Synthesis of tris(N,N-dimethylthiocarbamoyl)-1,1,1-tris-(methylaminomethyl) ethane and its application as ligand for Pauson-Khand reaction

Article abstract of DOI:10.1080/00397910701832470

Tris(N,N-dimethylthiocarbamoyl)-1,1,1-tris(methylaminomethyl)ethane ligand was prepared from very cheap and commercially availably tris-1,1,1- (hydroxymethyl)ethane in five steps and applied as ligand in 1:1 coordination to cobalt in a catalytic Pauson-Kh

Full text of DOI:10.1080/00397910701832470

This article was downloaded by: [Monash University Library]
On: 08 December 2014, At: 17:40
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Tris(N,N-
dimethylthiocarbamoyl)-1,1,1-
tris-
(methylaminomethyl)ethane
and Its Application as Ligand
for Pauson–Khand Reaction
Željko Petrovski a , Carlos C. Romão b & Carlos A. M.
Afonso a
a CQFM and IN (Institute of Nanoscience and
Nanotechnology), IST , Lisbon, Portugal
b ITQB, New University of Lisbon , Oeiras, Portugal
Published online: 25 Aug 2010.
To cite this article: Željko Petrovski , Carlos C. Romão & Carlos A. M. Afonso (2008)
Synthesis of Tris(N,N-dimethylthiocarbamoyl)-1,1,1-tris-(methylaminomethyl)ethane
and Its Application as Ligand for Pauson–Khand Reaction, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:16, 2761-2767, DOI: 10.1080/00397910701832470
To link to this article: http://dx.doi.org/10.1080/00397910701832470
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.

However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 38: 2761–2767, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701832470
Synthesis of Tris(N,N-dimethylthiocarbamoyl)-
1,1,1-tris-(methylaminomethyl)ethane and Its
Application as Ligand for Pauson–Khand
Reaction
1
Zeljko Petrovski, Carlos C. Romao, and Carlos A. M. Afonso
2
1
ˇ
˜
1CQFM and IN (Institute of Nanoscience and Nanotechnology), IST,
Lisbon, Portugal
2ITQB, New University of Lisbon, Oeiras, Portugal
Abstract: Tris(N,N-dimethylthiocarbamoyl)-1,1,1-tris(methylaminomethyl)ethane
ligand was prepared from very cheap and commercially available tris-1,1,1-
(hydroxymethyl)ethane in five steps and applied as ligand in 1:1 coordination
to cobalt in a catalytic Pauson–Khand reaction with Co2(CO)8 as catalyst.
Keywords: Pauson-Khand reaction, tris-ureas, tetrasubstituted thioureas, tris-
thioureas
Tetrasubstituted thioureas have been recently very successfully applied as
ligands for various transition-metal-catalyzed organic reactions. Some of
the most recent applications of tetrasubstituted thioureas are palladium-
catalyzed aerobic oxidation of alcohols;[1] palladium-catalyzed Suzuki,
Heck,[2,3] Suzyki carbonylative reactions[4] and palladium-catallized bis
(methoxycarbonylation) of terminal olefins;[5] Pauson–Khand reaction
(PKR) with palladium and cobalt catalysts;[6,7] and tetramethylthiourea-
TiCl4-mediated reaction of dimethyl acetylene dicarboxylate with p-nitro-
benzaldehyde.[8] When it was possible, tetramethylthiourea (TMTU) was
always used as ligand; however, in some cases the bulky thioureas,
especially with aryl substitution had more beneficial effect.[1–5] For this
Received 24 October 2007; accepted 31 October 2007.
Address correspondence to Carlos A. M. Afonso, CQFM, Departamento de
ꢀ
Engenharia Quımica e Biologica, Instituto Superior Tecnico, Complexo, I, Av.
Rovisco Pais 1, 1049001 Lisboa, Portugal. E-mail: carlosafonso@ist.utl.pt
´
´
2761

