Room-Temperature CuI-Catalyzed Amination of Aryl Iodides and Aryl Bromides

Article abstract of DOI:10.1021/acs.joc.7b00290

A general and effective CuI/N′,N′-diaryl-1H-pyrrole-2-carbohydrazide catalyst system was developed for the amination of aryl iodides and bromides at room temperature with good chemoselectivity between -OH and -NH₂ groups. Only 5 mol % of CuI and ligands was needed in this protocol to effect the amination of various aryl bromides and aryl iodides with a wide range of aliphatic and aryl amines (1.3 equiv).

Full text of DOI:10.1021/acs.joc.7b00290

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Note
Room-temperature CuI-catalyzed Amination of Aryl Iodides and Aryl Bromides
Xiaomei Ding, Manna Huang, Zhou Yi, Dongchen Du, Xinhai Zhu, and Yiqian Wan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017
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Room-temperature CuI-catalyzed Amination of Aryl Iodides and Aryl Bromides
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Xiaomei Ding,[a] Manna Huang,[a] Zhou Yi,[a] Dongchen Du,[b] Xinhai Zhu*[a] and Yiqian Wan*[a]
[a] School of Chemical Engineering and Technology ,Sun YatꢀSen University, Guangzhou 510275, P. R. China
[b] School of Chemistry,Sun YatꢀSen University, Guangzhou 510275, P. R. China
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Supporting Information
ABSTRACT: A general and effective CuI/N’,N’ꢀdiarylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide catalyst system was developed for the amination of aryl
iodides and bromides at room temperature with good chemoselectivity between –OH and –NH2 groups. Only 5 mol% CuI and ligands were
needed in this protocol to effect the amination of various aryl bromides and aryl iodides with a wide range of aliphatic and aryl amines (1.3
equiv).
The Nꢀarylation of amines for the preparation of anilines has
attracted considerable attention for over a century either because
of the critical role of anilines in academia and in industry or
because of the ubiquitous presence of anilines as highly valuable
moieties in numerous natural products, medicinally relevant
compounds, agrochemicals, and organic materials in our modern
society.1 One of the most attractive and direct approaches for the
preparation of anilines is the copperꢀmediated coupling of aryl
halides with amines due to the lower cost of copper than other
precious metals and not being used toxic phosphaneꢀcontaining
ligands. However, the need of harsh conditions (e.g., strong bases,
stoichiometric copper, high reaction temperatures) limited the
application of this reaction until the 2000s.2 Since then, several
breakthroughs have overcome most of these drawbacks3 and
have greatly extended the reaction scope, in particular to
nonactivated aryl chlorides.4 These breakthroughs have led to
numerous practical approaches to synthesizing anilines in both
academic and industrial settings.
To improve selectivity of reaction and save energy as well,
allowing transformations to be carried out at ambient temperature
is often effective.6 Hence, the development of roomꢀtemperature
Ullmannꢀtype CꢀN coupling reaction protocols has also been an
emerging and progressing field, as shown as follows. In 2006,
Shafir and Buchwald reported the first highly selective
roomꢀtemperature copperꢀcatalyzed CꢀN coupling reactions, in
which a wide range of aryl and heteroaryl iodides reacted with
aliphatic amines with the great advantage of a high tolerance of a
number of reactive functional groups, including ꢀBr and aromatic
ꢀNH2 groups as well as phenolic and aliphatic –OH groups.7
However, some disadvantages remained with need of 20 mol% of
supporting ligands and limitation of substrates to the aliphatic
amines.7 Shortly thereafter, Fu’s group reported that 20 mol% of
CuBr/1,1'ꢀbiꢀ2ꢀnaphthol catalyzed the Nꢀarylation of aliphatic
amines in room temperature with high selectivity and good
functionalꢀgroup tolerance.8 However, electronꢀrich aryl iodides
afforded slightly lower reaction yields, although they could provide
higher reactivity when the temperature was increased to 40 (for an
Me substituent) or 50 °C (for an OMe substituent).8 In 2010, Tao
et al.9 reported that copper(I) iodide (10 mol%)/3ꢀacetylcoumarin
(20 mol%) could catalyze the Nꢀarylation of aliphatic primary
amines and imidazole at room temperature. In 2015, Yao and
coworkers10 found that CuI (10 mol%)/Nꢀ(1ꢀoxyꢀ2ꢀpicolyl)oxalamic
acid (20 mol%) could effect the amination of aryl halides with
However, further endeavors are still required to make this class
of reactions more attractive and practical because of its limitations
in comparison to the Buchwald−Hartwig reaction, which include:
(1) less expensive aryl chlorides still being poor substrates for
Cu/ligandꢀcatalyzed aryl amination reactions;4a and (2) turnover
numbers and turnover frequencies being low at low temperatures
in the general catalytic version of the Ullmann reaction
(25ꢀ80 °C).2b,5
aliphatic amines or ammonia at 25 °C under
a nitrogen
atmosphere in a mixture of DMSO and H2O. In 2016, Evano et al.
A
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achieved CuI (20 mol%)/proline (40 mol%)ꢀcatalyzed Nꢀarylation
structures were identified by spectral methods and singleꢀcrystal
Xꢀray diffraction technique.
of aliphatic amines in DMSO without the need of purification by
column chromatography for most products.11
Scheme 1. The transformation of compound A in water.
Notably, Liu’s group has developed a series of novel organic
phosphorusꢀcontaining ionic bases to carry out Cuꢀcatalyzed CꢀN
couplings of aryl iodides and even bromides at room
temperature.12 They suggested that the reason for the good
performance of such organic bases for CꢀN coupling is their
different ionization abilities, which were determined with the aid of
conductivity measurements.12 Furthermore, the disadvantages
resulting from the expensive and fairly hygroscopic organic ionic
bases could be alleviated by covalently binding phosphonium
cations to hydrophobic polymers. The resultant resinꢀbound
organic base was easily recycled and reused.13
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Furthermore, this transformation occurred even more rapidly in
organic media at room temperature. These results partially
accounted for the need of the high loading of our previously
reported 1Hꢀpyrroleꢀ2ꢀcarbohydrazide ligands and for the poor
reactivity in organic media. After identifying the catalytic
efficiency of purified L1 and its structure to be
N’,N’ꢀdiphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide, we successfully
designed and synthesized a series of ligand candidates (Scheme
2). Subsequent optimization using the reaction of
4ꢀbromoanisole with aniline in water as the model reaction
indicated L1 was very effective at promoting the Ullmannꢀtype
CꢀN coupling because the model reaction was complete within 5
min under the catalysis of 5 mol% of CuI and L1 at 120 °C,
affording desired product in 95% isolated yield. Encouraged by
this result, we thus wished to investigate the roomꢀtemperature
Cuꢀcatalyzed amination of aryl halides.
Notably, carring out successfully the coupling of
(E)ꢀ1ꢀ(2ꢀbromophenyl)ethanone oximes with aniline under
catalysis of only partꢀperꢀmillion (ppm)ꢀlevels of CuCl2 at room
temperature keyed to prevetion of high catalyst loadings for
Cuꢀcatalyzed CꢀN couplings at low temperature with obvious the
substrate limitation to only specific types of oximes.5
In the search for effective ligands for general Cuꢀcatalyzed
coupling reactions, we found that CuO/oxalyldihydrazide/
hexaneꢀ2,5ꢀdione effected the reaction of 4ꢀbromoanisole with
aniline in 96 h to afford 86% isolated yield of the desired product.14
However, we were perplexed by the high catalyst loading (20
mol%) and ligand consumption (50 mol% oxalyldihydrazide and
100 mol% hexaneꢀ2,5ꢀdione) in the reaction. This substantial
limitation has partially been surmounted by the development of a
Scheme 2. The synthesis and structures of the ligands.
series of ligands.15 For example, only
5 mol% loading of
CuAc2/Nꢀmethoxyꢀ1Hꢀpyrroleꢀ2ꢀcarboxamide was sufficient for
effecting typical Ullmannꢀtype CꢀN coupling,15a although none of
the ligands developed could perform this type of reaction at room
temperature.
