Org. Synth. 2002, 78, 73
DOI: 10.15227/orgsyn.078.0073
1,4,7,10-TETRAAZACYCLODODECANE
Submitted by David P. Reed and Gary R. Weisman
1
.
Checked by Maya Escobar and Stephen F. Martin.
1. Procedure
Caution: Hydrogen sulfide (H2S) is generated
in Part A of this procedure. The reaction and associated operations must be carried
out with provision for H2S trapping in an efficient hood.
A.
2,3,5,6,8,9-Hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine
(1). A 500-mL, three-necked, round-bottomed flask is
equipped with a 125-mL pressure-equalizing addition funnel,
a Teflon-coated magnetic stirring bar, a fritted-gas
dispersion tube (initially closed) connected to a nitrogen manifold
, and a reflux
condenser fitted with a nitrogen (N2) inlet tube connected to the nitrogen
manifold. The nitrogen manifold exit line is routed
through two fritted-gas washing bottles charged with
30% aqueous sodium hydroxide
(NaOH) in order to scrub H2S evolved in the reaction (Note 1). The reaction flask is charged with
10.0
g
(83.2 mmol) of dithiooxamide
(Note 2) and
50 mL
of absolute ethanol
. A solution of
12.2
g
(83.2 mmol) of triethylenetetramine
(Note 3) in
50 mL of
absolute ethanol
is introduced into the reaction flask
in one portion via the addition funnel. The magnetically stirred reaction mixture
is heated at reflux for 4 hr under nitrogen with evolution of
H2S and ammonia (NH3)
(Note 4). The mixture is then cooled to room temperature and
residual H2S and NH3 are purged from the reaction mixture for
3 hr by entrainment with nitrogen, which is bubbled through the
submerged fritted-gas dispersion tube. Ethanol is removed by
rotary evaporation, and the residue is dissolved in
150
mL of chloroform (CHCl3). The
insoluble material is removed by gravity filtration through a glass wool
plug that is inserted in a short-stem glass funnel.
CHCl3 is then removed by rotary evaporation to give 14.0 g of crude product.
This solid is taken up in
50 mL of boiling
toluene
, insoluble impurities are removed by filtration
through a glass wool plug, and the flask and funnel are rinsed with a second
50-mL aliquot of boiling toluene
(Note 5). The combined filtrates are concentrated to afford 13.4 g of light yellow crystalline product.
Sublimation of this material (0.05 mm, 110°C) affords 10.4 g (76%)
of pure (>99%) white product (Notes 6,
7, 8).
B.
1,4,7,10-Tetraazacyclododecane
(2). A 1-L, three-necked, round-bottomed flask charged
with
8.96 g
(54.6 mmol) of 2,3,5,6,8,9-hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine
is equipped with a reflux condenser fitted with nitrogen inlet tube,
a 500-mL pressure-equalizing addition funnel, and a Teflon-coated
magnetic stirring bar. The system is flushed with N2 prior
to cannulation of
218 mL
(327 mmol)
of 1.5 M diisobutylaluminum hydride (DIBAL-H) in
toluene
(Note 9)
to the addition funnel. The reaction flask is cooled in an ice/water (H2O)
bath and the DIBAL-H solution is added to the reaction flask with stirring
over 5 min. The reaction mixture is heated at reflux under nitrogen
for 16 hr (Note 10). The reaction flask is again cooled in an
ice/H2O bath prior to the addition of
200
mL of toluene
. Excess DIBAL-H is quenched
by the cautious dropwise addition of
20 mL
of 3 M aqueous potassium hydroxide (KOH) solution.
When gas evolution ceases,
350 mL of 3 M
aqueous KOH is added in one portion and the two-phase mixture is transferred
to a separatory funnel (Notes 11, 12). The phases are separated
and chipped ice is added to the aqueous phase, which is further extracted with ice-cold CHCl3(12 × 150 mL).