ˇ
Z. Petrovski, C. C. Romao, and C. A. M. Afonso
˜
2762
Scheme 1.
reason, some effort has been directed for their synthesis and application
in reactions cited previously, including also some tetrasubstituted
bis-thioureas that prove to be useful ligands.[1,2] However, to the best
of our knowledge, there were no records in literature of synthesis of any
tetrasubstituted tris-thiourea and its application in catalysis.
Me3-tame ligand 2 was prepared from very cheap tris-1,1,1-(hydroxy-
methyl)ethane by the method of Kasowski and Bailar[9] using the pro-
cedure of Herzog[10] for preparation of tribromide (Scheme 1). We find
this method for synthesis very easy and reliable. We have already found
compound 2 and its tribenzyl derivative very useful as a tripodal ligand,
almost always as good for coordination to transition metals as 1,4,7-tri-
azacyclononane.[11] The cost of 1,4,7-triazacyclononane and difficulties in
its preparation prompted us to turn to the synthesis of 2, which could be
prepared easily and in large quantities.
All attempts to prepare the tris-thiourea compound by direct acyla-
tion of amine 2 with dimethylthiocarbamoyl chloride were unsuccessful.
However, it reacted easily with dimethylcarbamoyl chloride to provide
tris-urea 3. The product 3 was quite polar (Rf ¼ 0.36 in Et2O–MeOH
8:2) but enough pure to be used without any purification for the
next step. It was further transformed to tris-thiourea 4 by the reaction
with Lawesson’s reagent (Scheme 2). The tris-thiourea 4 was isolated
by crystallization from ethanol.
Our goal was to apply the thiourea ligand 4 in PKR. Recently, it was
discovered that TMTU is a very usuful ligand in Co2(CO)8-catalyzed
PKR.[7] The efficiency of tetrasubstituted thiourea ligand was evident
and since then well explored.[6] However, experimental procedure applied
especially to substrates less suitable for the PKR frequently required up
to 60 mol% load of TMTU and ratio of ligand to catalyst of 6:1.
Scheme 2.

Tris(thiourea) Ligand in Pauson-Khand Reaction
2763
Scheme 3.
However, taking in consideration the high toxic effect of TMTU,[12] it
would be preferable if thiourea loading could be reduced. We came to
believe that the main problem here was the dissociation of the ligand
from the metal. This problem was suppressed by high thiourea concen-
tration, but we envisioned it could be resolved if the tripodal tris-thiourea
4 could be applied as ligand.
The effect of 4 as ligand was studied by typical test PKR as depicted
in Scheme 3 and Table 1. The compound 5 was chosen as a substrate
model because it is one of the substrates that requires high TMTU load-
ing for good performance of PKR as shown by Tang et al.[7] The yield of
the product 6 was determined after purification by thin-layer chromato-
1
graphy (TLC), and its purity was confirmed by H NMR. The same
reaction was always repeated under the same conditions but TMTU
instead of 4 in triple loading was applied as ligand. The reaction results
are summarized in Table 1.
Following the procedure of Tang et al.[7] (the only substitution being
benzene instead of toluene for environmental reasons), we managed to
isolate product 6 in 90% yield (entry 1). As the authors reported the for-
mation of product 6 under the same conditions in benzene in 95% yield,
which is in line with authors’ reported yield of 95% in benzene under the
same conditions. The reaction was monitored by TLC. After 2.5 h, it
seemed to be very clean and only the PKR product seemed to form.
All of the starting material was consumed. However, the decrease of
quantity of TMTU to 0.1 eq. resulted in a drop of product yield to
Table 1. Pauson–Khand reaction of 5 in the presence of ligand 4 or tetra-
methylthiourea (TMTU)
Entry
Ligand
Ligand equivalent
Reaction time (h)
Yield of 6 (%)a
1
2
3
4
5
TMTU
TMTU
4
0.6 eq.
0.1 eq.
0.033 eq.
0.1 eq.
0.033 eq.
2.5
2.5
2.5
3.5
3.5
90
70
62
83
76
TMTU
4
aIsolated yield after purification by thin-layer chromatography (TLC).

