Practical direct synthesis of: N -aryl-substituted azacycles from N -alkyl protected arylamines using TiCl4and DBU

Article abstract of DOI:10.1039/d0ob00880j

A novel transformation of N-alkyl protected arylamines and cyclic ethers into N-aryl substituted azacycles is described. Alkyl groups have been used for the protection of amines in organic syntheses. In this synthesis, N-alkyl protected arylamines were reacted with cyclic ethers in the presence of TiCl4 and DBU, crucial reagents affording five- and six-membered azacycles. In particular, utilization of the novel TiCl4/DBU-mediated reaction allows various N-alkyl protected arylamines such as N-methyl-, N-ethyl-, N-isopropyl, and N-tert-butyl arylamines to be readily converted into N-aryl substituted azacycles in high yields. This practical approach using various N-alkyl arylamines leads to the efficient preparation of azacycles.

Full text of DOI:10.1039/d0ob00880j

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DOI: 10.1039/D0OB00880J
ARTICLE
Practical Direct Synthesis of N-Aryl-Substituted Azacycles from
N-Alkyl Protected Arylamines Using TiCl4 and DBU
Received 00th January 20xx,
Accepted 00th January 20xx
Van Hieu Tran a,b, Minh Thanh La a,b, Soosung Kang,c and Hee-Kwon Kim a,b,
*
DOI: 10.1039/x0xx00000x
Novel transformation of N-alkyl protected arylamines and cyclic ethers to N-aryl substituted azacycles is described. Alkyl
groups have been used for protection of amines in organic syntheses. In this synthesis, N-alkyl protected arylamines were
reacted with cyclic ethers in the presence of TiCl4 and DBU, crucial reagents affording five- and six-membered azacycles. In
particular, utilization of the novel TiCl4/DBU-mediated reaction allows various N-alkyl protected arylamines such as N-
methyl-, N-ethyl-, N-isopropyl, and N-tert-butyl arylamines to be readily converted to N-aryl substituted azacycles in high
yields. This practical approach using various N-alkyl arylamines provides an efficient preparation of azacycles.
dihalides or diols, reduction of tertiary lactams or azacyclodienes via
cyclocondensaion of dicarbonyl compounds, and cross-coupling of
N-unsubstituted azacycles with aryl halides.[11-17] Condensation
between a primary arylamine and cyclic ether was also reported as a
challenging approach due to production of water as a by-product.
Introduction
Heterocyclic moieties containing nitrogen are frequently used as
structures in organic chemistry, materials science, and drug
development. Increasing utilization of heterocyclic derivatives
containing nitrogen such as N-arylpyrrolidine and N-arylpiperidine
has been appealing recently due to their properties as building blocks
for a myriad of materials,[1,2] bioactive small molecules,[3-7] and
several new pharmaceuticals.[8-10] Specifically, various N-substituted
aryl azacycle structures are found in FDA-approved clinical drugs
(Figure 1). Exploring a novel methodology for preparation of N-
substituted five- and six-membered heterocyclic amines could
significantly contribute to the useful synthetic chemistry toolbox.
F
Several reagents such as aluminum-based reagents including Al2O3,
[21,22]
AlCl3, or AlMe3;[18-20] Lewis acids;
or protic acids[23,24] have
been employed for this primary amine-based synthesis. In a previous
study, we reported a metal-free N-heterocyclization method with
primary arylamines to generate N-substituted azacycles.[25-26]
Alkyl groups can be used for protection of amines in organic
syntheses. N-Alkyl arylamines, one of the NH protected forms of
arylamine, have frequently been used in multi-step syntheses since
several methods for protection of arylamines by an alkyl group were
reported,[27-30] and various N-alkyl deprotection methods were
developed for wide utilization of N-alkyl arylamines in organic
synthesis. Removal of the alkyl group was achieved by oxidative
demethylation using various reagents including I2/CaO,
PhIO/TMSN3, MCPBA with TEA and TFAA, and through reaction
with DEAD/acetone with MeOH/NH4Cl.[31-34] However, N-alkyl
arylamines, which are secondary arylamines, are considered inert in
many chemical transformations to cleave the alkyl group due to the
stability of the N-C bond. Even though scientists know that synthesis
of N-substituted azacycles is important in organic chemistry due to
their numerous applications, most synthetic reactions of N-
substituted azacycles have been carried out using primary arylamines,
while utilization of N-alkyl arylamines as substrate was rarely
reported due to low reactivity. For instance, Zhang and co-workers
reported various reaction examples using primary arylamines as
starting material, but they reported only one example using N-methyl
arylamine (secondary amine) for synthesis of N-substituted
azacycles.[23] Moreover, the method has several weaknesses: The
reaction of N-methyl arylamine requires high temperature such as
180 oC and a long reaction time. Furthermore, the synthetic yield of
N-substituted azacycle from N-methyl arylamine is less than 50%.
Thus, overcoming the drawbacks of secondary arylamines such
as low reactivity is necessary to efficiently prepare azacycles, and
development of a new useful synthetic method for direct azacycle
synthesis from secondary arylamines would be valuable. Herein, we
describe a novel facile Lewis acid/base-mediated azacycle synthesis
from N-alkyl protected arylamines and cyclic ethers.
