An Efficient Synthesis of the bis-Tetraazacyclodecane JM3100 Under PTC Conditions

Full text of DOI:10.1080/00304948.2018.1537749

Organic Preparations and Procedures International
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An Efficient Synthesis of the bis-
Tetraazacyclodecane JM3100 Under PTC Conditions
P. Venkata Narayana, Nareshvarma Seelam & Bethanamudi Prasanna
To cite this article: P. Venkata Narayana, Nareshvarma Seelam & Bethanamudi Prasanna (2018)
An Efficient Synthesis of the bis-Tetraazacyclodecane JM3100 Under PTC Conditions, Organic
Preparations and Procedures International, 50:6, 588-591, DOI: 10.1080/00304948.2018.1537749
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Organic Preparations and Procedures International, 50:588–591, 2018
2018 Taylor & Francis Group, LLC
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ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1537749
OPPI BRIEF
An Efficient Synthesis of the bis-
Tetraazacyclodecane JM3100 Under
PTC Conditions
1
,2
2
P. Venkata Narayana, Nareshvarma Seelam, and
1
Bethanamudi Prasanna
1
Department of Chemistry, Chaitanya Postgraduate College (Autonomous),
Kishanpura, Hanamkonda, Warangal, Telangana State, 506 001 India
2
Department of Chemistry, Koneru Lakshmaiah University, Guntur, Andhra
Pradesh, India
We now describe a facile synthesis of 1,4-bis((1,4,8,11-tetraazacyclotetradecan-1-yl)me-
thyl)benzene octahydrochloride 3 from 1, 4, 8, 11-tetrazacyclotetradecane 1 with
dibromo-p-xylene 2 under phase transfer catalysis. The method gives good yields with-
out protection and deprotection.
The chemistry of the tetraazacycloalkanes has undergone considerable development
in the last years. Among their other properties, these macrocyclic polyamines are able
to form stable complexes with transition metals, lanthanides, actinides, and other heavy
1–4
metals.
The affinity and selectivity towards the metal ion can be tuned by varying
the size of the macrocyclic core as well as the nature and the number of pendant coordi-
nating arms on the nitrogen atoms. In addition, these molecules exhibit numerous bio-
medical applications. These were described as a new class of antiviral agents with
potent inhibitory effects on HIV-1 and HIV-2 replication, along with high
5–7
selectivity.
Many methods have been devised for the synthesis of tetrazocyclodecanes and their
functionalized derivatives, including high dilution techniques, use of metal cations as
templates, protection/de-protection sequences and functionalization on either nitrogen
or carbon atoms. A recent key step in this chemistry is the use of bis-aminal intermedi-
8–15
ates.
Our new method avoids protection/de-protection sequences and is shown in
Scheme 1. Compound 3 was synthesized from 1 with dibromo-p-xylene 2 under phase
transfer conditions, using tetra-n-butyl ammonium bromide (TBAB), in good yield. The
spectral and analytical data strongly supported the structure of 3 (see Experimental
Received April 25, 2017; in final form May 18, 2018.
Address correspondence to Bethanamudi Prasanna, Department of Chemistry, Chaitanya
Postgraduate College (Autonomous), Kishanpura, Hanamkonda, Warangal, Telangana State, 506
0
01 India. E-mail: prasschem@gmail.com
588

