 2 H), 1.25 (dd, J = 7.4, 4.0 Hz, CH2, 3 H).13C
NMR (101 MHz, CDCl3) δ 169.5, 138.9, 105.9, 55.0, 33.1, 25.5, 24.7.
Nꢀbenzylthiazolꢀ2ꢀamine (4i).29a The crossꢀcoupling product was isolated in 75% yield (142.7 mg).
1H NMR (400 MHz, CDCl3) δ 7.40 – 7.28 (m, ArꢀH, 5 H), 7.06 (d, J = 3.6 Hz, ArꢀH, 1 H), 6.48 (d, J
= 3.6 Hz, ArꢀH, 1 H), 5.95 (s, NH, 1 H), 4.47 (s, CH2, 2 H). 13C NMR (101 MHz, CDCl3) δ 170.2,
139.0, 137.5, 128.7, 127.7, 127.7, 106.7, 49.9.
2ꢀ(Piperidinꢀ1ꢀyl)thiazole (4j).29b The crossꢀcoupling product was isolated in 95% yield (159.8 mg).
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 3.6 Hz, ArꢀH, 1 H), 6.50 (d, J = 3.7 Hz, ArꢀH, 1 H), 3.46
– 3.42 (m, CH2, 4 H), 1.69 – 1.61 (m, CH2, 6 H).13C NMR (101 MHz, CDCl3) δ 172.5, 139.4, 106.5,
49.7, 25.0, 24.1.
N,Nꢀdibutylthiazolꢀ2ꢀamine (4k).29c The crossꢀcoupling product was isolated in 99% yield (210.2
mg). 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 3.7 Hz, ArꢀH, 1 H), 6.40 (d, J = 3.7 Hz, ArꢀH, 1 H),
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3.41 – 3.37 (m, CH2, 4 H), 1.62 (ddd, J = 7.5, 6.0, 3.9 Hz, CH2, 4 H), 1.34 (dd, J = 15.1, 7.5 Hz, CH2,
4H), 0.93 (t, J = 7.4 Hz, CH3, 6 H).13C NMR (101 MHz, CDCl3) δ 170.9, 139.5, 105.1, 51.3, 29.3,
20.1, 13.9.
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2ꢀ(4ꢀPhenylpiperazinꢀ1ꢀyl)thiazole (4l). The crossꢀcoupling product was isolated in 98% yield
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(240.4mg). H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, ArꢀH, 2 H), 7.23 (d, J = 3.6 Hz, ArꢀH, 1
H), 7.01 – 6.96 (m, ArꢀH, 2 H), 6.92 (t, J = 7.3 Hz, ArꢀH, 1 H), 6.61 (d, J = 3.6 Hz, ArꢀH, 1 H), 3.65
(dd, J = 6.1, 4.3 Hz, CH2, 4 H), 3.31 (dd, J = 6.2, 4.2 Hz, CH2, 4 H).13C NMR (101 MHz, CDCl3) δ
172.1, 151.0, 139.5, 129.2, 120.5, 116.7, 107.7, 48.9, 48.5. HRMS calcd for C13H16N3S [M + H]+
246.1059, found 246.1058.
NꢀcyclohexylꢀNꢀmethylthiazolꢀ2ꢀamine (4m). The crossꢀcoupling product was isolated in 99%
yield (194.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 3.7 Hz, ArꢀH, 1 H), 6.43 (d, J = 3.7 Hz,
ArꢀH, 1 H), 3.91 – 3.83 (m, CH, 1 H), 2.93 (s, CH3, 3 H), 1.86 – 1.80 (m, CH2, 4 H), 1.70 – 1.64 (m,
CH2, 1 H), 1.49 – 1.35 (m, CH2, 4 H), 1.11 (dd, J = 12.7, 3.3 Hz, CH2, 1 H).13C NMR (101 MHz,
CDCl3) δ 171.7, 139.4, 105.2, 59.9, 32.3, 29.8, 25.7, 25.5. HRMS calcd for C10H17N2S [M + H]+
197.1107, found 197.1105
NꢀmethylꢀNꢀphenylthiazolꢀ2ꢀamine (4n).29b The crossꢀcoupling product was isolated in 97% yield
(184.6 mg). 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 6.2, 4.3 Hz, ArꢀH, 4 H), 7.29 – 7.20 (m,
ArꢀH, 2 H), 6.47 (d, J = 3.7 Hz, ArꢀH, 1 H), 3.53 (s, CH3, 3 H).13C NMR (101 MHz, CDCl3) δ 170.7,
146.4, 139.3, 129.6, 126.2, 124.8, 107.4, 40.3.