O
O
O
H
O
O
O
O
N
N
NH
HN
N
N
Cl
O
O
N
NH
N
N
N
F
F
N
N
N
P
HN
NH
O
N
F
F
Pibrentasvir
Brigatinib
Figure 1. FDA-approved novel drugs containing N-substituted
azacycles
There have been numerous methods developed to synthesize N-
substituted aryl azacycles to date: dialkylation of amines with
a.Address here Department of Nuclear Medicine, Molecular Imaging & Therapeutic
Medicine Research Center, Chonbuk National University Medical School and
Hospital, Jeonju, 54907, Republic of Korea
b.Research Institute of Clinical Medicine of Chonbuk National University-Biomedical
Research Institute of Chonbuk National University Hospital, Jeonju, 54907,
Republic of Korea
c. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha
Womans University, Seoul 03760, Republic of Korea
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Previous studies:
,
Table 1. Screening of reaction conditions for the preparation of
View Article Online
DOI: 10.1039/D0OB00880J
N N
of
using dihalides
azacycles[a]
-
or
diol
-dialkylation
primary arylamine
H
NH2
N
-
N
Reagents,
Base
n
+
X
n
X-(CH2)
O
+
N
=
X
Br,
I,
Cl,
OH
xylene
120 o 14h
C,
-
N
of
primary arylamine
-hetero-cyclization
3a
2a
1a
R2
NH2
Entry
Reagent
Base
Yield[b] (%)
metal-based
R2
reagents
O
N
+
R1
n
NR[c]
NR[c]
NR[c]
NR[c]
NR[c]
NR[c]
5
R1
Al2O3 AlCl AlMe TiO
n
1
2
3
4
5
6
7
8
CuCl2
BiCl2
ZrCl4
MnCl2
AlCl3
ZnCl2
SnCl2
TiCl4
-
-
-
-
-
-
-
-
=
metal-based
,
,
3
,
3
reagents
2
work:
This
R2
TiCl4
DBU
H
N
R2
N
O
+
n
APG
R1
R1
n
=
24
APG methyl,
tert-butyl
ethyl, isopropyl,
9
DABAL-Me3
TiCl4
-
NRc
4
10
12
3
9
47
93
Scheme 1. Synthesis of N-substituted azacycles.
10
11
12
13
14
15
16
17
18
NaOH
K2CO3
CsCO3
NaHCO3
Et3N
DBN
DBU
DMAP
DBU
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
None
Results and discussion
According to previously reported methods using arylamines, primary
arylamines are generally reacted with cyclic ethers to prepare N-
substituted azacycles. Thus, synthesis of azacycles from N-alkyl
protected arylamines would require two separate processes: removal
of the alkyl group of the N-alkyl arylamine to generate a primary
amine and reaction of the primary amine with cyclic ether to produce
azacycle. Therefore, direct conversion of an N-alkyl protected
arylamine to azacycle is a useful yet challenging reaction. In this
study, a novel Lewis acid/base-mediated reaction system was
investigated to produce N-aryl substituted azacycles. In the initial
exploratory study, reactions of N-ethyl protected arylamines (1a)
with THF (2a) were performed at 120 oC for 14 h.
3
NRc
a Reaction conditions: compound 1a (2.0 mmol), THF 2a (40 mmol),
reagent (3.0 mmol), DBU (4.0 mmol), xylene (0.5 mL), 120 oC, 14 h.
b Isolated yield after purification by flash column chromatography.
c No reaction.
Several metal-based reagents were examined: CuCl2, BiCl2,
ZrCl4, MnCl2, AlCl3, and ZnCl2 were employed to synthesize
azacycles; however, the target product was not produced using these
reagents. We found that introduction of SnCl2 to the reaction showed
a low product yield (5% for SnCl2). TiCl4 was also investigated for
preparation of azacycle and produced target product in 24% yield.
DABAL-Me3 also failed to produce the target product. Thus, TiCl4
was chosen for further examination.
Table 2. Screening of solvents for preparation of azacycles[a]
H
TiCl4
N
DBU
+
N
O
Solvent
120 o 14h
C,
3a
1a
2a
Next, screening of several bases for preparation of azacycle was
performed to generate a synergistic effect with TiCl4 for more
efficient synthesis. As shown in Table 1, K2CO3, CsCO3, NaOH, and
NaHCO3 did not produce the target product in satisfactory reaction
yields (less than 15%). Similarly, reaction in the presence of
trimethylamine (Et3N), a liquid organic base, did not increase the
synthetic yield of azacycles (9%). 1,5-Diazabicyclo[4.3.0]non-5-ene
(DBN) was also used for the reaction, and the corresponding product
was obtained in 47% yield, while utilization of 1,8-
diazabicyclo(5.4.0)undec-7-ene (DBU) afforded the target product in
higher yield (93%). This result suggested that the combination of
TiCl4 and DBU could be used for efficient azacycle synthesis.
Reaction solvents, a crucial factor in the reaction, were examined
(Table 2). Reactions in 1,4-dioxane, DMF, and DMSO solvent
afforded azacycles in less than 15% yield, while employment of
MeCN and PhCF3 for the reaction produced the corresponding
products in good synthetic yield (77% for MeCN and 81% for
PhCF3). However, when toluene and xylene were tested as reaction
solvents, the target products were prepared in high yield (92% for
toluene and 93% for xylene), indicating that toluene and xylene were
better solvents for direct preparation of azacycles from N-alkyl
arylamines.
Entry
Reagent
TiCl4
Solvent
Temp.
reflux
Yield[b](%)
8
1
1,4-
dioxane
2
3
4
5
6
7
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
DMF
120 °C
120 °C
reflux
reflux
reflux
120 °C
11
10
77
81
92
93
DMSO
MeCN
PhCF3
Toluene
Xylene
a Reaction conditions: compound 1a (2.0 mmol), THF 2a (40 mmol),
TiCl4 (3.0 mmol), DBU (4.0 mmol), solvent (0.5 mL), 14 h;
b Isolated yield after purification by flash column chromatography.
2 | J. Name., 2012, 00, 1-3
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Table 3. Screening of reaction conditions for preparation of entry 7). In addition, N-ethyl protected naphthylamine was treated
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azacyclesa
DOI: 10.1039/D0OB00880J
with THF, which produced the target product in high yield (85%).
H
TiCl4
DBU
N
Table 4. Scope of synthesis of azacycloalkanes from various N-ethyl
aryaminesa
+
O
N
Xylene
120 o 14h
C,
1a
2a
3a
H
TiCl4
N
R1
DBU
+
N
R1
O
120 o 14h
C,
Entry
THF
(equiv.)
TiCl4
(equiv.)
DBU
(equiv.)
Yieldb
(%)
1
2
3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
20
20
20
20
20
20
20
20
20
20
20
5
0
0.5
1
1.5
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
2
2
2
2
0
0.5
1
1.5
2
3
NRc
21
53
93
93
28
58
67
75
93
93
59
81
93
Entry N-ethylamine
Product
Yieldb (%)
H
N
1a
1
3a
3b
93
89
N
H
N
2
1b
N
H
N
1c
1d
3
3c
3d
95
93
N
H
N
4
MeO
N
N
2
2
2
MeO
H
N
10
30
5
1e
1f
3e
3f
85
87
Reaction conditions: compound 1a (2.0 mmol, 1.0 equiv.), 120 oC,
a
14 h.