To elucidate why large amounts of ligand were required in most
of the previously reported cases, we investigated in detail the
stability
of
our
previously
reported
typical
ligand,
After opimization through exploration of the copper sources,
bases, and solvents as well as different ratios of substrates,
catalysts, and ligands, the model reaction of 4ꢀiodoanisole with
aniline occurred smoothly under the catalysis of 5 mol% of CuI
and L1 in diethylene glycol (DEG) at room temperature (Table
S1).
N’ꢀphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide. We found that the
N’ꢀphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide (A) ligand actually
underwent partial transformation to afford at least three
compounds (Scheme 1). Significant exploration confirmed that
(phenyldiazenyl)(1Hꢀpyrrolꢀ2ꢀyl)methanone
(B)
and
N,N’,N’ꢀtriphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide (C) were inactive
Subsequently, a wide range of aryl iodides were aminated with
amines under the optimized conditions to explore the scope of this
catalyst system. As shown in Table 1, the direct amination of
under our CꢀN coupling experimental conditions after their
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unactivated and nonactivated aryl iodides readily provided the
completion. We therefore envisioned that the nitro group would
impede the formation of a key rateꢀdetermining copper complex.
Hence, considering the factor that either pꢀOMeꢀph (L4) or
pꢀNO2ꢀph (L5) replacing phenyl group of the ligand NꢀAr
substituent provided less catalytic efficiency, we modified L1 to
afford L2 and make the ligand more bulky. As expected, L2 was
found to adequately promote the Nꢀarylation of 4ꢀnitrophenyl
iodide, providing the desired product in 73% isolated yield,
probably because of compensation for the electronꢀdonating
effect of the isopropyl group and the steric hindrance. From this
point on, given the efficiency of the Nꢀarylation of bulky amines,
we speculated that the amine coordination to Cu(I) might be the
rateꢀdetermining step in Cu(I)/Cu(III) catalytic cycles17 under the
experimental conditions.
desired products in high yields; most of the amines functioned well
in the reaction irrespective of whether they were aromatic or
aliphatic amines. Even the bulky adamantyl (1h, 3h, 4h) and
acyclic secondary amines (1r, 1s, 4s, 8s, 12s), which were
previously considered difficult substrates for this type of reaction,16
afforded the desired products in very good yield. Notably, highly
selective Nꢀarylation of amino alcohols (1oꢀ1q, 3p, 8p) and amino
phenols (1c) further broadened the application scope of the
protocol.
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It should be noted that lifting the reaction temperature to 50 ºC
largely shortened the reaction time to 1 h with the same outcome
as that at room temperature (Table 1, 1a, 3a, 4a, 8a, 9a, 12a, 1g,
1l, 1n, 1o, 1s).
Addition of 1.0 equiv of TEMPO did not kill the model reaction
(Scheme S1). Futher radical clock experiment18 was carried out
as shown in Scheme 3, the product from CꢀN coupling was
isolated in 83%. These results revealed preliminarily that the
reaction proceeded via an ionic rather than a radical pathway
under the experimental conditions.
Table 1. Direct amination of aryl halides with amines.
CuI (5 mol%) ,
L (5 mol%) ,
K3PO4 (2.0 equiv.)
R2
R3
R2
HN
N
ArꢀX
+
R3
DEG (2 mL)
R1
1 mmol
1.3 mmol
H
H
H
N
O
N
N
R1
O
S
11a: 80%[a], 83%[d]
12a:
86%[a], 86%[b], 70%[c], 83%[d]
1a: R1 = 4ꢀOMe, 90%[a], 91%[b], 79%[c], 90%[d]
R1 = 4ꢀOH, 84%[a]
H
N
O
2a:
3a: R1 = 4ꢀCH3, 87%[a], 86%[b], 81%[c], 88%[d]
R1
4a: R1 = 4ꢀH, 90%[a], 87%[b], 79%[c]
5a: R1 = 4ꢀCl, 78%[a], 81%[d]
,
90%[d]
N
N
H
70%[c], 81%[d]
1b: R1=OCH3, 90%[a]
7b: R1=NO2, 73%[e], 88%[f]
13a:
R1 = 4ꢀCOCH3, 85%[e]
6a:
H
Scheme 3. Radical clock experiment.
7a: R1 = 4ꢀNO2, 61%[e], 73%[f], 63%[h], 75%[i]
8a: R1= 4ꢀCF3, 80%[e], 82%[b], 72%[g], 85%[d]
9a: R1 = 2ꢀOMe, 71%[a], 86%[b], 71%[c], 83%[d]
N
H
R2
N
O
R1 = 3,5ꢀMe, 93%[a]
1c: R2 = OH, 84%[a]
10a:
O
1d: R2 = OCH(CH3
)
2, 82%[a]
2, 84%[a], 85%[d]
1i: 85%[a], 74%[d], 87%[d]
H
N
1e:
R2 = 2,6ꢀCH(CH3
)
7b: R2 = NO2, 29%[e], 37%[f]
H
N
R1
H
H
R1 = 4ꢀOMe, 83%[a], 90%[b], 77%[c], 84%[d]
1g:
S
12g:
3g: R1 = 4ꢀMe, 86%[a]
80%[a], 71%[c], 80%[d]
4g: R1 = 4ꢀH, 89%[a]
7g: R1 = 4ꢀNO2, 63%[e], 72%[f], 60%[h]
N
R1
H
H
1h: R1 = 4ꢀOMe, 82%[a], 84%[d]
3h: R1 = 4ꢀMe, 86%[a]
4h: R1 = H, 87%[a]
N
R1
O
1j: R1=4ꢀOCH3,88%[a], 75%[c], 88%[d]
3j: R1=4ꢀCH3,77%[c]
N
N
R1
8j: R1=4ꢀCF3, 64%[g]
N
1k: R1 = 4ꢀOMe, 88%[a], 68%[c], 88%[d]
It is rarely documented that the roomꢀtemperature
copperꢀcatalyzed Nꢀarylation of arylamines with aryl bromides that
were believed to be either difficult to react with or unreactive
toward traditional alkaline bases. Liu’s group accomplished the
Nꢀarylation of bromobenzene with aliphtic amines with the 10
mol% CuI/20 mol% ligand system at room temperature using
organic ionic bases replacing traditional alkaline bases by taking
advantage of the concept of ionization ability.12ꢀ13
R1 = H, 81%[a]
3k:
N
O
6k: R1 = 4ꢀCOCH3, 77%[e]
83%[a], 83%[b], 83%[d]
1l:
H
N
O
H
N
1m: 89%[a], 87%[d]
OH
R1
H
N
OH
O
1n: R1 = 4ꢀOCH3, 87%[a], 93%[b], 71%[c], 90%[d]
R1
1o: 85%[a], 86%[b], 86%[d], 17%[j]
R1 = 4ꢀCH3, 83%[c]
,
3n:
R1 = 4ꢀOCH3, 74%[a], 57%[c]
3p: R1 = H, 65%[a], 55%[c]
8p: R1 = 4ꢀCF3, 80%[e]
7n: R1 = 4ꢀNO2, 60%[e], 68%[f], 60%[h]
1p:
N
R1
O
1r: 81%[a]
H
N
N
OH
S
1s: R1 = 4ꢀOMe, 86%[a], 78%[b], 48%[c], 82%[d]
3s: R1= 4ꢀCH3, 51%[c]
O
N
1q: 83%[a]
R1= H, 79%[a]
8s: R1
4ꢀCF3, 80%[e], 30%[g]
4s:
12s: 70%[a], 79%[d]
=
With the success of our catalyst system for the Nꢀarylation of
arylamines with aryl iodides, we investigated the Nꢀarylation of
arylamines with aryl bromides. Initially, the model reaction was
carried out as previously described, except using 4ꢀbromoanisole
instead of 4ꢀiodoanisole. Interestingly, although the reaction
initiated smoothly even at 14 °C, the starting material was difficult
to transfer completely to the product at room temperature. Given
the necessity of protic solvents for our catalyst system, we
Reaction conditions: aryl halide (1 mmol), amine (1.3 mmol), CuI (0.05
mmol), Ligand (0.05 mmol), K3PO4 (2 mmol), diethylene glycol (2 mL) [a]:
ArI, L1, RT, 12 h; [b]: ArI, L1, 50 °C, 1 h; [c]: ArBr, L1, 4Å MS (100 mg), RT,
6 d; [d]: ArBr, L1, 60 °C, 3 h; [e]: ArI, L1, RT,15 h; [f]: ArI, L2, RT, 15 h; [g]:
ArBr, L1, 4Å MS (100 mg), RT, 6.5 d; [h]: ArBr, L2, 4Å MS (100 mg), RT,
6.5 d; [i]: ArBr, L2, 60 °C, 3 h; [j]: ArI, ligand free. RT, 12 h.