ˇ
˜
Z. Petrovski, C. C. Romao, and C. A. M. Afonso
2764
70% after 2.5 h (entry 2). When 0.033 eq. of ligand 4 (entry 3), was used
the yield was 62%. Increasing the reaction time to 3.5 h (entries 4 and 5)
had a beneficial effect on the yield of 6, although still TMTU stayed
slightly superior to 4. A possible explanation for this phenomenon is that
there could be some tension in the coordination of 4 to the metal. It is
also not clear yet what kind of approach and coordination of thiourea
units is responsible for the high activity of this system.
In conclusion, we have described here an easy approach for the
synthesis of tris-thiourea compound 4 in high overall yield. We applied
compound 4 successfully in the PKR.
EXPERIMENTAL
General
All reagents were purchased from Aldrich, and were all used without
further purification. All solvents were distilled before use. Dry diisopro-
pylethylamine, toluene, and dichloromethane were distilled from CaH2,
while ethanol was dried and distilled from sodium–ethyl phtalate. Melt-
ing points are uncorrected. IR spectra were obtained as KBr pallets using
1
a FTIR Mattson-7000 infrared spectrophotometer. H NMR and 13C
NMR spectra were recorded on a Bruker CXP 300. Samples for NMR
were prepared in CDCl3 or C6D6, and tetramethylsilane was used as
the internal standard.
Synthesis of Tris(methylaminomethyl)ethane (2)
In a 500-ml, three-necked, round-bottomed flask equipped with a mech-
anical stirrer, a thermometer, and a dropping funnel, tris(hydroxymethyl)
ethane (11.9 g; 96 mmol) and pyridine (65 ml) were placed. The stirrer was
started, and benzenesulfonyl chloride (40.5 ml, 317 mmol, 3.3 eq) was
added dropwise to the resulting suspension at such a rate that the
temperature of the reaction did not rise to more than 30–35ꢀC. The
addition requires about 2 h. The resulting slurry was stirred at 40ꢀC for
1 h after the addition was complete. The slurry was added then slowly
to a vigorously stirred solution of 80 ml of concentrated hydrochloric
acid in 100 ml of water and 200 ml of methanol. The resulting suspension
of white solid tris-benzenesulfonate was cooled with ice, filtered, and
washed with water and cold methanol.
The crude, slightly wet tris-benzenesulfonate was immediatly added
to diethylene glycol (100 ml) in a 500-ml, two-necked, round-bottomed
flask equipped with a mechanical stirrer. Then sodium bromide was

Tris(thiourea) Ligand in Pauson-Khand Reaction
2765
added (45 g, 43.5 mmol, 4.5 eq), and the mixture was heated in an oil bath
at 140–150ꢀC with slow stirring overnight. The resulting orange mixture
was allowed to cool. After dilution with water tris-(bromomethyl)ethane
1 separates from the aqueous solution as a heavier oily layer. It was
further extracted from water by dichloromethane. The combined extracts
were washed with water, dried over anhydrous Na2SO4, and distilled under
vacuum to provide 21.5 g (72%) of pure tris(bromomethyl)ethane 1.
1H NMR (300 MHz, CDCl3): 3.44 (s, 6H), 1.22 (s, 3H).
Dry methylamine was slowly bubbled to the solution of tribromide 1
(17.3 g, 55.8 mmol) in 40 ml of anhydrous ethanol under argon at 0ꢀC
until the mass of the reaction mixture did not exceed 17.3 g (557 mmol,
10 eq). Then the reaction mixture was transfered to an autoclave and
heated at 170ꢀC for 10 h. The cooled reaction mixture was diluted with
distilled water and then neutralized with dilute hydrochloric acid. An
excess of water was evaporated, and the rest was made basic with solid
KOH. The amine layer was separated, the aqueous solution subsequently
extracted with diethyl ether, and the extracts were added to the main sol-
ution. The combined extracts were dried over KOH, ether was evapo-
rated, and the rest was distilled on an oil pump to provide 5.85 g of
ꢀ
1
pure amine 2 (66%) (bp8 ¼ 38–39 C). H NMR (300 MHz, C6D6): 2.45
(s, 6H), 2.26 (s, 9H), 1.31 (br, 3H), 0.82 (s, 3H).
Synthesis of Tris(N,N-dimethylcarbamoyl)-tris-1,1,1-
(methylaminomethyl)ethane (3)
A solution of triamine 2 (2.16 g, 13.6 mmol) in dry dichloromethane
(20 ml) was added to the solution of dimethylcarbamoyl chloride
(5.11 g, 47.6 mmol, 3.5 eq) in dry dichloromethane (60 ml) under argon.
Dry diisopropylethylamine (8.5 ml, 48.9 mmol, 3.6 eq) and DMAP (cat.)
were added, and the reaction mixture was stirred at room temperature
for 24 h. Then saturated aqueous solution of sodium bicarbonate was
added, and aqueous layer was extracted with dichloromethane. The
organic layer was washed with diluted hydrochloric acid and water, dried
with anhydrous sodium sulphate and dichloromethane, and evaporated to
provide 3.5 g (70%) of clean tris-urea 3 (mp 121–128ꢀC). 1H NMR
(300 MHz, C6D6): 3.24 (s, 6H), 2.90 (s, 27 H), 0.773 (s, 3 H); 13C NMR
(75 MHz, C6D6): 166.2, 56.5, 45.8, 43.0, 38.7, 19.8. FTIR (KBr, cmꢁ1):
3450 (br), 2971 (m), 2952 (m), 1641 (s), 1610 (s), 1547 (m), 1510 (vs),
1466 (m), 1441 (m), 1409 (m), 1384 (s), 1353 (s), 1284 (m), 1265 (m),
1228 (m), 1153 (s), 1108 (s), 1064 (m), 1039 (m), 983 (m), 945 (m), 926,
889 (m), 864 (m), 776 (s), 751, 644. Mass spectrum, LRMS (FABþ )
m=z calcd. for C17H37N6O3þ (M þ 1)þ : 373.29, found 373.29.