H
N
b Isolated yield after purification by flash column chromatography.
c No reaction.
6
N
Next, various equivalents of TiCl4 and DBU were screened to
determine optimal reaction conditions to produce azacycles (Table 3).
Reactions using N-ethyl arylamines were carried out with a series of
TiCl4 and DBU amounts. Employment of 1.5 equiv. of TiCl4 and 2
equiv. of DBU gave the desired product in high yield, while
additional equivalents of TiCl4 and DBU did not provide a positive
benefit to the synthetic yield. In addition, different amounts of THF
were tested, and 20 and 30 equiv. of THF gave a higher yield of
azacycle. Less than 20 equiv. of THF in the reaction led to a
decrease in synthetic yield (81% for 10 equiv. of THF and 59% for 5
H
N
1g
1h
3g
7
N
71
93
H
N
N
Cl
Cl
8
3h
3i
Cl
H
N
Cl
1i
1j
94
93
9
N
H
N
equiv. of THF).
Reaction was also conducted at various
F
N
3j
temperatures, and high yield was achieved via reaction at 120 oC and
130 oC (See Table S1).
10
11
F
F
H
N
With optimal reaction conditions, the TiCl4/DBU-mediated
synthetic method was applied to reactions with various types of N-
alkyl protected arylamines and cyclic ethers to determine the scope
of this reaction. First, a variety of N-ethyl protected arylamines was
tested for reaction with tetrahydrofuran (THF), a five-membered
cyclic ether (Table 4). Reactions using N-ethyl arylamines were
successfully conducted to give high yields of azacycles. Not only
reactions of N-ethyl arylamines containing electron-donating
substituents (methyl-, tert-butyl-, and methoxy-), but also reactions
of N-ethyl arylamines bearing electron-withdrawing substituents
(chloro-, fluoro-, nitrile-, and nitro-) with THF yielded the
corresponding azacycles in high yield, which indicates that the target
products are readily prepared via the novel TiCl4/DBU-mediated
reaction method regardless of the electronic effect of substituents.
Because steric hindrance usually has a negative effect on synthetic
yield, N-ethyl 2,6-dimethylaniline was employed for reaction with
THF to produce the desired azacycle in good yield (3g, Table 4,
1k
3k
92
F
N
N
F
F
H
N
NC
1l
12
13
3l
84
70
NC
H
N
N
O2
N
1m
3m
N
O2
H
N
3n
1n
14
85
N
a
Reaction conditions: compound 1 (2.0 mmol), THF 2a (40 mmol),
TiCl4 (3.0 mmol), DBU (4.0 mmol), 120 oC, 14h.
b Isolated yield after purification by flash column chromatography.
Next, reactions with several types of cyclic ethers were
examined. 2-Methyltetrahydrofuran is more sterically hindered than
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J. Name., 2013, 00, 1-3 | 3
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tetrahydrofuran even though both are five-membered cyclic ethers. and natural products contain nitrogen-fused heteVrioewcyAcrtlicicle Ornilninge
When 2-methyltetrahydrofuran was treated with several N-ethyl structures such as tetrahydroisoquinoline anDdOisI:o1i0n.d1o0l3i9n/eD.[03O5-3B70] 0T8h8u0sJ,
protected arylamines containing electron-donating and electron- facile preparation of molecules bearing tetrahydroisoquinoline and
withdrawing groups, the reactions readily afforded the target isoindoline is important in drug discovery. The novel TiCl4/DBU-
products (5, entries 1-4). In addition, a six-membered cyclic ether mediated reaction method was employed for synthesis of nitrogen-
was used to react with N-ethyl protected arylamines to produce the fused heterocyclic ring compounds. Various N-ethyl protected
corresponding azacycle in high yield (Table 5, entry 5).
Table 5. Scope of synthesis of azacycloalkanes using various cyclic
ethersa
arylamines were treated with phthalan or isochroman in the presence
of TiCl4 and DBU, and the desired N-aryl substituted azacycles were
generated in high yields (Table 5, entries 6-13). N-Ethyl protected
arylamines containing electron-donating or electron-withdrawing
groups were investigated for reaction with phthalan or isochroman,
and the target isoindoline and tetrahydroisoquinoline structures were
successfully obtained in satisfactory yields.
The scope of the TiCl4/DBU-mediated method was further
explored via - reaction of N-alkyl protected arylamines bearing
various alkyl groups to afford azacycles since several types of alkyl
groups have been used as protecting groups for amines. N-Methyl
arylamines bearing electron-donating or electron-withdrawing
groups were treated with THF, yielding the target products in good
yields. In addition, N-isopropyl and N-tert-butyl protected
arylamines were treated with THF under the same TiCl4/DBU-
mediated reaction conditions to successfully provide the
corresponding azacycles in high yields.
TiCl4
H
R2
R2
N
R1
DBU
N
+
R1
O
120 o 14h
C,
n
2
n
n =
1
1,
4
2
Entry N-ethylamine
Product
Yieldb (%)
H3C
H
N
1a
4a
93
1
2
3
N
H3C
N
H
N
4b
84
92
1b
1c
Table 6. Scope of synthesis of azacycloalkanes from various N-alkyl
protected arylaminesa
H3C
N
H
N
4c
4d
H
TiCl4
DBU
R1
N
H
R3
H3C
N
N
+
O
N
R1
1d
1e
120 o 14h
92
4
5
6
C,
F
F
2a
5
6
H
N
N
89
84
83
4e
4f
Entry N-alkylamine
Product
Yieldb (%)
H
N
H
N
1f
N
1
6a
5a
5b
93
N
H
N
H
N
4g
1g
1h
N
N
7
8
2
6b
6c
MeO
NC
N
87
82
H
MeO
N
4h
4i
88
85
H
N
N
H
N
5c
3
1i
1j
9
Cl
N
NC
Cl
H
N
H
N
N
N
4
4j
84
5d
5e
90
87
6d
6e
N
10
H
H
N
N
5
11
12
86
84
1k
1l
4k
4l
N
N
N
a
H
Cl
Reaction conditions: compound 5 (2.0 mmol), THF 2a (40 mmol),
N
TiCl4 (3.0 mmol), DBU (4.0 mmol), 120 oC, 14h.
b Isolated yield after purification by flash column chromatography.
