Synthesis of (14C6-3,4,7,8,11,12)-(1E,5E,9E)- cyclododeca-1,5,9-triene

Article abstract of DOI:10.1002/jlcr.1265

Trimerization of butadiene in the presence of Ni(0) affords (1E,5E,9E)-cyclododeca-1,5,9-triene 1 (ttt-CDT), (1E,5E,9Z)-cyclododeca-1,5,9- triene 2 (ttc-CDT), and other isomers/oligomers. After optimization of reaction conditions, [¹⁴C₆-3,4,7,8,11,12]-ttt-CDT 1 was synthesized efficiently either by homogenous or heterogeneous Ni(0) catalytic trimerization of [1,4-¹⁴C₂]butadiene 10, in 60-82% yield. Depending on the exact reaction conditions employed, the yields and ratio of 1/2 ranged from (59-90%) / (41-10%). The all-trans isomer was conveniently isolated via Ag ⁺-mediated reversed-phase HPLC. The important intermediate [1,4- ¹⁴C₂]-1,3-butadiene 10 was prepared from potassium [ ¹⁴C]cyanide and 1,2-dibromoethane 3 as starting materials, in seven steps with a 57% yield. The total radioactive yield of [¹⁴C ₆-3,4,7,8,11,12]-ttt-CDT 1 is 30% from [¹⁴C]KCN. Copyright

Full text of DOI:10.1002/jlcr.1265

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 407–409.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1265
Short Research Article
Synthesis of [14C6-3,4,7,8,11,12]-(1E,5E,9E)-cyclododeca-
1,5,9-trieney
BRUCE N. DIEL*, MINGCHENG HAN and JONATHAN M. WHITE
Midwest Research Institute, 425 Volker Boulevard, Kansas City, MO 64110, USA
Received 31 August 2006; Revised 8 January 2007; Accepted 20 January 2007
Abstract: Trimerization of butadiene in the presence of Ni(0) affords (1E,5E,9E)-cyclododeca-1,5,9-triene 1 (ttt-CDT),
(1E,5E,9Z)-cyclododeca-1,5,9-triene 2 (ttc-CDT), and other isomers/oligomers. After optimization of reaction
conditions, [14C6-3,4,7,8,11,12]-ttt-CDT 1 was synthesized efficiently either by homogenous or heterogeneous
Ni(0) catalytic trimerization of [1,4-14C2]butadiene 10, in 60–82% yield. Depending on the exact reaction conditions
employed, the yields and ratio of 1/2 ranged from (59–90%) / (41–10%). The all-trans isomer was conveniently
isolated via Ag+-mediated reversed-phase HPLC. The important intermediate [1,4-14C2]-1,3-butadiene 10 was
prepared from potassium [14C]cyanide and 1,2-dibromoethane 3 as starting materials, in seven steps with a 57%
yield. The total radioactive yield of [14C6-3,4,7,8,11,12]-ttt-CDT 1 is 30% from [14C]KCN. Copyright # 2007 John
Wiley & Sons, Ltd.
Keywords: trans,trans,trans-cyclododecatriene; cyclotrimerization; homogeneous catalysis; butadiene; carbon-14
Introduction
of all-trans [14C6-3,4,7,8,11,12]-ttt-CDT 1 as the pre-
dominant isomer. Additionally, we accomplished the
separation and purification of the ttt-CDT isomer using
a Ag+-mediated reversed-phase LC method, providing
the product as a white crystalline solid with a chemical
purity and radiochemical purity of >99%, and at a
specific activity of 43 mCi/mmol.
The cyclotrimerization of butadiene is a key reaction in
homogeneous catalysis1 and several transition metal
and Ziegler–Natta catalyst systems have been reported.2
By far, nickel complexes have been found to be the most
versatile,3 and Ni(0)-catalyzed reactions have been
studied in greatest detail.4 In such systems, the
[Ni0(butadiene)x] complex has been shown to be the
active catalyst, and the all-trans-isomer is the predomi-
nant product, while the all-cis-isomer is not formed.5
Susa´n and Duncan synthesized [14C6]-cyclododeca-
triene from [14C2-1,4]-1,3-butadiene using a Ziegler-
type catalyst system, in 1981.6 In their report, the
overall radiochemical yield was ꢀ15%, the product was
98% cis,trans,trans-CDT 2, and only 2% trans,
trans,trans-CDT 1, and separation and isolation of
the individual isomers were not addressed. Herein we
*
*
* * *
*
*
*
*
*
*
*
1
2
Results and discussion
describe
a high conversion, high stereoselectivity
The first requirement for this synthetic approach was a
high-yield process for the generation of doubly labeled
synthetic strategy (Scheme 1) that allowed synthesis
intermediate
[
14C2-1,4]-1,3-butadiene 10. As illu-
strated in Scheme 1, we chose as precursor the
quaternary ammonium hydroxide 9 (SA ꢀ15 mCi/
mmol), which was prepared via reaction of [14C]KCN
(SAꢀ7.5 mCi/mmol) and 1,2-dibromoethane, following
published methods, in six steps overall.3,7
*Correspondence to: Bruce N. Diel, Midwest Research Institute,
Chemical Sciences, 425 Volker Boulevard, Kansas City, MO 64110,
USA. E-mail: bdiel@mriresearch.org
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.

