Phosphoryl chloride-mediated solvent-free synthesis of N-aryl-substituted azacycles from arylamines and cyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2019.06.019

A solvent- and metal-free protocol for preparation of N-aryl substituted azacycles from arylamines and cyclic ethers is described. In this method, the combination of POCl₃ and DBU is crucial for conversion of arylamines and cyclic ethers to five- and six-membered azacycles. Without solvent, a variety of N-aryl-substituted, five-membered azacycles (pyrrolidines, 2-methylpyrrolidines, and piperidine) and six-membered azacycles (isoindolines and tetrahydroisoquinolines) are synthesized in high yields. This green method provides a sustainable and efficient approach for the preparation of azacycles from various cyclic ethers.

Full text of DOI:10.1016/j.tetlet.2019.06.019

Accepted Manuscript
Phosphoryl Chloride-Mediated Solvent-Free Synthesis of N-Aryl-Substituted
Azacycles from Arylamines and Cyclic Ethers
Van Hieu Tran, Minh Thanh La, Hee-Kwon Kim
PII:
S0040-4039(19)30559-3
https://doi.org/10.1016/j.tetlet.2019.06.019
TETL 50860
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 April 2019
7 June 2019
11 June 2019
Please cite this article as: Tran, V.H., La, M.T., Kim, H-K., Phosphoryl Chloride-Mediated Solvent-Free Synthesis
of N-Aryl-Substituted Azacycles from Arylamines and Cyclic Ethers, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.06.019
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Phosphoryl Chloride-Mediated Solvent-Free
Synthesis of N-Aryl-Substituted Azacycles
from Arylamines and Cyclic Ethers
Leave this area blank for abstract info.
Van Hieu Trana,b, Minh Thanh Laa,b, Hee-Kwon Kim a,b *
POCl3
R2
R2
n
NH2
R1
DBU
R1
O
N
+
110 oC, 10h
n
n = 1, 2
No solvent
No metal
22 examples

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Phosphoryl Chloride-Mediated Solvent-Free Synthesis of N-Aryl-Substituted
Azacycles from Arylamines and Cyclic Ethers
Van Hieu Tran a,b, Minh Thanh Laa,b, Hee-Kwon Kim a,b 
a 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
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: Tel: +82 63 250 2768; Fax: +82 63 255 1172; e-mail: hkkim717@jbnu.ac.kr (H. Kim)
Article history:
Received
A solvent- and metal-free protocol for preparation of N-aryl substituted azacycles from
arylamines and cyclic ethers is described. In this method, the combination of POCl3 and DBU is
Received in revised form
Accepted
Available online
crucial for conversion of arylamines and cyclic ethers to five- and six-membered azacycles.
Without solvent, a variety of N-aryl-substituted, five-membered azacycles (pyrrolidines, 2-
methylpyrrolidines, and piperidine) and six-membered azacycles (isoindolines and
tetrahydroisoquinolines) are synthesized in high yields. This green method provides a
sustainable and efficient approach for the preparation of azacycles from various cyclic ethers.
Keywords:
Azacycles
2009 Elsevier Ltd. All rights reserved.
Heterocycle
Cyclic ether
Metal-free reaction
1. Introduction
environmentally friendlier chemical reactions, we investigated an
efficient metal-free and solvent-free azacycle synthesis. In
Cyclization of amines to prepare N-substituted aryl azacycles
is highly desirable due to their application in a wide range of
biological small molecules and organic materials as a building
block motif.1 Moreover, their structures are present in multiple
types of clinical drugs that contribute considerably to the
treatment of hypertension, viruses, and cancer.2 Therefore,
development of efficient preparative methods for N-substituted
aryl azacycles is of considerable value in the fields of organic and
medicinal chemistry.