Intriguingly, 4ꢀnitrophenyl iodide, usually considered an
activated substrate,4a poorly participated in this transformation,
with a slow rate of initiation and an extended time required for
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envisioned that water could play a role in the reaction. In fact,
(iv) chemoselectivity between –OH groups (alcohols and phenol)
and –NH2 groups (aliphatic and aryl amines) is realized; and the
reaction has a universal substrate scope (including aryl bromides
and aryl iodides and aliphatic and aryl amines), irrespective of the
substrate’s electronic and steric effects. (4) raising reaction
temperature could largely shorten the reaction time as expected
without change of the reaction selectivigy. Together, these
benefits make this catalytic system more practical than other
procedures.
DEG dried over molecular sieves (4Å MS) ameliorated the model
reaction, affording 79% isolated yield of the desired product in 6
days at room temperature. Molecular sieves are well documented
to serve as general catalysts for many reactions. Hence, the
model reaction using almost the same conditions, except with
anhydrous Na2SO4 instead of 4Å MS, afforded 75% isolated yield
of the product, which demonstrated that the 4Å MS acted here
only as a desiccant in the reaction (Table S2).
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Consequently, the amination of various aryl bromides was run
in DEG with activated 4Å MS (100 mg/2 mL) for the purpose of
operational convenience, as shown in Table 1. The performance
of the direct amination of aryl bromides with various amines was
reminiscent of their aryl iodide counterparts in most cases,
requiring only a prolongation of the reaction times.
ꢀ
EXPERIMENTAL SECTION
General information. All starting materials and reagents are
analytical grade, commercially available and used as received,
unless otherwise mentioned. Aryl halides and amines were
purchased from Alfa Aesar and J&K companies. Diethylene glycol
(DEG) was purchased from J&K company and dried with
molecular sieve (4Å). All CꢀN coupling reactions were carried out
at room temperature in vials (size: 10 mL) sealed with a septum.
Flash column chromatography (flash c.c.) was performed on silica
gel (200ꢀ300 mesh). Thinꢀlayer chromatography was carried out
with Merck silica gel GF254 plates. All of the known compounds
were characterized by MS, 1H NMR and 13C NMR, which were
compared with the previously reported data. All the new
compounds were also characterized by elemental analytical and
Interestingly, elevating the reaction temperature to 60 °C clearly
made the amination of all tested aryl bromides completed within 3
h in 75ꢀ91% isolated yields without 4Å MS.
As well known, aryl chlorides were believed to be unactivated
substrates for the Ullmann type CꢀN coupling. We tried amination
of chlorobenzene with aniline using L1 as ligand at room
temperature, but the reaction unfortunately did not work.
To examine the practical application of the roomꢀtemperature
CꢀN coupling protocol, we carried out the synthesis of
phenothiazine, which has been demonstrated to play an important
role in both human medicine and materials science. As expected,
phenothiazine was obtained readily either in two steps in 58%
total yield at room temperature or in oneꢀpot in 70% yield at 90ºC
(Scheme 4).
1
IR data in addition. H NMR and 13C NMR spectra were recorded
at r.t. on a Bruker AVANCEIII 400MHz instrument with TMS as an
internal reference. ESIꢀMS was run on a LCMSꢀ2010A. EI mass
spectra were recorded on the Thermo DSQ mass spectrometer.
GCꢀMS was run on a Finnigan Voyager with an electron impact
(70 eV) mass selective detector and an innowax 30 m × 0.25 mm
Scheme 4. Synthesis of phenothiazine.
×
0.25 um capillary apolar column. GCꢀMS method: Initial
temperature: 50 °C, initial time: 3 min; Ramp: 20 °C /min; Final
temperature: 250 °C, Final time: 2 min. Element analyses were
carried out with a Vario EL series analyzer within errors of ± 0.4%
for CHN elements. The IR spectra were recorded on a Thermo
Nicolet Avatar 330 FTꢀIR. Melting points were determined on a
WRSꢀ1B digital melting point apparatus and the thermometer was
not calibrated.
In conclusion, we have developed a general and effective
method for the CuIꢀcatalyzed amination of aryl iodides and
bromides at room temperature. The advantages of this procedure
are summarized as follows: (1) a relatively low catalyst/ligand
loading (only 5 mol% CuI and ligand) is needed; (2) an organic
base is not required to achieve the roomꢀtemperature
copperꢀcatalyzed amination of aryl halides; (3) only a slight
excess of amine (1.3 equiv.) is required for complete amination;
The single crystals were grown from methanol (L3), and the
mixture of chloroform and hexane (B). Singleꢀcrystal Xꢀray
diffraction data were collected at 293(2) K on an Oxford Germini S
Ultra diffractometer or an Agilent SuperNova, Dual, Cu at zero,
Atlas S2 diffractometer, with CuꢀKα radiation (λ=1.54178 Å). The
CIF files for the crystal structures have been deposited with the
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CCDC and been given the deposition numbers 1527350 (B) and
10.54 (s, 1H), 7.01 (d, J = 8.8 Hz, 4H), 6.95 ꢀ 6.93 (m, 2H), 6.86 (d,
J = 8.8 Hz, 4H), 6.14ꢀ5.13 (m, 1H), 3.70 (s, 6H); 13C NMR (100
MHz, DMSOꢀd6) δ 160.7, 154.9, 141.0, 124.5, 122.8, 120.6, 114.7,
111.2, 109.3, 55.7; IR (KBr, cmꢀ1): 3408, 3233, 1607, 1507;
Anal.Calcd for C19H19N3O3•0.02H2O: C, 67.57; H, 5.68; N, 12.44.
Found: C, 67.31; H, 5.64; N, 12.81.
1527351 (L3).
General procedure for synthesis of L1-L5: A threeꢀneck flask
was charged with 1Hꢀpyrroleꢀ2ꢀcarbohydrazide (125 mg, 1 mmol,)
aryl iodides (2.4 mmol), CuI (38 mg, 0.2 mmol) and Cs2CO3 (652
mg, 2 mmol), under nitrogen atmosphere. After DMSO (2 mL) was
injected, the reaction mixture was stirred at 55 °C until
Nꢀmonoꢀsubstituted 1Hꢀpyrroleꢀ2ꢀcarbohydrazide completely
consumed by TLC indication. The cooled reaction mixture was
poured into water, and extracted with ethyl acetate (3 × 20 mL).
The combined organic phase was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified with
flash c.c. on silica gel eluting with petroleum ether/ethyl acetate
(10:1 and 3:1 stepwise) to provide the desired products.
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N',N'-bis(4-nitrophenyl)-1H-pyrrole-2-carbohydrazide (L5).
(312mg, 85%): yellow solid; m.p: 238 ꢀ 240 °C; MS(EI+): m/z: 367
(M+, 5); 94 (M+ꢀNHN(PhNO2)2,100) 1H NMR (400 MHz, DMSOꢀd6)
δ 11.80 (s, 1H), 11.38 (s, 1H), 8.25 (d, J = 9.2 Hz, 4H), 7.45 (d, J =
9.2 Hz, 4H), 7.05 ꢀ 7.03 (m, 2H), 6.22 ꢀ 6.21 (m, 1H); 13C NMR
(100 MHz, DMSOꢀd6) δ 160.3, 150.5, 142.6, 126.0, 124.1, 123.3,
119.4, 112.5, 109.8; IR(KBr, cmꢀ1): 3309, 1650, 1582; Anal.Calcd
for C18H16N5O5•0.3H2O): C, 54.78; H, 3.68; N, 18.79; Found: C,
54.71; H, 3.40; N, 19.01.