ˇ
˜
Z. Petrovski, C. C. Romao, and C. A. M. Afonso
2766
Synthesis of Tris(N,N-dimethylthiocarbamoyl)-tris-1,1,1-
(methylaminomethyl)ethane (4)
The mixture of tris-urea 3 (3.2 g, 11.8mmol) and Lawesson’s reagent (21.4g,
53.0 mmol; 4.5 eq) in dry toluene (60 ml) was stirred at reflux under argon
for 24 h. Then toluene was evaporated, and the rest was dissolved with
dichloromethane. Dichloromethane solution was washed with an aqueous
solution of sodium bicarbonate, diluted hydrochloric acid, and water and
then dried over anhydrous sodium sulphate. After evaporation of dichloro-
methane, the remaining residue was recrystallized from absolute ethanol to
provide 2.172g (60%) of pure tris-thiourea 4 (mp 200–220ꢀC decomp.). 1H
NMR (300 MHz, CDCl3): 4.01 (s, 6H), 3.13 (s, 18H), 3.10 (s, 9H), 0.83
(s, 3H). 13C NMR (75 MHz, CDCl3): 195.3, 62.2, 47.9, 47.0, 43.6, 18.0.
FTIR (KBr, cmꢁ1): 3400 (br), 2997, 2950 (sh), 2934, 1505 (s), 1465, 1442,
1394, 1371 (s), 1339 (s), 1307 (m), 1268 (m), 1197, 1150 (m), 1134 (m),
1094, 1078 (m), 936, 857, 494. Mass spectrum, LRMS EIþ m=z calcd. for
C17H36N6Sþ3 [M]þ: 420.22, found 420.25.
General Procedure for Pauson–Khand Reaction
A Schlenck tube stoppered with rubber septum, equipped with substrate
5 (124.5 mg, 0.5 mmol), ligand (as in Table 1), and Co2(CO)8 (17 mg,
0.05 mmol, 0.1eq) under argon, in a well-ventilated fume hood, was evac-
uated three times and filled with carbon monoxide. Dry toluene (10 ml)
was added to the Schlenck tube, with attached rubber balloon filled with
carbon monoxide. The tube was heated on an oil bath at 70ꢀC and fitted
with a cooling mantle of an appropriate size for a Schlenck tube. The
reaction was monitored by TLC. After 2.5 or 3.5 h, the reaction mixture
was cooled, passed through a small pad of silica, evaporated, and purified
by TLC (Merck silica gel 60 F254; eluent hexane=ethyl acetate 7:3). The
1
purity of the product 6[7] was confirmed by H NMR.
ACKNOWLEDGMENT
ˆ
The authors are grateful to the Fundac¸a˜o para a Ciencia e Tecnologia
(POCI 2010) and FEDER for financial support (Ref. SFRH=BPD=
18740=2004 and POCI=QUI=56582=2004).
REFERENCES
1. Yang, M.; Yip, K. T.; Pan, J. H.; Chen, Y. C.; Zhu, N. Y.; Yang, D. A sterically
bulky cyclic thiourea as an efficient ligand for palladium-catalyzed aerobic
oxidation of alcohols. Synlett 2006, 3057–3060.