Cl
H
NC
N
13
1m
In additions, reactions of aniline were performed under the same
condition to compare the reactivity of aniline and N-ethylaniline.
The result indicated that reactions of aniline gave high yield than
that of N-ethylaniline (95% yield for reactions of aniline for 10 h vs.
91% yield for reactions of N-ethylaniline for 10 h), which suggested
that primary arylamine is more reactive than ethyl protected aniline
(secondary arylamine).
Besides, reactions using nucleophiles such as dibenzyl amines,
benzyl alkyl amines, and phenyl ethyl N-ethyl amines were carried
out as shown in Scheme 2. The reactions using dibenzyl amines and
86
4m
NC
a
Reaction conditions: compound 1 (2.0 mmol), cyclic ether 4 (40
mmol), TiCl4 (3.0 mmol), DBU (4.0 mmol), 120 oC, 14 h.
b Isolated yield after purification by flash column chromatography.
Several biologically active molecules such as pharmaceuticals
4 | J. Name., 2012, 00, 1-3
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benzyl alkyl amines were not successful to afford the desired
products (7% yield for dibenzyl amines, 5% yield for benzyl alkyl
amines, and no reaction for phenyl ethyl N-ethyl amines). The result
suggested that our new reaction condition is more suitable for N-
Cl
View Article Online
Cl
N
Ti
DOI: 10.1039/D0OB00880J
Cl
Cl
NH
O
TiCl4
Cl
Cl
N
Ti
Cl
O
H
HCl
DBU
DBU
alkyl protected arylamine than N-alkyl protected aliphatic amine.
14
1a
15
TiCl4
DBU
Cl
Ti
Cl
N
+
N
O
Cl
Ti
Cl
H
Cl
Cl
Cl
Ti
Cl
Xylene
C,
N
Cl
120 o 14 h
N
O
N
O
8
2a
7
O
TiCl4
DBU
17
18
16
NH
+
O
N
Cl
Ti
-TiOCl2
CH2CH2Cl
Xylene
Cl
Cl
-
N
N
9
120 o 14 h
C,
8
2a
O
Scheme 2. Reactions with N-alkyl protected aliphatic amine
3a
19
Reaction of two N-alkyl secondary arylamine moieties within the
molecule with a different N-alkyl group (ethyl and iso-propyl) was
performed for the preparation of azacycles as shown in Scheme 3.
Reaction of N-alkyl secondary arylamine moieties containing ethyl
and iso-propyl group (compound 10) at 110 oC provided an azacycle
with one N-heterocycle (five membered heterocycle) (38%), and an
azacycle with two N-heterocycle (five membered heterocycle) (51%).
And then reaction of compound 12 with tetrahydropyran afforded an
azacycle with two different N-heterocycles (five membered
heterocycle and six membered heterocycle).
Scheme 4. A plausible mechanism for conversion of N-alkyl
arylamines to N-aryl substituted azacycles
Conclusions
In summary, a novel efficient Lewis acid/base-mediated
synthetic method for preparation of N‑aryl-substituted
azacycles from N-alkyl protected arylamines and cyclic ethers
is described. Both TiCl4 and DBU reagents were important to
enhance transformation of N-alkyl protected arylamines to the
target azacycles. This TiCl4/DBU-mediated method can utilize
a variety of N-alkyl arylamines including N-methyl arylamines,
N-ethyl arylamines, N-isopropyl arylamines, or N-tert-butyl
arylamines to successfully react with cyclic ethers to afford the
corresponding products in high yields. Thus, this efficient
synthetic method using N-alkyl arylamines could be an
important tool to directly provide useful azacycles.
N
N
THF
H
11
TiCl4
DBU
)
(51%
N
N
+
N
Xylene
H
110 o 14 h
C,
10
N
H
12
(38%)
N
Experimental
General procedure for the synthesis of azacyles
Tetrahydropyran
N
TiCl4
DBU
The mixture of N-ethylaniline (1a) (0.242 g, 2.00 mmol) and
DBU (0.609 g, 4.00 mmol) was added in a vial containing 0.50
ml o-xylene. TiCl4 (2.00 M in dichromethane) (1.50 mL, 3.00
mmol) was added dropwise to the reaction mixture at room
temperature. Tetrahydrofuran (3.2 mL, 40.00 mmol) were
added to the reaction mixture. The reaction mixture was heated
at 120°C for 14h after the vial was closed tightly by Teflon cap.
The reaction was cooled down to the room temperature, then
saturated aq. NaHCO3 (10 mL) and brine (10mL) were added to
the mixture. The aqueous mixture was extracted with Et2O (20
ml x 2) and the combine organic layer was dried over Na2SO4,
then the solvent was evaporated under reduced pressure. The
crude product was then purified by flash column
chromatography on silica gel by 2% diethyl ether in n-hexane
as eluent to afford the desired product 3a (0.273 g, 93%).
N
N
Xylene
H
130 o 15 h
C,
13
(74%)
12
Scheme 3. Synthesis of N‑azacycles with two N-heterocycles
To obtain a mechanistic insight into the new synthetic method,
control experiments were performed. Reaction with DBU alone did
not afford the corresponding product, while reaction with TiCl4
alone produced the corresponding product in low yield (Table 1). It
appears that DBU helps to enhance the synthetic yield by activation
of the arylamine. A plausible mechanism for direct conversion of N-
alkyl arylamines to N-aryl substituted azacycles in the presence of
TiCl4 and DBU is depicted in Scheme 4. The reaction begins with
formation of the N-alkyl arylamine-TiCl4-THF complex after 1a is
treated with TiCl4 and THF. HCl produced in the reaction is
removed by DBU, followed by ring opening to give 17.
Intramolecular attack of the nitrogen on the carbon nearest the
titanium atom and release of TiOCl2 and CH3CH2Cl from the cyclic
intermediate give the target product, 1-phenylpyrrolidine 3a.
1-phenylpyrrolidine (3a). Light yellow oil; 1H NMR (400
MHz, CDCl3) δ 7.29 (t, J = 7.2 Hz, 2H), 6.72 (t, J = 7.2 Hz,
1H), 6.63 (d, J = 8.0 Hz, 2H), 3.39 - 3.29 (m, 4H), 2.11 - 2.00
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 148.0, 129.1 (2C),
115.4, 111.7 (2C), 47.6 (2C), 25.5 (2C); HRMS (ESI) m/z
(M+H)+ calcd for C10H14N = 148.1126; found 148.1129.