1ꢀ(Benzo[b]thiophenꢀ5ꢀyl)ꢀ4ꢀphenylpiperazine (4o). The crossꢀcoupling product was isolated in 73%
yield (214.9 mg). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, ArꢀH, 1 H), 7.34 (d, J = 5.4 Hz,
ArꢀH, 1 H), 7.28 (d, J = 2.3 Hz, ArꢀH, 1 H), 7.26 – 7.21 (m, ArꢀH, 2 H), 7.18 (d, J = 5.4 Hz, ArꢀH, 1
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H), 7.07 (dd, J = 8.8, 2.3 Hz, ArꢀH, 1 H), 6.94 (dd, J = 8.7, 0.9 Hz, ArꢀH, 2 H), 6.83 (dd, J = 10.5,
4.1 Hz, ArꢀH, 1 H), 3.34 – 3.26 (m, CH2, 8 H). 13C NMR (101 MHz, CDCl3) δ 151.2, 149.1, 140.7,
132.2, 129.2, 127.1, 123.7, 122.8, 120.1, 116.9, 116.4, 110.0, 50.6, 49.5. HRMS calcd for C18H19N2S
[M + H]+ 295.1263, found 295.1262.
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NꢀcyclohexylꢀNꢀmethylbenzo[d]oxazolꢀ2ꢀamine (4p).30a The crossꢀcoupling product was isolated
in 99% yield (228.0 mg). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.8 Hz, ArꢀH, 1 H), 7.23 (d, J =
7.9 Hz, ArꢀH, 1 H), 7.13 (t, J = 7.7 Hz, ArꢀH, 1 H), 6.97 (t, J = 7.7 Hz, ArꢀH, 1 H), 4.17 – 4.08 (m,
CH, 1 H), 3.06 (s, CH3, 3 H), 1.88 – 1.81 (m, CH2, 4 H), 1.70 (d, J = 12.8 Hz, CH2, 1 H), 1.56 – 1.42
(m, CH2, 4 H), 1.19 – 1.08 (m, CH2, 1 H).13C NMR (101 MHz, CDCl3) δ 162.7, 148.6, 143.5, 123.7,
119.9, 115.7, 108.4, 56.7, 29.9, 29.5, 25.6, 25.4.
4ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)morpholine (4q).30b The crossꢀcoupling product was isolated in 71%
yield (147.1 mg). 1H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 8.4 Hz, ArꢀH, 1 H), 6.54 (d, J = 2.4 Hz,
ArꢀH, 1 H), 6.34 (dd, J = 8.4, 2.4 Hz, ArꢀH, 1 H), 5.89 (s, CH2, 2 H), 3.85 – 3.81 (m, CH2, 4 H), 3.04
– 3.00 (m, CH2, 4 H). 13C NMR (101 MHz, CDCl3) δ 148.2, 147.3, 141.6, 108.5, 108.1, 100.8, 99.5,
66.9, 50.9.
4ꢀ(3ꢀMethylpyridinꢀ2ꢀyl)morpholine (4r).31a The crossꢀcoupling product was isolated in 80% yield
(142.6 mg). 1H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 4.8, 1.3 Hz, ArꢀH, 1 H), 7.44 – 7.39 (m,
ArꢀH, 1 H), 6.88 (dd, J = 7.3, 4.9 Hz, ArꢀH, 1 H), 3.88 – 3.84 (m, CH2, 4 H), 3.17 – 3.13 (m, CH2, 4
H), 2.29 (s, CH3, 3 H). 13C NMR (101 MHz, CDCl3) δ 161.4, 145.4, 139.4, 124.8, 118.1, 67.2, 50.0,
18.3.
1ꢀ(6ꢀMethylpyridinꢀ2ꢀyl)ꢀ4ꢀphenylpiperazine (4s). The crossꢀcoupling product was isolated in 99%
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yield (250.8 mg). H NMR (400 MHz, CDCl3) δ 7.46 – 7.40 (m, ArꢀH, 1 H), 7.32 (t, J = 7.7 Hz,
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ArꢀH, 2 H), 7.01 (d, J = 8.5 Hz, ArꢀH, 2 H), 6.92 (td, J = 7.3, 0.7 Hz, ArꢀH, 1 H), 6.53 (dd, J = 14.2,
7.8 Hz, ArꢀH, 2 H), 3.74 – 3.69 (m, CH2, 4 H), 3.35 – 3.30 (m, CH2, 4 H), 2.45 (s, CH3, 3 H). 13C
NMR (101 MHz, CDCl3) δ 159.1, 156.8, 151.3, 137.7, 129.1, 119.9, 116.3, 112.9, 103.8, 49.2, 45.3,
24.5. HRMS calcd for C16H20N3 [M + H]+ 254.1652, found 254.1651.
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4ꢀ(Pyridinꢀ2ꢀyl)morpholine (4t).31b The crossꢀcoupling product was isolated in 93% yield (152.7
mg). 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 4.9, 1.2 Hz, ArꢀH, 1 H), 7.49 (ddd, J = 8.9, 7.2, 2.0
Hz, ArꢀH, 1 H), 6.69 – 6.60 (m, ArꢀH, 2 H), 3.84 – 3.79 (m, CH2, 4 H), 3.51 – 3.46 (m, CH2, 4 H).