N',N'-diphenyl-1H-pyrrole-2-carbohydrazide (L1). (216 mg,
78%): white solid; m.p: 238ꢀ239 °C; MS(ESI+): m/z: 300 ([M+Na]+);
1H NMR (400 MHz, DMSOꢀd6) δ 11.63 (s, 1H), 10.76 (s, 1H), 7.31
ꢀ 7.28 (m, 4H), 7.16 ꢀ 7.14 (m, 4H), 7.00 ꢀ 6.98 (m, 4H); 13C NMR
(100 MHz, DMSOꢀd6) δ 160.7, 146.5, 129.5, 124.3, 123.1, 122.4,
119.1, 111.4, 109.4; IR (KBr, cmꢀ1): 3411, 3239, 1613, 1587;
Anal.Calcd for C17H15N3O•0.1H2O: C, 73.15; H, 5.49; N, 15.05.
Found: C, 73.27; H, 5.41; N, 15.34.
N'-phenyl-N'-(o-tolyl)-1H-pyrrole-2-carbohydrazide (L6).
A
threeꢀneck flask was charged with N'ꢀphenylꢀ1Hꢀpyrroleꢀ
2ꢀcarbohydrazide (201 mg, 1 mmol), 2ꢀiodotoluene (262 mg, 1.2
mmol), CuI (38 mg, 0.02 mmol), and Cs2CO3 (652 mg, 2 mmol),
under nitrogen atmosphere. After DMSO (2 mL) was injected, the
reaction
mixture
was
stirred
at
55
°C
until
N'ꢀphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide disappeared monitored by
TLC. The cooled reaction mixture was poured into water and
extracted with ethyl acetate (3 × 20 mL). The combined organic
phase was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified with flash c.c. on
silica gel eluting with petroleum ether/ethyl acetate (10:1 and 3:1
stepwise) to provide L6. (210 mg, 72%): white solid; m.p:
249ꢀ250 °C; MS (ESI+): m/z: 314 ([M+Na]+); 1H NMR (400 MHz,
DMSOꢀd6) δ 11.56 (s, 1H), 10.62 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H),
7.29 ꢀ 7.16 (m, 5H), 6.97 ꢀ 6.95 (m, 2H), 6.78 (t, J = 7.2 Hz, 1H),
6.55 (d, J = 8.1 Hz, 2H), 6.16 ꢀ 6.14 (m, 1H), 2.25 (s, 3H); 13C
NMR (100 MHz, DMSOꢀd6) δ 160.6, 148.0, 144.2, 135.8, 131.2,
129.4, 127.7, 127.0, 126.9, 124.3, 123.0, 119.3, 113.5, 111.3,
109.4, 18.5; IR (KBr, cmꢀ1): 3404, 3236, 1644, 1594; Anal.Calcd
for C19H19N3O•0.03H2O: C, 74.07; H, 5.89; N, 14.40. Found: C,
73.80; H, 5.79; N, 14.74.
N',N'-bis(2-isopropylphenyl)-1H-pyrrole-2-carbohydrazide
(L2). (245 mg, 68%): white solid; m.p: 212ꢀ214 °C; MS(ESI+): m/z:
362 ([M+H]+); 1H NMR (400 MHz, DMSOꢀd6) δ 11.40 (s, 1H),
10.45 (s, 1H), 7.30 – 7.28 (m, 2H), 7.11 – 7.03 (m, 6H), 6.90 ꢀ 6.86
(m, 2H), 6.08 (d, J = 2.1 Hz, 1H), 3.45 ꢀ 3.40 (m, 2H), 1.03 (d, J =
55.6 Hz, 12H); 13C NMR (100 MHz, DMSOꢀd6) δ 159.0, 146.8,
143.6, 127.0, 126.2, 125.3, 125.0, 123.2, 122.3, 110.7, 109.2,
26.9, 24.1, 23.2; IR (KBr, cmꢀ1): 3367, 3265, 1657, 1554;
Anal.Calcd for C23H17N3O•0.2H2O: C, 75.67; H, 7.56; N, 11.51.
Found: C, 75.53; H, 7.48; N, 11.79.
N',N'-di-o-tolyl-1H-pyrrole-2-carbohydrazide (L3). (223 mg,
73%): white solid; m.p: 214ꢀ215 °C; MS(ESI+): m/z: 328 ([M+Na]+);
1H NMR (400 MHz, DMSOꢀd6) δ 11.42 (s, 1H), 10.50 (s, 1H), 7.17
ꢀ 7.10 (m, 4H), 7.01 ꢀ 6.97 (m, 4H), 6.93 ꢀ 6.91 (m, 2H), 6.12 ꢀ 6.10
(m, 1H), 2.04 (s, 6H); 13C NMR (100 MHz, DMSOꢀd6) δ 159.5,
146.8, 131.8, 131.6, 126.7, 124.6, 124.1, 122.6, 122.0, 110.9,
109.3, 18.7; IR (KBr, cmꢀ1): 3403, 3256, 1641, 1598; Anal.Calcd
for C19H19N3O•0.08H2O: C, 74.38; H, 6.29; N, 13.70. Found: C,
74.29; H, 6.21; N, 13.99.
(E)-(phenyldiazenyl)(1H-pyrrol-2-yl)methanone
(B):
A
threeꢀneck flask was charged with N'ꢀphenylꢀ1Hꢀpyrroleꢀ
2ꢀcarbohydrazide (201 mg, 1 mmol), 2 mL MeCN, Cs2CO3 (652
mg,
2
mmol),
stirred
at
room
temprature
until
N'ꢀphenylꢀ1Hꢀpyrroleꢀ2ꢀcarbohydrazide disappeared monitored by
TLC. The reaction mixture was poured into water and extracted
with ethyl acetate (3 × 20 mL). The combined organic phase was
N',N'-bis(4-methoxyphenyl)-1H-pyrrole-2-carbohydrazide
(L4). (253 mg, 75%): white solid; m.p: 230 ꢀ 231 °C; MS(ESI+):
m/z: 360 ([M+Na]+); 1H NMR (400 MHz, DMSOꢀd6) δ 11.53 (s, 1H),
E
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washed with brine, dried over Na2SO4, and concentrated in vacuo.
molecular sieve (4Å MS, 100 mg) and a magnetic stir bar. The
vessel was sealed with a septum. The reaction mixture was stirred
at room temperature for 6.5 d, then quenched with 2 mL water.
The mixture was added 15 mL water and extracted with ethyl
acetate (3 × 15 mL). The combined organic phase was washed
with brine (15 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified with flash .c.c on
silica gel to afford the target compound.
The residue was purified with flash c.c. on silica gel (eluting with
10:1 petroleum ether/ethyl acetate) to provide B. (119 mg, 60%):
red solid; m.p: 110ꢀ111 °C; MS(ESI+): m/z: 200 ([M+H]+); 1H NMR
(400 MHz, DMSOꢀd6) δ 12.30 (s, 1H), 7.82 (d, J = 6.8 Hz, 2H),
7.62 – 7.43 (m, 3H), 7.24 (s, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.19 (s,
1H); 13C NMR (100 MHz, DMSOꢀd6) δ 174.4, 153.4, 135.3, 131.5,
130.8, 125.8, 124.9, 122.4, 113.1; IR (KBr, cmꢀ1): 3204, 1671;
Anal. Calcd for C11H9N3O: C, 66.32; H, 4.55; N, 21.09. Found: C,
66.41; H, 4.57; N, 21.30.
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General procedure E: A 10 mL vial was charged with CuI (9.5
mg, 0.05 mmol), L1 (13.8 mg, 0.05 mmol), aryl iodides (1.0 mmol),
amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0 mL) and
a magnetic stir bar. The vessel was sealed with a septum. The
reaction mixture was stirred at 50 °C for 1 h, then quenched with 2
mL water. The mixture was added 15 mL water and extracted with
ethyl acetate (3 × 15 mL). The combined organic phase was
washed with brine (15 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified with flash .c.c on
silica gel to afford the target compound.