Various synthetic protocols have been developed for
preparation of N-substituted aryl azacycles including reduction of
tertiary lactam or unsaturated azacycles,3 aromatization of
enamines,4 N-C coupling of cyclic secondary amines and aryl
halides or aryl triflates,5 and reductive cyclization of N,N-
dialkylhalides.6 Additionally, reactions of primary arylamines as
starting material with alkyl dihalides, diols, or cyclic ethers are
generally reported to yield N-substituted aryl azacycles.7 The
latter is more favorable because of the generation of water as a
by-product. It was reported that various metals such as activated
alumina, AlCl3, Al2O3, AlMe3, TiO2, or TiCl4 could be employed
for synthesis of azacycles from primary arylamines and cyclic
ethers.8 Recently, metal-free synthetic methods using B(C6F5)3/
pTSA.H2O, HI, or BF3.Et2O were reported for reaction of
arylamines and cyclic ethers.9 However, these reactions require
harsh conditions with extremely high temperatures, which limit
the applicable range of this reaction. In addition, volatile organic
solvents were used, which led to generation of large amounts of
chemical waste. Thus, developing a more environmentally
benign method that minimizes the use of solvent is highly
desirable to minimize waste. With an interest in development of
particular, several kinds of arylamines were successfully treated
with a variety of cyclic ethers in the absence of solvent to yield
the corresponding azacycle products in high yields.
2. Result and Discussion
Previously reported methods to prepare N-aryl substituted
azacycles have usually employed toluene or xylene as a reaction
solvent. However, the present method simply involves mixing
arylamines with cyclic ethers in the presence of proper reagents
and bases without solvent and then stirring the reaction mixture
to give the corresponding azacycles.
In initial experiments, aniline and the 5-membered cyclic ether
tetrahydrofuran (THF) were used as model reactants to optimize
the synthesis of azacycles. The solvent-free reaction was
conducted in the presence of DBU, a liquid base, for 10 h.
Several reagents including CuCl2, CuBr2, ZrCl4, MnCl2, and
BiCl2 were examined for the reaction but did not produce the
corresponding product. Next, AlCl3 and AlMe3 were employed
for synthesis of azacycles, and they afforded the target azacycle,
although in unsatisfactory synthetic yield (11% for AlCl3 and
34% for AlMe3). The reaction using BF3∙OEt2, a metal-free
reagent, was also examined, and the corresponding azacycle was
obtained in low yield. N-P bond formation as a phosphoramidate
has a crucial role in organic synthesis for protection of amines
and is practically used as an intermediate in the preparation of
amines, imines, aziridines, azetidine, and azacycloalkanes.10
Therefore, we surmised that a phosphoramidate could play a
crucial role in the solvent-free synthesis of azacycles. Thus,

2
POCl3 was used to prepare the N-aryl substituted azacycles, and
the reaction gave the desired product in high yield (95%). In
particular, we found that the reaction using POCl3 with cyclic
ethers and arylamines was homogeneous with liquid base, and
that POCl3 plays a crucial role in high-yield synthesis of
azacycles. Several organic bases were also screened for synthesis
of N-substituted azacycles. As shown in Table S1 (see supporting
information), utilization of 1,8-diazabicyclo(5.4.0)undec-7-ene
(DBU) provided better yield (95%) than the other bases
examined.
Table 2. Screening of cyclic ether amount for preparation of
azacyclesa
POCl3
DBU
NH2
O
N
+
110 oC, 10 h
1a
2a
3a
Entry Aniline
THF
POCl3
DBU
Yieldb
(%)
(equiv.) (equiv.) (equiv.) ( (equiv.)
Table 1. Screening of reagent for preparation of azacyclesa
1
2
3
4
5
6
1
1
1
1
1
1
30
20
10
5
1.3
1.3
1.3
1.3
1.3
1.3
1.5
1.5
1.5
1.5
1.5
1.5
95
95
Reagents,
DBU
110 oC, 10 h
NH2
+
N
O
95
1a
2a
3a
95
Entry
1
Reagents
CuCl2
CuBr2
ZrCl4
Time (h)
Temp.
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
Yieldb (%)
NRc
NRc
NRc
NRc
NRc
11
2.5
1.5
95
10
10
10
10
10
10
10
10
10
10
10
10
NRc
2
a Reaction conditions: compound 1a (0.2 mmol), POCl3 (0.26
mmol), Base (0.3 mmol), 110 oC, 10 h
3
b Isolated yield after purification of flash column chromatography.
c No reaction.