13C NMR (101 MHz, CDCl3) δ 159.6, 147.9, 137.5, 113.8, 106.9, 66.7, 45.6.
4ꢀ(6ꢀMethoxypyridinꢀ2ꢀyl)morpholine (4u).31c The crossꢀcoupling product was isolated in 95%
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yield (184.5 mg). H NMR (400 MHz, CDCl3) δ 7.41 (t, J = 8.0 Hz, ArꢀH, 1 H), 6.12 (dd, J = 9.4,
8.0 Hz, ArꢀH, 2 H), 3.86 (s, OCH3, 3 H), 3.83 – 3.79 (m, CH2, 4 H), 3.49 – 3.45 (m, CH2, 4 H). 13C
NMR (101 MHz, CDCl3) δ 163.0, 158.3, 140.1, 98.7, 97.9, 66.7, 52.9, 45.5.
6ꢀMorpholinonicotinonitrile (4v).32a The crossꢀcoupling product was isolated in 93% yield (176.0
mg). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 1.8 Hz, ArꢀH, 1 H), 7.63 (dd, J = 9.0, 2.3 Hz, ArꢀH,
1 H), 6.58 (d, J = 8.8 Hz, ArꢀH, 1 H), 3.81 – 3.76 (m, CH2, 4 H), 3.66 – 3.61 (m, CH2, 4 H). 13C
NMR (101 MHz, CDCl3) δ 159.5, 152.6, 139.9, 118.4, 105.6, 96.9, 66.4, 44.6.
NꢀmethylꢀNꢀphenylpyridinꢀ2ꢀamine (4w).32b The crossꢀcoupling product was isolated in 99% yield
(182.4 mg). 1H NMR (400 MHz, CDCl3) δ 8.27 – 8.21 (m, ArꢀH, 1 H), 7.41 (t, J = 7.6 Hz, ArꢀH, 2
H), 7.33 – 7.20 (m, ArꢀH, 4 H), 6.63 – 6.59 (m, ArꢀH, 1 H), 6.54 (d, J = 8.6 Hz, ArꢀH, 1 H), 3.48 (s,
CH3, 3 H). 13C NMR (101 MHz, CDCl3) δ 158.8, 147.7, 146.8, 136.5, 129.6, 126.3, 125.4, 113.1,
109.1, 38.4.
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mg). H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 2.7 Hz, ArꢀH, 1 H),
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11.1, 5.6 Hz, CH2, 4 H), 1.57 (dd, J = 11.0, 5.7 Hz, CH2, 2 H). 13C NMR (101 MHz, CDCl3) δ
147.6, 139.9, 138.8, 123.3, 122.5, 49.8, 25.4, 24.0.
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N,Nꢀdibutylpyridinꢀ3ꢀamine (4y).32d The crossꢀcoupling product was isolated in 83% yield (171.3
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mg). H NMR (400 MHz, CDCl3) δ 8.06 (s, ArꢀH, 1 H), 7.87 (d, J = 3.7 Hz, ArꢀH, 1 H), 7.07 (dd, J
= 8.5, 4.5 Hz, ArꢀH, 1 H), 6.87 (ddd, J = 8.6, 3.1, 1.2 Hz, ArꢀH, 1 H), 3.28 – 3.24 (m, CH2, 4 H),
1.59 – 1.52 (m, CH2, 4 H), 1.35 (dd, J = 15.0, 7.5 Hz, CH2, 4 H), 0.95 (t, J = 7.3 Hz, CH3, 6 H). 13C
NMR (101 MHz, CDCl3) δ 143.9, 136.4, 134.5, 123.5, 117.7, 50.4, 29.2, 20.2, 13.9.