General procedure A: A 10 mL vial was charged with CuI (9.5
mg, 0.05 mmol), L1 (13.8 mg, 0.05 mmol), aryl iodides (1.0 mmol),
amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0 mL) and
a magnetic stir bar. The vessel was sealed with a septum. The
reaction mixture was stirred at room temperature for 12ꢀ15 h, then
quenched with 2 mL water. The mixture was added 15 mL water
and extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with brine (15 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified with flash .c.c on silica gel to afford the target compound.
General procedure B: A 10 mL of vial was charged with CuI
(10 mg, 0.05 mmol), L1 (13.8 mg, 0.05 mmol), aryl bromides (1.0
mmol), amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0
mL), molecular sieve (4ÅꢀMS, 100 mg) and a magnetic stir bar.
The vessel was sealed with a septum. The reaction mixture was
stirred at room temperature for 6ꢀ6.5 d, then quenched with 2 mL
water. The mixture was added 15 mL water and extracted with
ethyl acetate (3 × 15 mL). The combined organic phase was
washed with brine (15 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified with flash .c.c on
silica gel to afford the target compound.
General procedure F: A 10 mL of vial was charged with CuI
(10 mg, 0.05 mmol), L1 (13.8 mg, 0.05 mmol), aryl bromides (1.0
mmol), amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0
mL), molecular sieve (4ÅꢀMS, 100 mg) and a magnetic stir bar.
The vessel was sealed with a septum. The reaction mixture was
stirred at 60 °C for 3 h, then quenched with 2 mL water. The
mixture was added 15 mL water and extracted with ethyl acetate
(3 × 15 mL). The combined organic phase was washed with brine
(15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was purified with flash .c.c on silica gel to afford the
target compound.
4-Methoxy-N-phenylaniline (1a).19 General procedure A (180
mg, 90%), general procedure
B (158 mg, 79%), general
General procedure C: A 10 mL vial was charged with CuI (9.5
mg, 0.05 mmol), L2 (18 mg, 0.05 mmol), aryl iodides (1.0 mmol),
amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0 mL) and
a magnetic stir bar. The vessel was sealed with a septum. The
reaction mixture was stirred at room temperature for 15 h, then
quenched with 2 mL water. The mixture was added 15 mL water
and extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with brine (15 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was
purified with flash .c.c on silica gel to afford the target compound.
General procedure D: A 10 mL vial was charged with CuI (9.5
mg, 0.05 mmol), L2 (18 mg, 0.05 mmol), aryl bromides (1.0 mmol),
amine (1.3 mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0 mL) ,
procedure E (181 mg, 91%), general procedure F (181 mg, 91%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.27 – 7.17 (m, 2H), 7.13 – 7.02 (m, 2H),
6.97 – 6.80 (m, 5H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
155.3, 145.2, 135.8, 129.4, 122.2, 119.6, 115.7, 114.7, 55.6.
4-(Phenylamino)phenol (2a).20 General procedure A (155 mg,
84%), eluting with petroleum ether/ethyl acetate (10:1), white
solid; 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.8 Hz, 2H), 7.03 (d,
J = 8.3 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 6.84 (t, J = 7.3 Hz, 1H),
6.79 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 151.1,
145.2, 135.8, 129.4, 122.5, 119.7, 116.2, 115.8.
19
4-Methyl-N-phenylaniline (3a)
General procedure A (159
mg, 87%), general procedure
B (148 mg, 81%), general
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procedure E (157 mg, 86%), general procedure F (161 mg, 88%),
petroleum ether/ethyl acetate (20:1), colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.32 – 7.23 (m, 3H), 7.15 (d, J = 8.1 Hz, 2H), 6.95
– 6.86 (m, 4H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4,
142.7, 133.0, 129.3, 121.2, 120.9, 120.0, 118.6, 114.8, 110.6,
55.6.
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.23 (t, J = 7.6 Hz, 2H), 7.11 – 7.06 (m,
2H), 7.04 – 6.97 (m, 4H), 6.88 (t, J = 7.2 Hz, 1H), 2.30 (s, 3H). 13
C
NMR (100 MHz, CDCl3) δ 144.0, 140.3, 131.0, 129.9, 129.4,
3,5-Dimethyl-N-phenylaniline (10a).21 General procedure A
(183 mg, 93%), eluting with petroleum ether/ethyl acetate (20:1),
white solid; 1H NMR (400 MHz, CDCl3) δ 7.25 (t, J = 7.7 Hz, 2H),
7.05 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 6.70 (s, 2H), 6.59
(s, 1H), 2.26 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.5, 143.2,
139.1, 129.4, 123.0, 120.9, 118.0, 115.8, 21.5.
9
120.4, 119.0, 116.9, 20.8.
Diphenylamine (4a).19 General procedure A (152 mg, 90%),
general procedure B (133 mg, 79%), general procedure E (147
mg, 87%), general procedure F (152 mg, 90%), eluting with
petroleum ether/ethyl acetate (20:1), white solid; 1H NMR (400
MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 4H), 7.07 (d, J = 8.0 Hz, 4H),
6.92 (t, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 143.3,
129.5, 121.2, 118.0.
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N-phenylbenzo[d][1,3]dioxol-5-amine
(11a).15a
General
procedure A ( 170 mg, 80%), general procedure F (177 mg, 83%),
eluting with petroleum ether/ethyl acetate (10:1), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.24 (t, J = 7.5 Hz, 2H), 6.94 (d, J = 7.9
Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.71 (s,
1H), 6.56 (d, J = 8.2 Hz, 1H), 5.93 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 148.3, 144.7, 142.9, 137.3, 129.4, 120.1, 116.4, 113.0,
108.6, 102.6, 100.1.
4-Chloro-N-phenylaniline (5a).19 General procedure A (158
mg, 78%), general procedure F (164 mg, 81%), eluting with
petroleum ether/ethyl acetate (20:1), white solid; 1H NMR (400
MHz, CDCl3) δ 7.27 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H),
7.04 (d, J = 7.9 Hz, 2H), 7.01 – 6.92 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.7, 142.0, 129.5, 129.3, 125.5, 121.6, 118.9, 118.2.
1-(4-(Phenylamino)phenyl)ethanone
(6a).19
General
N-phenylthiophen-3-amine (12a).21 General procedure
A(151mg, 86%), general procedure B (122 mg, 70%), general
procedure E (151 mg, 86%), general procedure F (145 mg, 83%),
eluting with petroleum ether/ethyl acetate (20:1), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.26 – 7.22 (m, 3H), 7.00 (d, J = 7.8 Hz,
2H), 6.95 (d, J = 5.0 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.78 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 144.7, 141.6, 129.5, 129.4, 125.2,
122.9, 119.9, 115.6, 106.5.
procedure (179 mg, 85%),
A
eluting
with
dichloromethane/methanol (20:1), yellow solid; 1H NMR (400 MHz,
CDCl3) δ 7.86 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.18 (d,
J = 7.8 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H),
6.22 (s, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.8,
148.7, 140.8, 130.7, 129.5, 123.2, 120.7, 114.4, 26.2.
4-Nitro-N-phenylaniline (7a). 19 General procedure C: (156 mg,
73%), general procedure D, eluting with petroleum ether/ethyl
acetate (10:1), (134 mg, 63%), general procedure F (161 mg,
75%): yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 9.1
Hz, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.29ꢀ7.20 (m, 3H), 6.97 (d, J =
9.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 150.4, 139.5, 129.7,
126.3, 124.6, 121.9, 113.7, 29.7.
N-Phenylpyridin-2-amine (13a).15a General procedure B (119 mg,
70%), general procedure
F (138 mg, 81%), eluting with
dichloromethane/methanol (20:1), white solid; 1H NMR (400 MHz,
CDCl3) δ 8.20 (d, J = 4.6 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.33 –
7.25 (m, 4H ), 7.06 – 7.03 (m, 2H), 6.88 (d, J = 8.4 Hz, 1H), 6.73 –
6.70 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.1, 148.3, 140.5,
137.7, 129.3, 122.8, 120.4, 115.0, 108.2.