408 B. N. DIEL ET AL.
O
conc. HCl(aq)
97%
K*CN, EtOH
OH
*
+
2 K*CN
Br
Br
*
NC
*
CN
HO
*
O
87%
3
4
5
BH3 . THF
94%
Me3N, EtOH
100%
N+(Me)3Br -
48% HBr
93%
*
Br
OH
Br - (Me)3N+
*
*
*
Br
HO
*
*
8
7
6
Ag2O, H2O
100%
250˚C
77%
N+(Me)3OH -
*
*
OH - (Me)3N+
*
*
* indicates carbon-14
9
10
Scheme 1
Table 1 Optimization of butadiene cyclotrimerizationa
Ni(acac)2
AlEt3
Entry
Method
(mmol/ml)
(mg/mmol)
(ml/mmol)
Solvent/(ml)
Yield (%)
ttt:ttc
Color
1
2
3
4
5
6
7b
A
B
B
A
A
A
A
11.5/1
11.5/1
13.8/1.2
30/2.6
11.4/1
11.4/1
28.8/2.7
119/0.04
110/0.4
27/0.1
27/0.1
27/0.1
100/0.2
1.0/2
toluene/2.0
toluene/5.0
toluene/2.0
toluene/5.0
toluene/5.0
1,5-COD/5.0
toluene/5.0
14
22
78
82
60
34
78
90:10
N/A
Light brown
Black
Black
Brown
Brown
Yellow
220/0.4
220/0.4
220/0.4
220/0.4
277/0.5
66:34
67:33
79:21
59:41
67:13
27/0.1
34/0.12
Brown
a Reaction conditions: sealed glass vessel, 808C, 20 h under He.
b ‘Hot run,’ using labeled butadiene; yield is total mCi isolated.
Method A: AlEt3 to a mixture of Ni(acac)2/butadiene in solution.
Method B: Butadiene condensed into preformed Ni(acac)2/AlEt3 catalyst solution.
Refluxing of 1,2-dibromoethane 3 (1 equiv.) with
14C]KCN (1 equiv.) in 70% EtOH(aq.) gave [14C2-1,
scrubber to remove Me3N(g), followed by passage over
DrieriteTM to remove water.
[
4]succinonitrile 4 in 87% yield (based on KCN). Acidic
hydrolysis of 4 with conc. HCl under refluxing condi-
tions afforded [14C2-1,4]succinic acid 5 in quantitative
yield. The reduction of 5 with borane–THF at 08C
provided diol 6 (94%), which was easily converted into
the dibromide 7 by refluxing the diol 6 with 48% HBr.
A limited number of cyclotrimerization experiments
were conducted to optimize the reaction conditions,
with the intent of maximizing total conversion and
isomer-selectivity. (Table 1) Consideration was given
to (i) the reduction of Ni(II) in the presence of the
butadiene (Method A) versus addition of butadiene to
a zerovalent ‘bare’ nickel complex (Method B), (ii) the
ratio of Ni:butadiene, and (iii) the ratio of AlEt3:buta-
diene. Based on the results of these experiments, the
conditions used for Entry 4 were employed for execu-
tion of the ‘hot run,’ using the [14C2-1,4]-1,3-butadiene
10; these results are shown as Entry 7, and the ratio of
ttt-CDT:ttc-CDT is the actual total isolated activity
(mCi) for each isomer (Table 1).
Reaction of
[
14C2-1,4]-1,4-dibromobutane
7
with
trimethylamine gas in ethyl alcohol provided the
ammonium bromide 8. Compound 8 was converted to
the corresponding ammonium hydroxide in quantita-
tive yield using freshly prepared silver(I) oxide,
generated in situ. Finally, the generation of [14C2-
1,3]butadiene 10 was accomplished by pyrolysis of 9,
passing the evolved gases first through a 2 N H2SO4 gas
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 407–409
DOI: 10.1002.jlcr