bis-Tetraazacyclodecane JM3100
589
Scheme 1
Section). An efficient and convenient route has thus been developed with an overall
yield of 92% with 99.6% purity. We expect this route may be scalable for synthesis.
Experimental Section
Melting points were uncorrected. Infrared spectra were obtained by using a Bruker
1
13
WM-4(X) spectrometer 577 model. H NMR (400MHz) and C NMR (100MHz) spec-
tra were recorded on a Bruker WM-400 spectrophotometer in CDCl with tetramethylsi-
3
lane as reference. Mass spectra (ESI) were carried out on a JEOL SX-102
spectrophotometer. Elemental analysis was done on a Carlo Erba EA 1108 automatic
elemental analyzer. The chemicals and solvents were commercial grade, used without
further purification. Purification of the synthesized compounds by column chromatog-
raphy and thin-layer chromatography (TLC) was carried out by using alumina sheets
purchased from Merck with ethanol as the moving phase.
Synthesis of 1,4-bis((1,4,8,11-Tetraazacyclotetradecan-1-yl)methyl)benzene
octahydrochloride (3)
1
,4,8,11-Tetraazacyclotetradecane 1 (0.205 mol) was dissolved in a mixture of water
0
(160 mL) and chloroform (160 mL); sodium carbonate (0.205 mol) and a, a -dibromo-
p-xylene 2 (0.1mol) were added, followed by addition of 10% of TBAB catalyst
0.0205 mol). The solution was refluxed for 1-2 h, cooled to room temperature, poured
(
into ice cold water and extracted with toluene (3x200 mL). The organic phases were
combined, dried over anhydrous MgSO and concentrated in vacuo to give a white solid
4
3. The obtained solid material was dissolved in a minimum amount of dry methanol
(250 mL) and dry HCl gas was gently passed through the solution to form a white pre-
cipitate which was filtered and dried to give 3 octahydrochloride.
ꢀ
ꢀ
16
Yield 92% with 99.6% purity, free base mp 131-132 C, lit mp 129-131 C; HCl
ꢀ
ꢀ
7
salt mp 240.0-245.5 C, lit mp 232 C.
ꢁ
1
1
Free Base IR (cm ): 3417, 3283, 2937, 2817, 1645, 1531, 1464, 751; H NMR
(
(
400 MHz, CDCl ) 7.28 (s, 4H), 4.08 (s, 4H), 3.36 (bb, 8H), 3.26 (bb, 8H), 3.18-3.17
m, 4H), 2.59-2.59 (m, 16H),179-1.68 (m, 4H), 1.58-1.48 (m,4H); C NMR (100 MHz,
3
13
CDCl ): 26.4, 29.6, 47.9, 48.1, 49.2, 50.10, 50.4, 51.2, 52.2, 54.9, 58.3, 129.2. 137.2.
3
HRMS (M þ 1): Calcd for C
H N , 502.78196; Found (HRMS (M þ 1)),
55 8
2
8
7
5
03.44962. (See Figure 1)
Anal. Calcd for C28 H N : C, 66.75; H, 11.00; N, 22.24. Found: C, 66.85; H,
55
8
1
0.81; N, 22.19.

5
90
Prasanna et al.
Figure 1. HRMS of bis-Tetraazacyclodecane JM3100.
HPLC Analysis
We used an HPLC equipped with ultraviolet spectrophotometer as detector, an auto
sampler and a Zorbaxeclips plus C18 3.5 mm (100 mm ꢂ4.6mm) column. Mobile phase
A: we dissolved 6.32 g of sodium perchlorate and 1.73 g of 1-octane sulfonic acid
sodium salt anhydrous in 1000 mL of water, then adjusted the pH to 2.00 ± 0.05 with
diluted perchloric acid (10%). Mobile phase B: We mixed acetonitrile and the buffer
(
the same used in Mobile phase A) in the ratio of 95:5 v/v, flow rate 1.0 ml/min; col-
ꢀ
ꢀ
umn temperature 35 C ±5 C; wavelength 210 nm and run time 55 min. Gradient:
0
9
min: 84% A, 16% B; 5 min: 74% A, 26% B; 30 min: 57% A, 43% B; 32 min: 70% A,
3% B; 35 min: 70% A, 93% B; 36 min: 84% A, 16% B; 55 min: 84% A, 16% B; UV
ꢀ
detection at 210 nm; flow rate: 1.0 mL/min; column oven temperature: 25 C .
Acknowledgment
The authors are thankful to the Indian Institue of Chemical Technology, Hyderabad,
for providing spectra and especially to Mr. Anjaneyulu and Dr G. Saikrishna for high
resolution mass spectrometry.
ORCID
Bethanamudi Prasanna
http://orcid.org/0000-0001-6532-9905

bis-Tetraazacyclodecane JM3100
591
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