Tris(thiourea) Ligand in Pauson-Khand Reaction
2767
2. Chen, W.; Li, R.; Wu, Y.; Ding, L. S.; Chen, Y. C. Self-supported thiourea–
palladium complexes: Highly air-stable and recyclable catalysts for the Suzuki
reaction in neat water. Synthesis 2006, 3058–3062; Chen, W.; Li, R.; Han, B.;
Li, B. J.; Chen, Y. C.; Wu, Y.; Ding, L. S.; Yang, D. The design and synthesis
of bis(thiourea) ligands and their application in Pd-catalyzed Heck and Suzuki
reactions under aerobic conditions. Eur. J. Org. Chem.. 2006, 1177–1184.
3. Yang, D.; Chen, Y. C.; Zhu, N. Y. Sterically bulky thioureas as air- and
moisture-stable ligands for Pd-catalyzed Heck reactions of aryl halides.
Org. Lett. 2004, 6, 1577–1580.
4. Dai, M. J.; Liang, B.; Wang, C. H.; You, Z. J.; Xiang, J.; Dong, G. B.; Chen, J.
H.; Yang, Z. A novel thiourea ligand applied in the Pd-catalyzed Heck, Suzuki,
and Suzuki carbonylative reactions. Adv. Synth. Catal. 2004, 346, 1669–1673.
5. Dai, M. J.; Wang, C. H.; Dong, G. B.; Xiang, J.; Luo, T. P.; Liang, B.; Chen, J. H.;
Yang, Z. Development of thiourea-based ligands for the palladium-catalyzed
bis(methoxycarbonylation) of terminal olefins. Eur. J. Org. Chem. 2003, 4346–4348.
6. Mukai, C.; Yoshida, T.; Sorimachi, M.; Odani, A. CO2(CO)(8)-catalyzed intra-
molecular hetero–Pauson–Khand reaction of alkynecarbodiimide: Synthesis of
( ꢂ )-physostigmine. Org. Lett. 2006, 8, 83–86; Tang, Y. F.; Zhang, Y. D.;
Dai, M. J.; Luo, T. P.; Deng, L. J.; Chen, J. H.; Yang, Z. A highly efficient
synthesis of the FGH ring of micrandilactone A: Application of thioureas as
ligands in the co-catalyzed Pauson–Khand reaction and Pd-catalyzed carbony-
lative annulation. Org. Lett.. 2005, 7, 885–888; Tang, Y. F.; Deng, L. J.; Zhang,
Y. D.; Dong, G. B.; Chen, J. H.; Yang, Z. Thioureas as ligands in the Pd-cata-
lyzed intramolecular Pauson–Khand reaction. Org. Lett. 2005, 7, 1657–1659.
7. Tang, Y. F.; Deng, L. J.; Zhang, Y. D.; Dong, G. B.; Chen, J. H.; Yang, Z.
Tetramethyl thiourea=Co-2(CO)(8)-catalyzed Pauson–Khand reaction under
balloon pressure of CO. Org. Lett. 2005, 7, 593–595.
8. Kinoshita, S.; Kinoshita, H.; Iwamura, T.; Watanabe, S.; Kataoka, T. Chal-
cogenide–Lewis acid mediated reactions of electron-deficient alkynes with
aldehydes. Chem. Eur. J. 2003, 9, 1496–1502.
9. Kasowski, W. J.; Bailar, J. C. Steric effects in coordination of 1,1,1-tris(di-
methylaminomethyl)ethane and of 1,1,1-tris(monomethylaminomethyl)
ethane I: Zinc(2) complexes. J. Am. Chem. Soc. 1969, 91, 3212–3218.
10. Herzog, H. L. Pentaerythrityl tetrabromide [propane, 1,3-dibromo-2,2-
bis(Bromomethyl)-]. Org. Synth. 1951, 31, 82–84.
11. Valente, A. A.; Petrovski, Z.; Branco, L. C.; Afonso, C. A. M.; Pillinger, M.;
Lopes, A. D.; Romao, C. C.; Nunes, C. D.; Goncalves, I. S. Epoxidation of
cyclooctene catalyzed by dioxomolybdenum(VI) complexes in ionic liquids. J.
Mol. Catal. A—Chem. 2004, 218, 5–11; Petrovski, Z.; Valente, A. A.; Pillinger,
M.; Dias, A. S.; Rodrigues, S. S.; Romao, C. C.; Goncalves, I. S. Molybde-
num(VI) oxides bearing 1,4,7-triazacyclononane and 1,1,1-tris(aminomethyl)
ethane ligands: Synthesis and catalytic applications. J. Mol. Catal. A—Chem.
2006, 249, 166–171. In our experience, the only case when 2 and its derivatives
could not accompany triazacyclononane in reactivity was in reaction with Re2O7.
12. Freyberger, A.; Ahr, H. J. Studies on the goitrogenic mechanism of action of
N,N,N’,N’-tetramethylthiourea. Toxicology 2006, 217, 169–175.