The combined organic extracts are dried over sodium sulfate
(Na2SO4), filtered, and the solvents are removed
by rotary evaporation to afford 6.19 g
of white crystalline solid. Sublimation (0.05 mm, 90°C) of this material gives 5.44 g (58%) of product 2 (>98%
purity by NMR; Notes 13, 14, 15).
2. Notes
1.
The nitrogen manifold (Tygon tubing is suitable) is connected
as follows, in this order: (a)
nitrogen source, (b)
T-connector
to fritted-gas dispersion tube with shutoff valve or clamp, (c)
shutoff
valve or clamp (enables nitrogen to be routed through fritted-gas dispersion tube
when closed and dispersion tube is opened), (d)
T-connector
to nitrogen inlet tube on reflux condenser, (e)
safety flask,
(f)
gas washing bottle #1, (g)
gas washing bottle
#2, and (h)
mineral oil exit bubbler (See Figure
1).
Figure 1
2.
Dithiooxamide was
purchased from Fluka Chemical Corp.
3.
Triethylenetetramine
was purchased from Aldrich Chemical Company, Inc.
,
as a hydrate. Anhydrous
triethylenetetramine must be used in
this procedure. The anhydrous tetraamine was obtained by azeotropic distillation of
water (
Dean-Stark trap, 3 days) from a solution of 125 g of
the commercial hydrate in
150 mL of toluene
.
Analysis by
1H NMR verified the removal of water, and no further purification
was necessary.
4.
Dithiooxamide
dissolved to give a homogeneous orange solution soon after the initiation of heating.
5.
The hot filtration must be carried out quickly to avoid crystallization
of product. This step can be omitted, but a second sublimation may then be necessary
to obtain product of sufficient purity for reduction to cyclen.
6.
Compound
1 has the following physical and spectroscopic
properties:
mp 148-150°C (lit
2
mp 150-151°C);
1H
NMR (CDCl
3, 360 MHz) δ: 3.26 (s, 4 H), 3.35 [apparent
t (XX' of AA'XX'), 4 H, J
appar = 9.6], 3.86 [apparent t (AA'
of AA'XX'), 4 H, Jappar = 9.6]
;
13C NMR (CDCl
3, 90.56 MHz) δ: 45.3,
52.1, 53.9, 155.4
; IR (KBr) cm
−1: 1629 (C=N); MS (EI) 164.15 (M)+; Anal. Calcd
for C
8H
12N
4: C, 58.52; H, 7.37; N, 34.12. Found:
C, 58.38; H, 7.55; N, 34.22.
7.
Bisamidine
1 is hydrolyzed in water (in minutes to hours depending upon purity). While
it is not necessary to handle
1 in a dry atmosphere, it is prudent to store
it in a
desiccator.
8.
The checkers found that when the reaction was conducted on 1/2
scale, significantly lower yields (
55
- 70% before sublimation) were obtained.
9.
DIBAL-H in toluene
(1.5 M) was purchased from Aldrich Chemical Company, Inc.
10.
The submitters found that a small scale (0.4 g of
1) reaction
with 5 equivalents of DIBAL-H at reflux for 8 hr afforded product in
94% crude yield. However, these conditions gave incomplete
reduction and a lower yield when the reaction was scaled up to 10 g of
1. Therefore,
the number of equivalents of DIBAL-H was increased to 6 and the reaction was run for
16 hr.
11.
A small amount of solid remains undissolved, but this tends to
be distributed in the aqueous phase, making filtration at this stage unnecessary.
12.
Originally,
2 a NaF/H
2O
workup was used. Soxhlet extraction of the solids generated in the work-up was required
to obtain good yields of crude
2. The present aqueous KOH work-up simplifies
the procedure and gives comparable or better yields of crude
2.
13.
Compound
2 has the following physical and spectroscopic
properties:
mp 105-107°C;
1H NMR (CDCl
3,
360 MHz) δ: 2.69 (s, 16 H), 2.16 (br s, 4 H)
;
13C NMR (CDCl
3,
90.56 MHz) δ: 46.11
.
1H NMR relative integrations
are consistent with anhydrous
2. There has been much confusion in the literature
concerning the mp of
2. Stetter and Mayer
3
originally reported mp 35°C. Buøen, et al. reported
mp
119-120°C.