4
MnCl2
BiCl2
5
Table 3. Screening of reagent and base amount for the
preparation of azacyclesa
6
AlCl3
POCl3
DBU
NH2
7
AlMe3
CaI2
34
O
N
+
110 oC, 10 h
8
NRc
NRc
22
1a
2a
3a
9
CaBr2
BF3∙OEt2
POCl3
None
Entry
Aniline
THF
POCl3
DBU
Yieldb
(%)
10
11
12
(equiv.) (equiv.)
(equiv.) (equiv.)
95
NRc
1
2
1
1
1
1
1
1
1
1
1
1
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0
1.5
1.5
1.5
1.5
1.5
0
NRc
48
a Reaction conditions: compound 1a (0.2 mmol), THF 2a (0.5
0.5
1
mmol), reagent (0.26 mmol), DBU (0.3 mmol), 10 h
3
72
b
Isolated yield after purification of flash column
chromatography.
4
2
95
c No reaction.
5
3
79
Examination of the amount of cyclic ether reagent was also
carried out to optimize the preparation of azacycles (Table 2).
Generally, previously reported synthetic methods used a large
amount of cyclic ether, such as 20 or 10 equiv., to prepare
azacycles. However, in this study, we tried to employ a smaller
amount of cyclic ether. A series of cyclic ether amounts was
explored to find the minimum quantity of cyclic ether needed to
provide an efficient reaction. As shown in Table 3, a satisfactory
result was achieved using less than 10 equiv. of cyclic ether. In
particular, the target azacycle was obtained in higher yield (95%)
with 2.5 equiv. of cyclic ether, but a further decrease in the
amount of cyclic ether did not benefit the reaction. In addition,
examination of a temperature effect on the synthetic yield
6
1.3
1.3
1.3
1.3
1.3
1.3
NRc
12
7
0.5
1
8
81
9
1.5
2
95
10
11
95
3
95
a Reaction conditions: compound 1a (0.2 mmol), 110 oC,10 h
b Isolated yield after purification of flash column
chromatography.
o
indicated that reaction at 110 C provided the desired product in
c No reaction.
high yield (Table S2).
The effects of quantities of POCl3 and DBU to obtain suitable
reaction conditions between aniline and cyclic ether are shown in
Table 3. The results suggest that the reaction using 1.3 equiv. of
POCl3 and 1.5 equiv. of DBU produced the corresponding
product in high yield (95%). However, increasing the amounts of
POCl3 and DBU did not provide significant improvement in the
synthesis of azacycles.
Having determined optimized reaction conditions, the scope
of the solvent-free reaction to prepare N-aryl substituted
azacycles was examined. Different arylamines were treated with
cyclic ethers, and all of the desired compounds were obtained in
high yields using this protocol (Table 4). The results also
indicated that that the electronic effects of the aromatic ring did
not give big influence on the reaction yields. For example, high

3
yields of N-aryl-substituted azacycles were observed when cyclic
ethers reacted with arylamines containing either electron-
withdrawing (cyano-, chloro-, fluoro-) or electron-donating
substituents (methyl-, ethyl-, methoxy-) (Table 4, entries 2-10).
Interestingly, the reaction of tetrahydrofuran with 2,6-
dimethylaniline, which might have given a lower yield due to
steric hindrance, produced similar results to other arylamines
(Table 4, entry 9). A more sterically bulky reactant, 2,6-
diisopropylaniline, was introduced into the reaction, and the
desired product was obtained in good yield (Table 4, entry 10).
electron-withdrawing groups (Table 5, entries 2-4).