N-phenyl-4-(trifluoromethyl)aniline (8a).19 General procedure
A (190 mg, 80%), general procedure B (170 mg, 72%), general
procedure E (194 mg, 82%), general procedure F (201 mg, 85%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.3 Hz, 2H), 7.33 (t, J = 7.6
Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 – 7.01 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 146.8, 141.2, 129.6, 126.8, 126.7, 126.7,
123.0, 121.8, 121.5, 120.1, 115.4.
2-(allyloxy)-N-phenylaniline.(14a). General procedure A (187
mg, 83% ), eluting with petroleum ether, colorless oil, MS(ESI+):
m/z: 226 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.24 (m,
3H), 7.15 (d, J = 7.8 Hz, 2H), 6.97 – 6.78 (m, 4H), 6.14 – 6.01 (m,
1H), 5.40 (d, J = 17.2 Hz, 1H), 5.29 (d, J = 10.5 Hz, 1H), 4.59 (d, J
= 5.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 147.3, 142.8, 133.4,
129.4, 121.3, 121.2, 119.9, 118.8, 117.9, 114.9, 112.2, 69.6; IR
(KBr, cmꢀ1): 3415, 1230, 1648; Anal.Calcd for C15H15NO•0.3H2O:
C, 78.10; H, 6.82; N, 6.07; Found: C, 78.21; H, 6.80; N, 5.89.
2-Methoxy-N-phenylaniline (9a).15a General procedure A (141
mg, 71), general procedure B (140 mg,71%), general procedure E
(171 mg, 86%), general procedure F (165 mg, 83%), eluting with
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Bis(4-methoxyphenyl)amine (1b).19 General procedure A (206
6.97 (d, J = 6.3 Hz, 2H), 6.54 (d, J = 7.6 Hz, 2H), 4.28 (s, 2H), 2.22
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.9, 139.7, 129.8, 128.6,
127.6, 127.2, 126.8, 113.1, 48.7, 20.4.
mg, 90%), eluting with petroleum ether/ethyl acetate (20:1), white
solid; 1H NMR (400 MHz, CDCl3) δ 7.05 – 6.86 (m, 4H), 6.85 –
6.78 (m, 4H), 3.78 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 154.2,
138.0, 119.5, 114.7, 55.7.
19
N-benzylaniline (4g). General procedure A (164 mg, 89%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.37 – 7.21 (m, 5H), 7.15 (t, J = 7.5 Hz,
2H), 6.70 (t, J = 7.1 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 4.29 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 148.2, 139.5, 129.3, 128.7, 127.6,
127.3, 117.7, 113.0, 48.4.
4-Methoxy-N-(4-nitrophenyl)aniline (7b).22 General procedure
C (214mg, 88%), eluting with petroleum ether/ethyl acetate (10:1),
yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 9.0 Hz, 2H),
7.18 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 9.1
Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 151.8,
139.0, 132.0, 126.4, 125.4, 114.9, 112.6, 55.6.
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60
N-benzyl-4-nitroaniline (7g). 19 General procedure C (164 mg,
72%), general procedure D (137 mg, 60%), eluting with petroleum
1
4-((4-Methoxyphenyl)amino)phenol
(1c).23
General
ether/ethyl acetate (10:1), white solid; H NMR (400 MHz, CDCl3)
procedure A (180 mg, 84%), eluting with petroleum ether/ethyl
acetate (10:1), white solid; 1H NMR (400 MHz, CDCl3) δ 7.00 –
6.78 (m, 6H), 6.77 – 6.70 (m, 2H), 3.78 (s, 3H); 13C NMR (100
MHz, DMSOꢀd6 and CDCl3) δ 153.9, 151.5, 138.5, 136.7, 120.5,
118.8, 116.2, 114.7, 55.7.
δ 8.06 (d, J = 8.5 Hz, 2H), 7.44 – 7.25 (m, 5H), 6.56 (d, J = 8.5 Hz,
2H), 4.97 (s, 1H), 4.43 (s, 2H);13C NMR (100 MHz, CDCl3) δ 153.1,
138.4, 137.4, 128.9, 127.9, 127.3, 126.4, 111.4, 47.7.
N-benzylthiophen-3-amine (12g).25 General procedure A (134
mg, 71%), general procedure F (151 mg, 80%), eluting with
petroleum ether/ethyl acetate (20:1), colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.42 – 7.24 (m, 5H), 7.16 – 7.12 (m, 1H), 6.63 (d, J
= 5.0 Hz, 1H), 5.96 (s, 1H), 4.25 (s, 2H), 3.95 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 148.5, 139.3, 128.6, 127.7, 127.3, 125.2,
119.9, 96.1, 50.7.
4-isopropoxy-N-(4-methoxyphenyl)aniline (1d). General
procedure A (210 mg, 82%), eluting with petroleum ether/ethyl
acetate (20:1), colorless oil; MS(ESI+): m/z: 258 ([M+H]+); 1H NMR
(400 MHz, CDCl3) δ 7.04 – 6.88 (m, 4H), 6.85 – 6.78 (m, 4H),
4.47ꢀ4.41 (m, 1H), 3.78 (s, 3H), 1.31 (d, J = 6.1 Hz, 6H); 13C NMR
(126 MHz, CDCl3) δ 154.3, 152.4, 138.0, 119.7, 119.4, 117.4,
114.7, 70.8, 55.7, 22.2; IR (KBr, cmꢀ1): 3386, 1232; Anal.Calcd for
C16H19NO2:C, 74.68; H, 7.44; N, 5.44. Found: C, 74.55; H, 7.53; N,
5.67.
N-(4-methoxyphenyl)adamantan-1-amine (1h).20 General
procedure A (211 mg, 82%), general procedure F (216 mg, 84%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 6.89 – 6.82 (m, 2H), 6.78 – 6.73 (m, 2H),
2,6-Diisopropyl-N-(4-methoxyphenyl)aniline (1e).24 General
procedure A (238 mg, 84%), general procedure F (241 mg, 85%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.29 – 7.16 (m, 3H), 6.73 (d, J = 8.6 Hz,
2H), 6.49 – 6.40 (m, 2H), 3.73 (s, 3H), 3.24 – 3.12 (m, 2H), 1.13 (d,
J = 6.9 Hz, 12H); 13C NMR (126 MHz, CDCl3) δ 152.3, 147.1,
142.3, 136.1, 126.8, 123.9, 114.8, 114.3, 55.7, 28.2, 23.9.
N-benzyl-4-methoxyaniline (1g). 19 General procedure A (190
3.77 (s, 3H), 2.08 (s, 3H), 1.76 (s, 6H), 1.69 – 1.56 (m, 6H); 13
C
NMR (100 MHz, CDCl3) δ 154.9, 138.2, 124.3, 113.9, 55.5, 52.7,
43.7, 36.5, 29.7.
N-(p-tolyl)adamantan-1-amine (3h).26 General procedure A
(207mg, 86%), eluting with petroleum ether/ethyl acetate (20:1),
white solid; 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J = 8.0 Hz, 2H),
6.74 (d, J = 8.0 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 3H), 1.81 (s, 6H),
1.70 – 1.58 (m, 6H,); 13C NMR (100 MHz, CDCl3) δ 143.1, 129.4,
129.2, 120.9, 52.4, 43.6, 36.5, 29.8, 20.6.
mg, 89%), general procedure
B (164 mg, 77%), general
procedure E (192 mg, 90%), general procedure F (179 mg, 84%),
eluting with petroleum ether/ethyl acetate (20:1), white solid; 1H
NMR (400 MHz, CDCl3) δ 7.38ꢀ7.24 (m, 5H), 6.77 (d, J = 8.9 Hz,
2H), 6.61 (d, J = 8.8 Hz, 2H), 4.28 (s, 2H), 3.73 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.3, 142.6, 139.8, 128.7, 127.6, 127.2,
N-phenyladamantan-1-amine (4h).20 General procedure
A
(198 mg, 87%), eluting with petroleum ether/ethyl acetate (20:1),
white solid; 1H NMR (400 MHz, CDCl3) δ 7.13 (t, J = 7.8 Hz, 2H),
6.78 (d, J = 7.6 Hz, 3H), 3.25 (s, 1H), 2.09 (s, 3H), 1.86 (s, 6H),
1.71–1.61 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 146.1, 128.8,
119.2, 119.1, 52.2, 43.5, 36.5, 29.8.