4
Zhang and Busch subsequently reported
mp 36-38°C.
5 Aldrich and Fluka list melting point ranges of
110-113°C (97%) and
105-110°C (=97%) respectively in their catalogs. The submitter's
mp range for
2 (calibrated thermometer) is lower than that reported in reference
4, but is consistent with the mp
range of sublimed material (no detectable impurities by high S/N NMR) that they have
prepared by the Richman-Atkins procedure
6 (
mp 105-109°C).
14.
The checkers have found it necessary to perform as many as twelve
extractions with cold
chloroform to obtain the product from the
aqueous solution.
15.
The submitters obtained yields as high as
88% at scale.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The title compound,
2,
3 ("cyclen") and its
derivatives are important ligands,
7
some of which have biomedical applications
8 (for example, as ligand components of MRI
contrast agents). Cyclen is commercially available, but expensive.
9
This procedure is a modification of the method originally reported by Weisman and
Reed.
2 In the first reaction of the two-step sequence
(Step A), a two-carbon, permanent, covalently-bound template
10 is introduced by way of
dithiooxamide
to convert
triethylenetetramine
to
tricyclic bisamidine
1. Step A is analogous to the synthesis of
2,2'-bi-2-imidazoline
reported by Forssell in 1891.
11 Step B is a double
reductive ring expansion,
which converts the two amidine (template) carbons of
bisamidine
1 to a -CH
2CH
2- unit of
2. The reaction is conceptually
based upon Yamamoto and Maruoka's highly regioselective DIBAL-H reduction of bicyclic
amidines to ring-expanded cyclic diamines.
12
The advantages of this procedure are: (a) it is short and relatively efficient
(
44-68% overall yield), (b)
it is atom-economic,
13 (c) starting materials are readily available,
(d) purifications are simple, and (e) it permits preparation of moderate quantities
of product with modest effort. The disadvantages are the production of hydrogen sulfide
(highly toxic) in Step A and the required use of DIBAL-H, an active hydride
reducing agent. However, the former can be efficiently trapped and the latter can
be handled safely at the reported scale.
There are alternative methods for preparation of cyclen. Since the mid-1970's,
the standard method for preparation of cyclen has been based upon the general Stetter-Richman-Atkins
synthesis of macrocyclic polyamines,
6,
14
a medium-dilution cyclization approach that uses tosyl protection of nitrogen. The
cyclen syntheses developed by Richman and Atkins
6 (5
steps) and related modifications
2,
15 (4 steps), while very
reliable, are still labor-intensive sequences that suffer from atom economy and solvent
requirement problems. These problems are largely overcome by the shorter approach
documented here. Three additional syntheses of
2 have recently appeared in
the literature.
16
17
18 The syntheses (each
3 steps) rely upon carbon templating for preorganization, subsequent
cyclization, and final template removal. Such an approach may prove superior for large
scale production of
2, since active hydride reducing agents are avoided. However,
the procedure reported here is very satisfactory for the laboratory-scale preparation
of
2.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
1,4,7,10-Tetraazacyclododecane (9); (294-90-6)
Hydrogen sulfide: HIGHLY TOXIC (8,9); (7783-06-4)
2,3,5,6,8,9-Hexahydrodiimidazo[1,2-a:2',1'-c]pyrazine:
Diimidazo[1,2-a:2',1'-c]pyrazine, 2,3,5,6,8,9-hexahydro- (13);
(180588-23-2)
Dithiooxamide:
Ethanedithioamide
(9); (79-40-3)
Triethylenetetramine (8);
1,2-Ethanediamine,
N,N'-bis(2-aminoethyl)- (9); (112-24-3)
Chloroform: HIGHLY TOXIC. CANCER SUSPECT AGENT: (8);
Methane, trichloro- (9); (67-66-3)
Diisobutylaluminum hydride:
Aluminum, hydrodiisobutyl-
(8);
Aluminum, hydrobis(2-methylpropyl)- (9); (1191-15-7)
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