1-p-tolylpyrrolidine (3b). Light yellow oil; 1H NMR (400
MHz, CDCl3) δ 7.05 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.4 Hz,
2H), 3.28 - 3.25 (m, 4H), 2.26 (s, 3H), 2.01 - 1.98 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 146.1, 129.6 (2C), 124.4, 111.8
(2C), 47.8 (2C), 25.4 (2C), 20.3; HRMS (ESI) m/z (M+H)+
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Journal Name
1-(4-nitrophenyl)pyrrolidine (3m). Yellow soliVdie;wmAr.tipcl.e O1n6li7ne-
calcd for C11H16N = 162.1283; found 162.1284.
1
1-
m
-tolylpyrrolidine (3c). Colorless oil; H NMR (400 MHz, 168 °C; 1H NMR (400 MHz, CDCl3) δ 8.15- 8.12 (dt, J = 9.2
DOI: 10.1039/D0OB00880J
CDCl3) δ 7.21 – 7.17 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.47 (d, Hz, J = 2.0 Hz, 2H), 6.49 – 6.45 (dt, J = 9.2 Hz, J = 2.0 Hz, 2H),
J = 6.0 Hz, 2H), 3.35 – 3.33 (m, 4H), 2.39 (s, 3H), 2.08 - 2.02 3.44 – 3.41 (m, 4H), 2.11 – 2.08 (m, 4H); 13C NMR (100 MHz,
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 148.1, 138.8, 129.1, CDCl3) δ 151.8, 136.6, 126.4 (2C), 110.4 (2C), 47.9 (2C), 25.4
116.4, 112.4, 108.9, 47.6 (2C), 25.5 (2C), 21.9; HRMS (ESI) (2C); HRMS (ESI) m/z (M+H)+ calcd for C10H13N2O2
=
m/z (M+H)+ calcd for C11H16N = 162.1283; found 162.1285.
193.0977; found 193.0978.
1
1-(4-methoxyphenyl)pyrrolidine (3d) Colorless oil; H NMR 1-(naphthalen-1-yl)pyrrolidine (3n). Light yellow oil; 1H
(400 MHz, CDCl3) δ 6.78 – 6.83 (m, 2H), 6.56 (d, J = 8.4 Hz, NMR (400 MHz, CDCl3) δ 8.23 - 8.21 (m, 1H), 7.82 - 7.79 (m,
2H), 3.76 (s, 3H), 3.26 - 3.22 (m, 4H), 2.03 - 1.98 (m, 4H); 13C 1H), 7.45 - 7.43 (m, 3H), 7.36 (t, J = 8.0 Hz, 1H), 7.01 – 6.99
NMR (100 MHz, CDCl3) δ 152.3, 143.1, 115.02, 112.67, 56.01 (d, J = 6.0 Hz, 1H), 3.42 - 3.39 (m, 4H), 2.08 - 2.04 (m, 4H);
(2C), 48.31, 25.36 (2C); HRMS (ESI) m/z (M+H)+ calcd for 13C NMR (100 MHz, CDCl3) δ 147.7, 134.9, 128.2, 128.1,
C11H16NO = 178.1232; found 178.1236.
125.9, 125.6, 124.7, 124.4, 121.4, 111.5, 52.8 (2C), 24.8 (2C);
1-(4-tert-butylphenyl)pyrrolidine (3e). Light yellow oil; 1H HRMS (ESI) m/z (M+H)+ calcd for C14H16N = 198.1283; found
NMR (400 MHz, CDCl3) δ 7.32 – 7.28 (m, 2H), 6.59 (d, J = 8.8 198.1284.
Hz, 2H), 3.33 - 3.29 (t, J = 6.0 Hz, 4H), 2.03 – 2.01 (m, 4H), 2-methyl-1-phenylpyrrolidine (4a). Light yellow oil; 1H NMR
1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 145.9, 137.9, (400 MHz, CDCl3) δ 7.28 - 7.24 (m, 2H), 6.69 – 6.61 (tt, J =
125.9, (2C), 111.3 (2C), 47.7 (2C), 33.7, 31.6 (3C), 25.5 (2C); 7.2 Hz, J = 1.2 Hz, 1H), 6.62 (dd, J = 8.0 Hz, J = 0.8 Hz, 2H),
HRMS (ESI) m/z (M+H)+ calcd for C14H22N = 204.1752; found 3.95 - 3.88 (m, 1H), 3.48 - 3.44 (m, 1H), 3.23 - 3.17 (m, 1H),
204.1751.
2.11 - 1.99 (m, 3H), 1.76 - 1.70 (m, 1H), 1.22 (d, J = 6.4 Hz,
1-(3,5-dimethylphenyl)pyrrolidine (3f). Colorless oil; 1H 3H); 13C NMR (100 MHz, CDCl3) δ 147.2, 129.1 (2C), 115.1,
NMR (400 MHz, CDCl3) δ 6.38 (s, 1H), 6.27 (s, 2H), 3.33 - 111.7 (2C), 53.6, 48.2, 33.1, 23.3, 19.4; HRMS (ESI) m/z
3.29 (m, 4H), 2.32 (d, J = 0.4 Hz, 6H), 2.05 – 2.00 (m, 4H); 13
NMR (100 MHz, CDCl3) δ 148.2, 138.7 (2C), 117.5, 109.7 2-methyl-1-
C
(M+H)+ calcd for C11H16N = 162.1283; found 162.1285.
1
m
-tolylpyrrolidine (4b). Colorless oil; H NMR
(2C), 47.6 (2C), 25.5 (2C), 21.7 (2C); HRMS (ESI) m/z (400 MHz, CDCl3) δ 7.15 - 7.11 (m, 1H), 6.51 – 6.49 (d, J =
(M+H)+ calcd for C12H18N = 176.1439; found 176.1441.