115.0, 114.2, 55.8, 49.3.
19
N-benzyl-4-methylaniline (3g).
General procedure A (170
N-cyclohexyl-4-methoxyaniline (1i).15a General procedure A:
174mg, 85%, general procedure B (152 mg, 74%), general
procedure F (178 mg, 87%), eluting with petroleum ether/ethyl
mg, 86%), eluting with petroleum ether/ethyl acetate (20:1),
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.20 (m, 5H),
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acetate (20:1), white solid; 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J
1-(4-Methoxyphenyl)-4-methylpiperazine (1l).30
General
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5
6
7
8
9
= 8.4 Hz, 2H), 6.58 (d, J = 8.3 Hz, 2H), 3.74 (s, 3H), 3.21 – 3.09
(m, 1H), 2.08 – 1.98 (m, 2H), 1.78 – 1.68 (m, 2H), 1.68 – 1.59 (m,
1H), 1.42 – 1.28 (m, 2H), 1.26 – 1.06 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.0, 141.5, 115.0, 55.8, 52.9, 33.6, 26.0, 25.1.
procedure A (172 mg, 83%), general procedure E (179 mg, 87%),
general procedure F (177 mg, 86%), eluting with petroleum
1
ether/ethyl acetate (20:1), white solid; H NMR (400 MHz, CDCl3)
δ 6.93 – 6.87 (m, 2H), 6.86 – 6.80 (m, 2H), 3.76 (s, 3H), 3.14 –
3.06 (m, 4H), 2.61 – 2.54 (m, 4H), 2.35 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 153.8, 145.7, 118.2, 114.4, 55.6, 55.3, 50.6, 46.1.
1-(4-Methoxyphenyl)pyrrolidine (1m).21 General procedure A
(158 mg, 89%), general procedure F (156 mg, 87%), eluting with
petroleum ether/ethyl acetate (20:1), white solid; 1H NMR (400
MHz, CDCl3) δ 6.84 (d, J = 8.5 Hz, 2H), 6.54 (d, J = 8.2 Hz, 2H),
3.75 (s, 3H), 3.30 – 3.10 (m, 4H), 2.05 – 1.91 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 150.9, 143.2, 115.1, 112.7, 56.0, 48.4, 25.4.
N-butyl-4-methoxyaniline (1n).15a General procedure A (156
1-(4-Methoxyphenyl)piperidine (1j).27 General procedure A
(168 mg, 88%), general procedure B (143 mg, 75%), general
procedure F (169 mg, 88%), eluting with petroleum ether/ethyl
acetate (20:1), coloeless oil; 1H NMR (400 MHz, CDCl3) δ 6.93 (d,
J = 8.7 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.06 – 2.97
(m, 4H), 1.77 – 1.68 (m, 4H), 1.60 – 1.48 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 153.6, 146.9, 118.8, 114.3, 55.6, 52.3, 26.2, 24.2.
1-(P-tolyl)piperidine (3j).28 General procedure B (135 mg,
77%), eluting with petroleum ether/ethyl acetate (20:1), colorless
oil; 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 8.2 Hz, 2H), 6.85 (d,
J = 8.3 Hz, 2H), 3.11 – 3.03 (m, 4H), 2.25 (s, 3H), 1.75 – 1.65 (m,
4H), 1.58 – 1.49 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.3,
129.6, 128.8, 117.0, 51.4, 26.0, 24.4, 20.5.
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mg, 87%), general procedure
B (127 mg, 71%), general
procedure E (166 mg, 93%), general procedure F (161 mg, 90%),
eluting with petroleum ether/ethyl acetate (20:1), colorless oi; 1H
NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9
Hz, 2H), 3.74 (s, 3H), 3.06 (t, J = 7.1 Hz, 2H), 1.64 – 1.54 (m, 2H),
1.46ꢀ1.37 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.0, 142.9, 114.9, 114.0, 55.8, 44.7, 31.8, 20.4, 14.0.
N-butyl-4-methylaniline (3n).31 General procedure B (135 mg,
83%), eluting with petroleum ether/ethyl acetate (20:1), colorless
oil; 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.1 Hz, 2H), 6.55 (d,
J = 8.2 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.65 – 1.51
(m, 2H), 1.46 – 1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 146.3, 129.7, 126.4, 113.0, 44.1, 31.7, 20.4,
20.4, 14.0.
1-(4-(Trifluoromethyl)phenyl)piperidine
(8j).29
General
procedure B (146 mg, 64%), eluting with petroleum ether/ethyl
acetate (20:1), colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.44 (d,
J = 8.5 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 3.26 – 3.24 (m, 4H), 1.68
ꢀ 1.61 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 153.8, 128.9, 126.4,
126.3, 126.3, 126.3, 123.6, 120.9, 119.7, 119.4, 114.6, 49.3, 25.4,
24.3.
4-(4-Methoxyphenyl)morpholine (1k).15a General procedure A
(170 mg, 88%), general procedure B (131 mg, 68%), general
procedure F (170 mg, 88%), eluting with petroleum ether/ethyl
acetate (20:1), white solid; 1H NMR (400 MHz, CDCl3) δ 6.92 ꢀ
6.85 (m, 4H), 3.90 – 3.83 (m, 4H), 3.78 (s, 3H), 3.10 – 3.03 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 154.1, 145.8, 117.9, 114.5,
67.0, 55.6, 50.9.
N-butyl-4-nitroaniline (7n).19 General procedure C (132 mg,
68%), general procedure D (116 mg, 60%), eluting with petroleum
ether/ethyl acetate (20:1), yellow solid; 1H NMR (400 MHz, CDCl3)
δ 8.07 (d, J = 9.1 Hz, 2H), 6.52 (d, J = 9.1 Hz, 2H), 4.67 (s, 1H),
3.21 (t, J = 7.1 Hz, 2H), 1.69 – 1.59 (m, 2H), 1.50 – 1.38 (m, 2H),
0.97 (t, J = 7.3 Hz, 3H);13C NMR (100 MHz, CDCl3) δ 153.6, 137.5,
126.5, 110.9, 43.1, 31.1, 20.2, 13.8.
4-Phenylmorpholine (3k).15a General procedure A (132 mg,
81%), eluting with petroleum ether/ethyl acetate (20:1), white
solid; 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.24 (m, 2H), 6.97 –
6.84 (m, 3H), 3.89 – 3.83 (m, 4H), 3.19 – 3.13 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 151.2, 129.2, 120.1, 115.8, 66.9, 49.4.
1-(4-Morpholinophenyl)ethanone (6k).15a General procedure
A (158 mg, 77%), eluting with dichloromethane/methanol (20:1),
yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.9 Hz, 2H),
6.90 (d, J = 8.9 Hz, 2H), 3.90 – 3.83 (m, 4H), 3.35 – 3.28 (m, 4H),
2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.5, 154.0, 130.4,
128.4, 113.5, 66.5, 47.7, 26.2.
2-((4-Methoxyphenyl)amino)ethanol
(1o).32
General
procedure A (142 mg, 85%), general procedure E (144 mg, 86%),
general procedure F (144 mg, 86%), eluting with dichloromethane
1
/methanol (20:1), colorless oil; H NMR (400 MHz, CDCl3) δ 6.79
(d, J = 8.9 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.84 – 3.78 (m, 2H),
3.75 (s, 3H), 3.28 – 3.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
152.5, 142.2, 115.0, 114.9, 60.9, 55.8, 47.2.
3-((4-Methoxyphenyl)amino)propan-1-ol (1p).33 General
procedure
A (134 mg, 74%), eluting with dichloromethane
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/methanol (20:1), colorless oil, general procedure B (103 mg,
(t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 151.1, 143.3,
114.8, 114.5, 55.8, 51.8, 29.5, 20.5, 14.1.