2ꢀ(4ꢀMethylpiperazinꢀ1ꢀyl)quinolone (4z).33a The crossꢀcoupling product was isolated in 82% yield
(186.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.1 Hz, ArꢀH, 1 H), 7.70 (d, J = 8.4 Hz, ArꢀH,
1 H), 7.59 (dd, J = 8.0, 1.2 Hz, ArꢀH, 1 H), 7.56 – 7.50 (m, ArꢀH, 1 H), 7.25 – 7.20 (m, ArꢀH, 1 H),
6.99 (d, J = 9.1 Hz, ArꢀH, 1 H), 3.82 – 3.73 (m, CH2, 4 H), 2.60 – 2.52 (m, CH2, 4 H), 2.36 (s, CH3,
3 H). 13C NMR (101 MHz, CDCl3) δ 157.5, 147.9, 137.5, 129.5, 127.2, 126.6, 123.1, 122.4, 109.6,
55.0, 46.2, 45.1.
4ꢀ(4,6ꢀDimethoxyꢀ1,3,5ꢀtriazinꢀ2ꢀyl)morpholine (4aa).33b The crossꢀcoupling product was isolated
in 96% yield (217.2 mg). 1H NMR (400 MHz, CDCl3) δ 3.92 (s, OCH3, 6 H), 3.84 – 3.79 (m, CH2, 4
H), 3.71 – 3.67 (m, CH2, 4 H). 13C NMR (101 MHz, CDCl3) δ 172.3, 166.7, 66.5, 54.5, 43.9.
4ꢀ(Quinoxalinꢀ2ꢀyl)morpholine (4ab).33c The crossꢀcoupling product was isolated in 94% yield
(202.3 mg). 1H NMR (400 MHz, CDCl3) δ 8.56 (s, ArꢀH, 1 H), 7.90 (dd, J = 8.2, 1.3 Hz, ArꢀH, 1 H),
7.70 (dd, J = 8.4, 1.0 Hz, ArꢀH, 1 H), 7.59 (ddd, J = 8.4, 7.0, 1.4 Hz, ArꢀH, 1 H), 7.42 (ddd, J = 8.3,
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6.9, 1.4 Hz, ArꢀH, 1 H), 3.90 – 3.85 (m, CH2, 4 H), 3.79 – 3.74 (m, CH2, 4 H). 13C NMR (101 MHz,
CDCl3) δ 152.3, 141.48, 137.1, 135.4, 130.2, 128.7, 126.6, 125.1, 66.6, 45.0.
4,6ꢀDimethylꢀ2ꢀ(4ꢀphenylpiperazinꢀ1ꢀyl)pyrimidine (4ac). The crossꢀcoupling product was
isolated in 97% yield (260.3 mg). 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 8.7, 7.3 Hz, ArꢀH, 2
H), 7.00 – 6.95 (m, ArꢀH, 2 H), 6.88 (t, J = 7.3 Hz, ArꢀH, 1 H), 6.29 (s, ArꢀH, 1 H), 4.00 – 3.96 (m,
CH2, 4 H), 3.25 – 3.21 (m, CH2, 4 H), 2.30 (s, CH3, 6 H). 13C NMR (101 MHz, CDCl3) δ 167.1,
161.8, 1515, 129.1, 120.0, 116.5, 109.3, 49.4, 43.7, 24.1. HRMS calcd for C16H21N4 [M + H]+
269.1761, found 269.1760.
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2ꢀ(4ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀylmethyl)piperazinꢀ1ꢀyl)pyrimidine (4ad).33d The crossꢀcoupling
product was isolated in 98% yield (292.4 mg). 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 4.7 Hz,
ArꢀH, 2 H), 6.88 (s, ArꢀH, 1 H), 6.75 (d, J = 0.7 Hz, ArꢀH, 2 H), 6.45 (t, J = 4.7 Hz, ArꢀH, 1 H), 5.93
(s, CH2, 2 H), 3.84 – 3.77 (m, CH2, 4 H), 3.44 (s, CH2, 2 H), 2.50 – 2.43 (m, CH2, 4H). 13C NMR
(101 MHz, CDCl3) δ 161.6, 157.6, 147.6, 146.6, 131.8, 122.2, 109.7, 109.4, 107.8, 100.8, 62.8, 52.8,
43.6.
ASSOCIATED CONTENT
Supporting Information
The supporting information including NMR spectra and Xꢀray crystallographic data is available free
of charge on the ACS Publications website http://pubs.acs.org.
ORCID
FengꢀShou Liu: 0000ꢀ0002ꢀ7525ꢀ3876
Notes
The authors declare no competing financial interest.
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AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail: fengshou2004@126.com.
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ACKNOWLEDGMENTS
This work was supported by Science and Technology Department of Guangdong Province (no.
2015A010105030), Natural Science Foundation of Guangdong Province (no. 2017A030313085) and
Key Laboratory of Polymeric Composite & Functional Materials of Ministry of Education (no.
PCFMꢀ2017ꢀ03)
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