7.6 Hz, 1H), 6.44 – 6.42 (d, J = 6.4 Hz, 2H), 3.92 - 3.86 (m,
1-(2,6-dimethylphenyl)pyrrolidine (3g). Colorless oil; 1H 1H), 3.45 - 3.41 (m, 1H), 3.20 - 3.14 (m, 1H), 2.33 (s, 3H), 2.07
NMR (400 MHz, CDCl3) δ 7.08 – 6.99 (m, 3H), 3.24 – 3.21 (d, – 2.06 (m, 3H), 1.75-1.68 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H); 13
C
J = 6.4 Hz, 4H), 2.30 (s, 6H), 2.04 - 1.98 (m, 4H); 13C NMR NMR (100 MHz, CDCl3) δ 147.3, 138.8, 129.0, 116.1, 112.5,
(100 MHz, CDCl3) δ 145.5, 138.4 (2C), 128.5 (2C), 124.9, 50.0 109.02, 53.6, 48.2, 33.1, 23.3, 21.94, 19.5; HRMS (ESI) m/z
(2C), 26.5 (2C), 18.7 (2C); HRMS (ESI) m/z (M+H)+ calcd for (M+H)+ calcd for C12H18N = 176.1439; found 176.1436.
C12H18N = 176.1439; found 176.1440.
1-(3,5-dimethylphenyl)-2-methylpyrrolidine (4c). Colorless
1
1
1-(4-chlorophenyl)pyrrolidine (3h). Colorless oil; H NMR oil; H NMR (400 MHz, CDCl3) δ 6.36 (s, 1H), 6.27 (s, 2H),
(400 MHz, CDCl3) δ 7.19 - 7.16 (m, 2H), 6.51 - 6.47 (m, 2H), 3.92 - 3.88 (m, 1H), 3.46 - 3.42 (m, 1H), 3.19 - 3.15 (m, 1H),
3.29 - 3.26 (m, 4H), 2.05 - 2.02 (m, 4H); 13C NMR (100 MHz, 2.31 (s, 6H), 2.08 - 1.97 (m, 3H), 1.73 - 1.71 (m, 1H), 1.21 (d, J
CDCl3) δ 146.5, 128.8 (2C), 120.1, 112.6 (2C), 47.7 (2C), 25.5 = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.4, 138.71
(2C); HRMS (ESI) m/z (M+H)+ calcd for C10H13ClN = (2C), 117.3, 109.7 (2C), 53.5, 48.2, 33.1, 23.3, 21.8, 19.5;
182.0737; found 182.0739.
HRMS (ESI) m/z (M+H)+ calcd for C13H20N = 190.1596; found
1-(3-chlorophenyl)pyrrolidine (3i). Colorless oil; 1H NMR 190.1598.
(400 MHz, CDCl3) δ 7.14 - 7.10 (t, J = 8.0 Hz, 1H), 6.63 – 1-(4-fluorophenyl)-2-methylpyrrolidine (4d). Colorless oil;
6.61 (m, 1H), 6.54 – 6.53 (t, J = 2.0 Hz, 1H), 6.44 – 6.42 (dd, J 1H NMR (400 MHz, CDCl3) δ 6.98 - 6.94 (m, 2H), 6.54 - 6.49
= 8.0 Hz, J = 2.0 Hz, 1H), 3.28 - 3.25 (m, 4H), 2.05-1.98 (m, (m, 2H), 3.86 - 3.80 (m, 1H), 3.42 - 3.39 (m, 1H), 3.17 - 3.11
4H); 13C NMR (100 MHz, CDCl3) δ 148.8, 134.9, 129.9, 115.2, (m, 1H), 2.12 - 1.99 (m, 3H), 1.74 - 1.71 (m, 1H), 1.19 (d, J =
111.5, 109.9, 47.6 (2C), 25.4 (2C); HRMS (ESI) m/z (M+H)+ 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 155.8 & 153.5 (d,
calcd for C10H13ClN = 182.0737; found 182.0736.
JC-F = 231.8 Hz, 1C), 144.0, 115.6 & 115.4 (d, JC-F = 21.9 Hz,
1-(4-fluorophenyl)pyrrolidine (3j). Colorless oil; 1H NMR 2C), 112.2 & 112.1 (d, JC-F = 7.3 Hz, 2C), 54.0, 48.7, 33.2, 23.4,
(400 MHz, CDCl3) δ 6.98 - 6.92 (m, 2H), 6.51 - 6.46 (m, 2H), 19.4; HRMS (ESI) m/z (M+H)+ calcd for C11H15FN = 180.1189;
3.27 - 3.24 (m, 4H), 2.06 – 1.98 (m, 4H); 13C NMR (100 MHz, found 180.1186.
1
CDCl3) δ 155.9 & 153.7 (d, JC-F = 231.8 Hz, 1C), 144.8, 115.5 1-phenylpiperidine (4e). Colorless oil; H NMR (400 MHz,
& 115.3 (d, JC-F = 21.9 Hz, 2C), 112.1 & 112.0 (d, JC-F = 6.6 Hz, CDCl3) δ 7.29-7.26 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.87 –
2C), 48.1(2C), 25.50(2C); HRMS (ESI) m/z (M+H)+ calcd for 6.83 (tt, J = 7.6 Hz, J = 0.8 Hz, 1H), 3.20 - 3.17 (t, J = 5.2 Hz,
C10H13FN = 166.1032; found 166.1037.
4H), 1.77 - 1.72 (m, 4H), 1.62 - 1.57 (m, 2H); 13C NMR (100
1-(2,4-difluorophenyl)pyrrolidine (3k). Colorless oil; 1H MHz, CDCl3) δ 152.3, 128.9 (2C), 119.2, 116.5 (2C), 50.7 (2C),
NMR (400 MHz, CDCl3) δ 6.83 - 6.75 (m, 2H), 6.74 (s, 1H), 25.9 (2C), 24.3; HRMS (ESI) m/z (M+H)+ calcd for C11H16N =
3.30 - 3.38 (m, 4H), 2.00 - 1.95 (m, 4H); 13C NMR (100 MHz, 162.1283; found 162.1283.
1
CDCl3) δ 156.0 - 153.6 (d, JC-F = 242.7 Hz, 1C), 153.2 - 150.7 2-phenylisoindoline (4f). White solid; m.p. 171-173 °C; H
(dd, JC-F = 247.1 Hz, JC-F = 10.9 Hz, 1C), 134.3, 115.3, NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 6H), 6.75 (t, J = 7.2
110.5&110.3 (d, JC-F = 21.1 Hz, 1C), 104.7 - 104.2 (t, JC-F
25.6 Hz, 1C), 50.1 (2C), 24.9 (2C); HRMS (ESI) m/z (M+H)+ MHz, CDCl3) δ 147.1, 137.9 (2C), 129.4 (2C), 127.2 (2C),
calcd for C10H12F2N = 184.0938; found 184.0940. 122.6 (2C), 116.2, 111.4 (2C), 53.8 (2C); HRMS (ESI) m/z
4-(pyrrolidin-1-yl)benzonitrile (3l). White solid; m.p. 88- (M+H)+ calcd for C14H14N = 196.1126; found 196.1129.