57%); 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J = 8.9 Hz, 2H), 6.64
(d, J = 8.9 Hz, 2H), 3.80 (t, J = 5.8 Hz, 2H), 3.75 (s, 3H), 3.24 (t, J
= 6.4 Hz, 2H), 1.90 – 1.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
152.3, 142.5, 114.9, 114.8, 61.3, 55.8, 43.0, 31.8.
N,N-dibutyl-4-methylaniline (3s).31 General procedure B (112
mg, 51%), eluting with petroleum ether, colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.01 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.1 Hz, 2H),
3.24 – 3.20 (m, 4H), 2.27 (s, 3H), 1.57 – 1.50 (m, 4H), 1.36ꢀ1.26
(m, 4H), 0.93 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
146.2, 129.7, 124.4, 112.2, 51.1, 29.5, 20.5, 20.2, 14.1.
N,N-dibutylaniline (4s).36 General procedure A (162 mg, 79%).
eluting with petroleum ether, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.22 – 7.14 (m, 2H), 6.68 – 6.55 (m, 3H), 3.25 (t, J = 7.5
Hz, 4H), 1.61 – 1.50 (m, 4H), 1.42 – 1.29 (m, 4H), 0.95 (t, J = 7.2
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 148.3, 129.2, 115.2, 111.8,
50.8, 29.5, 20.4 14.03.
3-(Phenylamino)propan-1-ol (3p).34 General procedure A (98
mg, 65%), general procedure B (83 mg, 55%), eluting with
dichloromethane /methanol (20:1), colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.18 (t, J = 7.6 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H),
6.64 (d, J = 8.1 Hz, 2H), 3.78 (t, J = 5.8 Hz, 2H), 3.26 (t, J = 6.4 Hz,
2H), 1.90–1.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.2,
129.3, 117.8, 113.2, 61.6, 42.0, 31.9.
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3-((4-(Trifluoromethyl)phenyl)amino)propan-1-ol
(8p).
General procedure A (175 mg, 80%), eluting with dichloromethane
/methanol (20:1), colorless oil; MS(ESI+): m/z: 220 ([M+H]+); 1H
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 6.62 (d, J = 8.4
Hz, 2H), 3.81 (t, J = 5.8 Hz, 2H), 3.30 (t, J = 6.1 Hz, 2H), 1.93 –
1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.7, 126.6, 126.5,
126.3, 123.7, 119.0 118.6, 112.0, 61.3, 41.3, 31.5; IR (KBr, cmꢀ1):
3409, 2944; Anal.Calcd for C10H12F3NO: C, 54.79; H, 5.52; N, 6.39.
Found: C, 54.52; H,5.54; N, 6.02.
N,N-dibutyl-4-(trifluoromethyl)aniline
(8s).35
General
procedure A (218 mg, 80%), general procedure B ( 82 mg, 30%),
eluting with petroleum ether, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.3 Hz, 2H), 3.32 –
3.25 (m, 4H), 1.62 – 1.51 (m, 4H), 1.41 – 1.30 (m, 4H), 0.96 (t, J =
7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.2, 138.0, 126.6,
126.4, 123.9, 110.6, 50.7, 29.2, 20.3, 13.9.
5-((4-Methoxyphenyl)amino)pentan-1-ol
(1q).
General
N,N-dibutyl-4-(thiophen-3-yl)aniline
(12s).35
General
procedure (173 mg, 83%), eluting with dichloromethane
A
procedure A (148 mg, 70%), general procedure F (167 mg, 79%),
eluting with petroleum ether, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.17 (d, J = 2.6 Hz, 1H), 6.73 (d, J = 5.0 Hz, 1H), 5.80 (s,
1H), 3.18 – 3.11 (m, 4H), 1.58 – 1.49 (m, 4H), 1.38 – 1.27 (m, 4H),
0.93 (t, J = 7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.5,
/methanol (20:1), colorless oil; MS(ESI+): m/z: 210 ([M+H]+) ;1H
NMR (400 MHz, CDCl3) δ 6.78 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8
Hz, 2H), 3.75 (s, 3H), 3.65 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 7.0 Hz,
2H), 1.68 – 1.57 (m, 4H), 1.53 – 1.43 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 152.1, 142.7, 114.9, 114.4, 62.4, 55.8, 45.1, 32.4, 29.3,
23.4. IR (KBr, cmꢀ1): 3371, 2934, 1513, 1235; Anal.Calcd for
C12H19NO2•0.33H2O: C, 66.96; H, 9.21; N, 6.51; Found: C, 67.08;
H, 9.45; N, 6.23.
124.6, 118.9, 94.6, 52.3, 29.5, 20.4, 14.0.
15a
Synthesis of 2-((2-bromophenyl)thio)aniline (15t).
A 10
mL vial was charged with CuI (9.5 mg, 0.05 mmol), L1 (13.7 mg,
0.05 mmol), 1ꢀbromoꢀ2ꢀiodobenzene (283 mg, 1.0 mmol),
2ꢀaminobenzenethiol (163 mg, 1.3 mmol), K3PO4 (424 mg, 2.0
mmol), DEG (2.0 mL) and a magnetic stir bar. The vessel was
sealed with a septum. The reaction mixture was stirred at room
temperature for 12h. Then, 15 mL water was added, and the
reaction mixture was extracted with ethyl acetate (3 × 15 mL). The
combined organic phases were washed with brine (15 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified using flash column chromatograph on silica gel
eluting with petroleum ether/ethyl acetate (20:1) to afford
2ꢀ((2ꢀbromophenyl)thio)aniline (233 mg, 84%): yellow solid; 1H
NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6
Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.93 (t, J
= 7.5 Hz, 1H), 6.77 (dd, J = 16.2, 8.0 Hz, 2H), 6.59 (d, J = 7.9 Hz,
N,N-diethyl-4-methoxyaniline (1r).11 General procedure
A
(145 mg, 81%), eluting with petroleum ether/ethyl acetate (20:1),
colorless oil; 1H NMR (400 MHz, CDCl3) δ 6.82 (d, J = 9.0 Hz, 2H),
6.71 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 3.25 (q, J = 7.0 Hz, 4H), 1.10
(t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 151.6, 142.9,
115.3, 114.8, 55.8, 45.4, 12.5.
N,N-dibutyl-4-methoxyaniline (1s).35 General procedure A
(202 mg, 86%), general procedure B (113 mg, 48%) general
procedure E (183 mg, 78%), general procedure F (192 mg, 82%),
eluting with petroleum ether, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 6.86 – 6.77 (m, 2H), 6.70 – 6.60 (m, 2H), 3.76 (s, 3H),
3.21 – 3.13 (m, 4H), 1.59 – 1.45 (m, 4H), 1.38 – 1.25 (m, 4H), 0.93
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1H), 4.19 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 149.1, 138.0,
137.9, 132.8, 131.8, 127.8, 126.3, 126.3, 120.7, 119.1, 115.6,
113.2.
ꢀ
ACKNOWLEDGMENTS
This work was supported financially by grants from the National
Natural Science Foundation of China (21272287, 21272282).
Synthesis of 10H-phenothiazine (15u). 15a
A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), L1
(13.8 mg, 0.05 mmol), 2ꢀ((2ꢀbromophenyl)thio)aniline (280mg, 1.0
mmol), K3PO4 (424 mg, 2.0 mmol), DEG (2.0 mL), molecular sieve
(4Å MS, 100 mg) and a magnetic stir bar. The vessel was sealed
8
9
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with
a septum. The reaction mixture was stirred at room
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10Hꢀphenothiazine (133 mg, 67%). Green solid; 1H NMR (400
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A 10 mL vial was charged with CuI (10 mg, 0.05 mmol), L1
(13.7 mg, 0.05 mmol), 1ꢀbromoꢀ2ꢀiodobenzene (283 mg, 1.0
mmol), 2ꢀaminobenzenethiol (163 mg, 1.3 mmol), K3PO4 (1060
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10Hꢀphenothiazine (139 mg, 70%).
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AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: ceswyq@mail.sysu.edu.cn; zhuxinh@mail.sysu.edu.cn
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ORCID
0000ꢀ0002ꢀ9591ꢀ9022
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Notes
The authors declare no competing financial interest.
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