SYNTHESIS OF [14C6-3,4,7,8,11,12]-(1E,5E,9E)-CYCLODODECA-1,5,9-TRIENE 409
Separation and purification of the ttt-CDT and ttc-
New York, 1975; 133–212; (b) Jolly PW. In Compre-
hensive Organometallic Chemistry, vol. 8,
CDT isomers were accomplished using Ag+-mediated
complexation-based chromatography. Complexation-
based chromatography (GC, LC), involving electron-
rich metal salts such as AgNO3, Rh(OAc)2, etc. has been
studied extensively and there are two basic approaches
for LC separation: (i) p-complex formation between the
analyte and metal ions dissolved in the mobile phase,8
and (ii) p-complexing metal ions immobilized on the
stationary phase.9
Wilkinson G, Stone FGA, Abel EW (eds). Pergamon:
New York, 1982; 671–711.
2. (a) Wilke G. Angew Chem 1957; 69: 397; (b) Breil H,
¨
¨
Heimbach P, Kroner M, Muller H, Wilke G. Makromol
Chem 1963; 69: 18.
3. (a) Wilke G. Angew Chem 1963; 75: 10; Angew
Chem Int Ed Engl 1963; 2: 105; (b) Wilke G. Angew
Chem 1988; 100: 189; Angew Chem Int Ed Engl
1988; 27: 185.
The mixture of isomers 1 and 2 separated success-
fully by reversed-phase flash chromatography
(VersaPackTM C18 Cartridge, 40 ꢁ 75 mm), eluting with
Ag+ salt) gave high pure compound 1.
4. (a) Wilke G. Pure Appl Chem 1978; 50: 677; (b) Wilke
G. J Organomet Chem 1980; 200: 349.
¨
5. Bogdanovic B, Heimbach P, Kroner M, Wilke G.
Liebigs Ann Chem 1969; 727: 143.
6. Susa´n AB, Duncan WP. J Label Compd Radiopharm
1981; 18: 1227.
Conclusion
7. (a) Hara T, Xu YJ, Sasaki H, Niitu M, Samejima K.
J Label Compd Radiopharm 2000; 43: 1005; (b)
Bottari P, Aebersold R, Turecek F, Gelb MH. Bioconj
Chem 2004; 15: 380.
A new synthesis has been developed and the reaction
conditions optimized to provide high purity [14C6-
3,4,7,8,11,12]-(1E,5E,9E)-cyclododeca-1,5,9-triene in
30% overall radioactive yield from [14C]-KCN.
8. See, for example: (a) Schomburg G, Zegarski K.
J
Chromatogr 1975; 114: 174; (b) Vonach B,
REFERENCES
Schomburg G. J Chromatogr 1978; 149: 417.
9. Houx NWH, Voerman S. J Chromatogr 1976; 129:
456.
1. (a) Jolly PW, Wilke G. In The Organic Chemistry of
Nickel, Vol. 2, Organic Synthesis. Academic Press:
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 407–409
DOI: 10.1002.jlcr