=
Hz, 1H), 6.70 (d, J = 8.0 Hz, 2H), 4.66 (s, 4H); 13C NMR (100
90 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 - 7.44 (m, 2H), 6.53 2- -tolylisoindoline (4g). White solid; m.p. 171-173°C; 1H
p
– 6.50 (m, 2H), 3.37 – 3.33 (m, 4H), 2.09 – 2.04 (m, 4H); 13C NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 4H), 7.13 (d, J = 8.4
NMR (100 MHz, CDCl3) δ 150.0, 133.5 (2C), 121.0, 111.5 Hz, 2H), 6.63 – 6.60 (dt, J = 8.8 Hz, J = 2.4 Hz, 2H), 4.64 (s,
(2C), 96.6, 47.5 (2C), 25.4 (2C); HRMS (ESI) m/z (M+H)+ 4H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.2, 138.1
calcd for C11H13N2 = 173.1079; found 173.1082.
(2C), 129.9 (2C), 127.1 (2C), 125.3, 122.6 (2C), 111.6 (2C),
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
53.9 (2C), 20.3; HRMS (ESI) m/z (M+H)+ calcd for C15H16N =
210.1283; found 210.1285.
1-(4-(pyrrolidin-1-yl)phenyl)piperidine (13)
View Article Online
1
Yellowish white solid; H NMR (400 MHz, DMSO-d6) δ 6.84 –
DOI: 10.1039/D0OB00880J
2-(4-ethylphenyl)isoindoline (4h). Yellowish solid; m.p. 96- 6.83 (m, 2H), 6.81 – 6.79 (m, 2H), 3.16 – 3.12 (m, 4H), 2.88 (t, J =
98 °C; 1H NMR (400 MHz, CDCl3) δ 7.35 - 7.29 (m, 4H), 7.17 5.2 Hz, 4H), 1.96 – 1.88 (m, 4H), 1.65 – 1.59 (m, 4H), 1.49 -1.44 (m,
(d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.65 (s, 4H), 2.63 2H); 13C NMR (100 MHz, DMSO-d6) δ 143.48, 142.99, 119.23 (2C),
- 2.58 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR 112.80 (2C), 52.48 (2C), 48.18 (2C), 26.25 (2C), 25.30 (2C), 24.35;
(100 MHz, CDCl3) δ 145.1, 137.95 (2C), 128.8 (3C), 127.2 HRMS (ESI) m/z (M+H)+ calcd for C15H23N2 = 231.1861; found
(2C), 122.6 (2C), 111.9 (2C), 54.3 (2C), 27.9, 16.1; HRMS 231.1865.
(ESI) m/z (M+H)+ calcd for C16H18N = 224.1439; found
224.1436.
Conflicts of interest
2-(4-chlorophenyl)isoindoline (4i). White solid; m.p. 190-
192 °C; H NMR (400 MHz, CDCl3) δ 7.37 - 7.31 (m, 4H),
1
There are no conflicts to declare
7.28 – 7.24 (m, 2H), 6.63 – 6.59 (dt, J = 9.2 Hz, J = 2.4 Hz,
2H), 4.65 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 145.7, 137.6
(2C), 129.2 (2C), 127.3 (2C), 122.6 (2C), 121.1, 112.6 (2C),
53.9 (2C); HRMS (ESI) m/z (M+H)+ calcd for C14H13ClN =
230.0737; found 230.0739.
Acknowledgements
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
2-phenyl-1,2,3,4-tetrahydroisoquinoline (4j). White solid;
1
(NRF)
funded
by
the
Ministry
of
Education
m.p. 45-46 °C; H NMR (400 MHz, CDCl3) δ 7.36 – 7.30 (m,
(2018R1D1A1B07047572).
2H), 7.24 – 7.18 (m, 4H), 7.04 – 7.01 (m, 2H), 6.89 – 6.85 (tt, J
= 7.6 Hz, J = 1.2 Hz, 1H), 4.45 (s, 2H), 3.61 (t, J = 5.6 Hz, 2H)
3.03 (t, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 150.5,
134.9, 134.5, 129.2 (2C), 128.5, 126.5, 126.3, 126.0, 118.7,
115.2 (2C), 50.7, 46.6, 29.1; HRMS (ESI) m/z (M+H)+ calcd
for C15H16N = 210.1283; found 210.1284.
Notes and references
1. J. Chen, R. Sun, X. Liao, H. Han, Y. Li, M. Xie.
Macromolecules. 2018, 51, 10202 -10213.
2-(3,5-dimethylphenyl)-1,2,3,4-tetrahydroisoquinoline (4k).
2. K. Kyoda, Y. Yamamoto, Y. Tezuka. J. Am. Chem. Soc.
2019, 141, 7526-7536.
White solid; m.p. 49-51 °C; 1H NMR (400 MHz, CDCl3) δ 7.20
- 7.16 (m, 4H), 6.64 (s, 2H), 6.52 (s, 1H), 4.39 (s, 2H), 3.54 (t, J 3. X. Ding, L. P. Stasi, X. Dai, K. Long, C. Peng, B. Zhao, H.
= 5.6 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 2.32 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 150.8, 138.7 (2C), 134.9, 134.6, 128.5,
126.52, 126.2, 125.9, 120.7, 113.2 (2C), 50.9, 46.6, 29.3, 21.7
(2C); HRMS (ESI) m/z (M+H)+ calcd for C17H20N = 238.1596;
found 238.1597.
Wang, C. Sun, H. Hu, Z. Wan, K. S. Jandu, O. J. Philps, Y.
Chen, L. Wang, Q. Liu, C. Edge, Y. Li, K. Dong, X. Guan,
F. D. Tattersall, A. D. Reith, F. Ren, Bioorg. Med. Chem.
2019, 29, 212-215.