Tetrahydropyran, which was previously reported to give a low
reaction yield with arylamines in the synthesis of N-aryl
substituted azacycles,9(a) successfully reacted with aniline to give
the six-membered azacycles in high yield using the same
Table 5. Scope of synthesis of azacycloalkanes from various
cyclic ethersa
POCl3
R2
n
R2
n
NH2
R1
DBU
Table 4. Scope of the synthesis of azacycloalkanes from various
R1
N
O
+
aminesa
110 oC, 10 h
POCl3
n = 1, 2
1
2
4
NH2
R1
DBU
N
R1
O
Entry
Amine
Product
Yieldb (%)
+
110 oC, 10 h
NH2
N
1
1a
1e
1g
3
4a
4b
4c
2
90
91
1
Entry
(%)
Amine
Product
Yieldb
F
F
NH2
NH2
F
N
NH2
2
3
N
N
N
95
3a
3b
1a
1b
1
F
CN
CN
93
91
N
N
NH2
91
2
NH2
Cl
4
4d
1k
Cl
NH2
NH2
3c
3d
3
4
1c
1d
92
95
NH2
N
5
6
1a
1a
4e
4f
92
85
F
N
NH2
F
F
N
N
F
F
NH2
Cl
5
3e
F
N
93
1e
Cl
NH2
1c
4g
7
83
MeO
MeO
NH2
NH2
6
1f
3f
94
93
96
91
N
N
1h
1i
4h
4i
8
9
81
71
NH2
NH2
NH2
1g
3g
7
8
N
N
N
1h
1i
NH2
3h
3i
N
1a
1d
4j
82
87
10
11
NH2
F
NH2
N
9
4k
N
F
NH2
NH2
1k
N
12
4l
81
74
3j
1j
10
N
a
Reaction conditions: compound 1a (0.2 mmol), THF 2a (0.5
mmol), POCl3 (0.26 mmol), DBU (0.3 mmol), 10 h, 110 oC,
bIsolated yield after purification by flash column chromatography.
a
Reaction conditions: compound 1a (0.2 mmol), THF 2a (0.5
mmol), POCl3 (0.26 mmol), DBU (0.3 mmol), 10 h, 110 oC,
b
Isolated yield after purification by flash column chromatography.
protocol (Table 5, entry 5). Based on these results, we extended
the scope of the reaction to include aryl-fused azacycles such as
tetrahydroisoquinoline and isoindoline, which are considered
important moieties in many biological and medical applications.11
The tolerance of the solvent-free reaction in the presence of
Next, various cyclic ethers were explored to assess the
reaction scope. 2-Methyltetrahydrofuran was utilized to react
with arylamines (Table 5), and despite more steric hindrance of
this cyclic ether than THF, high yields of azacycles were
achieved with arylamines bearing both electron-donating and

4
POCl3/DBU with several benzene-fused cyclic ethers was
examined to prepare N-aryl substituted benzene-fused azacycles.
Aniline without any substituents reacted with phthalan or
isochroman in the presence of POCl3 and DBU to give the
corresponding azacycles in moderate yields (Table 5, entries 6
and 10). The effect of arylamine substituents on the yield of the
reaction was also examined, and the target products were
successfully obtained. Yields from reactions of arylamines
containing electron-donating groups did not differ significantly
from those of arylamines bearing electron-withdrawing groups
(Table 5, entries 7-9 and 11-12). These results demonstrate that,
despite not employing a solvent, this method using POCl3 and
DBU provides an efficient green synthetic approach to the facile
synthesis of various N-aryl-substituted azacycles from arylamines
and cyclic ethers.
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To gain reaction mechanism idea of this protocol, aniline was
treated with POCl3 and DBU without THF under same
reaction condition, and phosphoramidic dichloride 5 was
successfully obtained. Previously reported studies showed that
cyclization can be achieved through breaking N-P bond and
forming O-P bond during cyclization.10(c)-10(f) Thus, a plausible
reaction mechanism can be proposed, as shown in Scheme 1.
The initial reaction of arylamine with POCl3 and DBU
probably yields phosphoramidic dichloride 5. Then,
phosphoramidic dichloride 5 reacts with THF to afford 6. The
target product 3a was prepared via intramolecular attack of
the nitrogen on the carbon next to phosphorus atom.
(d) Marsh, J. D.; Smith, T. W. Pharmacotherapy 1984, 4,
170-178.
3. (a) Collins, C. J.; Lanz, M.; Singaram, B. Tetrahedron Lett.
1999, 40, 3673-3676;
(b) Shim, S. C.; Huh, K. T.; Park, W. H. Tetrahedron 1986,
42, 259-263;
(c) Watanabe, Y.; Shim, S. C.; Uchida, H.; Mitsudo, T.;
Takegami, Y. Tetrahedron 1979, 35, 1433-1436;
(d) Selvakumar, K.; Rangareddy, K.; Harrod, J. F. Canadian
Journal of Chemistry 2004, 82, 1244-1248.