4. R. Jia, J. Zhang, W. Ai, X. Ding, S. Desta, L. Sun, Z. Sun,
X. Ma, Z. Li, D. Wang, B. Huang, P. Zhan, X. Liu. Eur. J.
Med. Chem. 2019, 178, 64-80.
5. J. Fedorowicz, J. Sączewski, A. Konopacka, K. Waleron, D.
Lejnowski, K. Ciura, T. Tomašič, Ž. Skok, K. Savijoki, M.
Morawska, S. Gilbert-Girard, A. Fallarero. Eur. J. Med.
Chem. 2019, 179, 576-590.
6. H. A. Allam, S. H. Fahim, M. F. Abo-Ashour, A. Nocentini,
M. E. Elbakry, M. A. Abdelrahman, W. M. Eldehna, H. S.
Ibrahim, C. T. Supuran, Eur. J. Med. Chem. 2019, 179,
547-556.
7. K. J. Okolotowicz, M. Dwyer, D. Ryan, J. Cheng, E. A.
Cashman, S. Moore, M. Mercola, J. R. Cashman, Bioorg.
Med. Chem. 2018, 26, 4441-4451.
2-(4-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline (4l).
1
White solid; m.p. 60 - 62°C; H NMR (400 MHz, CDCl3) δ
7.28– 7.17 (m, 6H), 6.95 (d, J = 8.4Hz, 2H), 4.42s, 2H), 3.57(t,
J = 6.0 Hz, 2H), 2.98 (t, J = 5.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 148.7, 134.6, 129.1 (2C), 128.5, 126.6 (2C), 126.5,
126.2, 116.1, 50.7, 46.5, 28.9; HRMS (ESI) m/z (M+H)+ calcd
for C15H15ClN = 244.0893; found 244.0895.
4-(3,4-dihydroisoquinolin-2(1H)-yl)benzonitrile (4m). White
1
solid; m.p. 80 - 82°C; H NMR (400 MHz, CDCl3) δ 7.57 -
7.53 (dt, J = 9.6 Hz, J = 2.4 Hz, 2H), 7.29 – 7.20 (m, 4H), 6.92
– 6.89 (dt, J = 8.8 Hz, J = 2.0 Hz, 2H), 4.53 (s, 2H), 3.67 (t, J =
6.0 Hz, 2H), 3.04 (t, J = 5.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 152.2, 134.9, 133.56, 133.4 128.2, 126.9, 126.6,
126.5, 120.4, 112.7, 98.8, 48.8, 44.6, 28.9; HRMS (ESI) m/z
(M+H)+ calcd for C16H15N2 = 235.1235 found 235.1237.
1-benzylpyrrolidine (8)
8. H. Hubbard, E. Lawitz, Expert. Rev. Gastroen. 2018, 12, 9-
17.
9. S. Siena, R. C. Doebele, A. T. Shaw, C. S. Karapetis, D. S.
-W. Tan, B. C. Cho, D.-W. Kim, M.-J. Ahn, M. Krebs, K.
Goto, P. Garrido Lopez, A. F. Farago, H. H. F Loong, D.
Tosi, M. A. Barve, B. P. Simmons, C. Ye, S. Eng, A. E.
Drilon, J. Clin. Oncol. 2019, 37, 3017-3017.
Light yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.25 (m, 5H),
3.62 (s, 2H), 2.53 – 2.50 (m, 4H), 1.83 – 1.75 (m, 4H); 13C NMR
(100 MHz, CDCl3) 139.3, 128.9 (2C), 128.2 (2C), 126.9, 60.7, 54.2
(2C), 23.4 (2C); HRMS (ESI) m/z (M+H)+ calcd for C11H16N =
162.1283; found 162.1285.
10. H. V. Vangapandu, N. Jain, V. Gandhi. Expert Opin.
Investig. Drugs. 2017, 26, 625-632.
1,4-di(pyrrolidin-1-yl)benzene (11)
11. Z. Chen, X. Chen, C. M. So. J. Org. Chem. 2019, 84, 6366-
6376.
12. Y.-Y. Liu, D. Liang, L.-Q. Lu, W.-J. Xiao. Chem. Commun.
2019, 55, 4853-4856.
13. L. J. Bole, L. Davin, A. R. Kennedy, R. McLellan, E. Hevia.
Chem. Commun. 2019, 55, 4339-4342.
14. P. Yang, C. Zhang, W.-C. Gao, Y. Ma, X. Wang, L. Zhang,
J. Yue, B. Tang. Chem. Commun. 2019, 55, 7844-7847.
15. X. Ge, S. Zhang, X. Chen, X. Liu, C. Qian. Green Chem.
2019, 21, 2771-2776.
16. Y. Kawamata, J. C. Vantourout, D. P. Hickey, P. Bai, L.
Chen, Q. Hou, W. Qiao, K. Barman, M. A. Edwards, A. F.
White solid; m.p. 148-150 °C; 1H NMR (400 MHz, CDCl3) δ 6.49 (s,
4H), 3.11 (s, 8H), 1.94 – 1.88 (m, 8H); 13C NMR (100 MHz, CDCl3)
δ 135.8 (2C), 113.7 (4C), 48.3 (4C), 25.1 (4C); HRMS (ESI) m/z
(M+H)+ calcd for C14H21N2 = 217.1705; found 217.1706.
N-isopropyl-4-(pyrrolidin-1-yl)anilin (12)
1
Yellow oil; H NMR (400 MHz, DMSO-d6) δ 6.51 – 6.39 (dd, J =
30 Hz, J = 8.8 Hz, 4H), 4.39 (s, 1H), 3.43 (s, 1H), 3.09 (s, 4H), 3.09
(s, 4H), 1.95 – 1.84 3.09 (m, 4H), 1.08 (d, J = 6.4 Hz, 6H); 13C NMR
(100 MHz, DMSO-d6) δ 140.8, 139.6, 115.2 (2C), 113.6 (2C), 48.5
(2C), 44.6, 25.2 (2C), 23.2 (2C); HRMS (ESI) m/z (M+H)+ calcd for
C13H21N2 = 205.1705; found 205.1709.
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< Entry for the Table of Contents >
Highly efficient direct transformations from N-alkyl protected arylamines such as N-methyl-, N-
ethyl-, N-isopropyl, and N-tert-butyl arylamines to N-aryl substituted azacycles in the presence of
TiCl4 and DBU has been developed.