H
O
NH2
N
Cl
Cl
O
POCl3
Cl
Cl
P
N
P
O
O
4. Bigdeli, M. A.; Rahmati, A.; Abbasi-Ghadim, H.;
Mahdavinia, G. H. Tetrahedron Letters 2007, 48, 4575-4578.
5. (a) Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007,
9, 3397-3399;
DBU
DBU HCl
1a
5
6
(b) Khatri, P. K.; Jain, S. L. Tetrahedron Lett. 2013, 54, 2740-
2743;
(c) Xu, G.; Wang, Y.-G. Organic Letters 2004, 6, 985-987.
Cl
Cl
P
O
N
O
N
6. Xue, W.; Xu, H.; Liang, Z.; Qian, Q.; Gong, H. Organic
Letters 2014, 16, 4984-4987.
3a
7
Scheme 1. Proposed reaction pathway
7. (a) Craig, L. C.; Hixon, R. M. J. Am. Chem. Soc. 1930, 52,
804-808;
3. Conclusion
(b) Cui, X.; Dai, X.; Deng, Y.; Shi, F. Chem. Eur. J. 2013,
19, 3665-3675; (c) Yur'ev, Y. K.; Minkina, G. A. J. Gen.
Chem. (USSR) 1937, 1, 2945.
In conclusion, a practical metal- and solvent-free method for
direct conversion of arylamines and cyclic ethers to N‑ aryl-
substituted azacycles was reported. High yields of N‑ aryl-
substituted azacycles were observed via solvent-free reaction
conditions using POCl3 and DBU. Moreover, the solvent-free
method is advantageous with respect to reduced generation of
waste and cost. With outstanding outcomes, this practical and
efficient synthesis should contribute to the development of
sustainable and applicable approaches to preparation of five- and
six-membered azacycles.
8. (a) Bourns, A. N.; Embleton, H. W.; Hansuld, M. K. Can. J.
Chem. 1952, 30, 1-8;
(b) Walkup, R. E.; Searles, S. Tetrahedron 1985, 41, 101-
106;
(c) Olsen, C. J.; Furst, A. N-Phenylpyrrolidine1. J. Am.
Chem. Soc. 1953, 75, 3026-3026;
(d) Hargis, D. C.; Shubkin, R. L. Tetrahedron Lett. 1990, 31,
2991-2994;
(e) Sun, Z.; Hu, S.; Huo, Y.; Wang, Z. RSC Adv. 2017, 7,
4363-4367;
Acknowledgments
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education (2018R1D1A1B07047572).
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8988.
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References and notes
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12. General experimental procedure for the synthesis of azacyles:
To a 20 mL vial containing a stirring mixture of aniline (1a)
(0.186 g, 2.00 mmol) and DBU (0.456 g, 3.00 mmol) was
added dropwise POCl3 (0.398 g, 2.60 mmol) at room
temperature. The mixture was then heated at 90 °C for 15 min.
Tetrahydrofuran (2a) (0.36 g, 5.00 mmol) were added to the
reaction mixture and the vial was closed tightly with Teflon
cap. The reaction mixture was allowed to heat at 110 °C for
10 h. The reaction was cooled down to the ambient
temperature, then saturated aqueous NaHCO3 (10 mL) and
brine (10mL) were added to the mixture. The aqueous
mixture was extracted with Et2O and the organic layer was
dried over sodium sulfate and subsequently concentrated
under reduced pressure. The crude product was then purified
by flash column chromatography on silica gel with hexane-
dichloromethane as eluent to afford the desired product 3a
(0.281 g, 95%).
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Day, J. E. H.; Hopkins, A.; Howard, S.; Lewis, E. J.; Martins,
V.; Millemaggi, A.; Munck, J. M.; Page, L. W.; Peakman, T.;
Reader, M.; Rich, S. J.; Saxty, G.; Smyth, T.; Thompson, N.
T.; Ward, G. A.; Williams, P. A.; Wilsher, N. E.; Chessari, G.
J. Med. Chem. 2018, 61, 7314-7329;

6
Highlight
• Facile preparation of azacycles from arylamines
and cyclic ethers has been reported.
• POCl3 and DBU were used for synthesis of
azacyles
• Various azacycles were obtained in high yield
• No metals are required in this azacycle synthesis.