Thioureas as ligands in the Pd-catalyzed intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1021/ol050410y

(Chemical Equation Presented) The thiourea-Pd complex was established as a novel type of catalyst in the PKR of allylpropargylamine, and the demonstrated chemistry may prove to be valuable for developing thiuorea as a ligand for the Pd-catalyzed Pauson-Kh

Full text of DOI:10.1021/ol050410y

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1657-1659
Thioureas as Ligands in the
Pd-Catalyzed Intramolecular
Pauson−Khand Reaction
Yefeng Tang,† Lujiang Deng,† Yangdong Zhang,† Guangbin Dong,†
Jiahua Chen,*,† and Zhen Yang*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, College of Chemistry, Beijing 100871, China, Laboratory of Chemical
Genetics, Shenzhen Graduate School of Peking UniVersity, The UniVersity Town,
Shenzhen 518055, China, and ViVoQuest, Inc., 711 ExecutiVe BlVd.,
Valley Cottage, New York 10989
zyang@pku.edu.cn
Received February 24, 2005
ABSTRACT
The thiourea−Pd complex was established as a novel type of catalyst in the PKR of allylpropargylamine, and the demonstrated chemistry may
prove to be valuable for developing thiuorea as a ligand for the Pd-catalyzed Pauson
−Khand reaction.
The Pauson-Khand reaction1 (PKR) is utilized as an
effective method to construct cyclopentenone frameworks
in the synthesis of many complex molecules,1b-d such as (+)-
epoxydictymene.2 Catalytic PKRs with the use of Co,3 Ti,4
Ni,5 Ru,6 Rh,7 and Ir8 complexes have been reported in the
past decade; however, no successful example of the Pd-
catalyzed PKR is currently known.9
Recently we reported tetramethyl thiourea (tmtu) as an
effective additive in the Co-catalyzed PKR.10 In view of a
lack of any precedents in the utilization of palladium as a
catalyst in the PKR, we decided to apply thioureas in the
Pd-catalyzed PKR. We now report herein our preliminary
results on the Pd-catalyzed PKR using thioureas as effective
ligands.
† Peking University.
‡ VivoQuest, Inc.
(1) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. For recent reviews, see:
(b) Geis, O.; Schmalz, H. G. Angew. Chem., Int. Ed. 1998, 37, 911. (c)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (d) Bon˜aga, L.
V. R.; Krafft, M. E. Tetrahedron 2004, 60, 9795.
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Am. Chem. Soc. 1994, 116, 5505. (b) Jamison, T. F.; Shambayati, S.; Crowe,
W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
(3) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. (b) Rautenstrauch, V.;
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J. W.; Chung, Y. K. Synthesis 1998, 142. (h) Sugihara, T.; Yamaguchi, M.
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(9) The Pd-catalyzed [2 + 2 + 1] intramolecular cycloaddition for the
preparation of bicyclo[3.3.0]octa-1.5-dien-3-ones from 1,6-diynes was
reported recently. See: Grigg, R.; Zhang, L.; Collard, S.; Keep, A. Chem.
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10.1021/ol050410y CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

We selected commercially available thiourea (I), dimethyl
thiourea (II), and tmtu (III), as well as our synthesized
thiourea (IV)11 (Figure 1) as the ligands for studying the
reaction at all (entries 6-8). It became clear that the N,N-
tetrasubstituted feature of thioureas, and the 1:1 ratio of PdCl2
with thiourea represented the key elements in this PKR.
Among the solvents used (entries 4 and 9-12), THF was
the best choice. Reaction temperature is also important, and
a better result is achieved when the reaction was carried out
at 50 °C (entries 4, 5, 13, and 14). Interestingly, PdCl2
without ligand can also catalyze the reaction; however, the
palladium catalyst was completely precipitated after a few
hours of the reaction and only 27% yield of product was
obtained (entry 1 in Table 1).
Since the PdCl2/tmtu-catalyzed reaction gave the best
result, especially with consideration to commercial avail-
ability, tmtu (III) was then used as a ligand to perform the
Pd-catalyzed PKRs with a broad range of substrates. To this
end, allylpropargylmalonates 3a-5a (entries 1-3 in Table
2), allylpropargyl ethers 6a-8a (entries 4-6 in Table 2),
Figure 1. Selected thioureas for the Pd-catalyzed PKR.
Pd-catalyzed PKR. The Pd(II)-thiourea complexes were
made by mixing Pd(II) with thioureas I-IV in ratios ranging
from 1/1 to 1/4, and enyne 1 was selected as the substrate
for the PKR. The screening reactions were run in parallel,
and the results are summarized in Table 1.
Table 2. Pd-tmtu-Catalyzed Intramolecular PKRa
Table 1. Pd-Catalyzed PKRa
Pd(II):
ligand temp
yield
entry
Pd(II)
PdCl2
ligand
none
ratiob
(°C) solvent (%)c
1
50
50
50
50
50
50
50
50
50
50
50
50
25
80
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
DCE
DME
toluene
THF
THF
27
33
16
72
56
0
2
3
4
5
6
7
8
9
10
11
12
13
14
PdCl2
PdCl2
PdCl2
PdCl2
tu (I)
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
dmtu (II)
tmtu (III)
VI
Pd(OAc)2
Pd(CN)2Cl2 tmtu (III)
tmtu (III)
0
0
Pd(dba)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
tmtu (III)
tmtu (III)
tmtu (III)
tmtu (III)
tmtu (III)
tmtu (III)
tmtu (III)
67
70
50
29
38
10
a Reagent and conditions: enyne (0.05 mmol) in THF (10 mL),
50 °C under CO (balloon pressure). b Yield of isolated product. The
yields in parentheses are those obtained based on recovery of starting
materials.
a Reagent and conditions: enyne 1 (0.5 mmol) in 10 mL of solvent, 50
°C under CO (balloon pressure). The rest of the data regarding the complexes
derived from thioureas I and II, as well as the other ratios of the
Pd-complexes made from thiourea III and IV are not included in this table
because those reactions either gave low yields or did not promote the
reaction at all. c Yield of isolated product.
and allylpropargylamines 9a-20a (entries 1-12 in Table
3) were synthesized and evaluated.
First, we examined the reaction of allylpropargyl malonates
3a-5a. Unlike the Co/thiuorea-catalyzed PKR,10 these
substrates were found either to be not reactive or to suffer
from low conversion under the conditions listed in Table 2.
We then investigated the allylpropargyl ethers 6a-8a in the
PKR. A similar trend in reactivity was observed.
We finally evaluated the allylpropargylamines 9a-20a.
To our delight, all of the enynes possessing alkyl and phenyl
substituents on the alkyne moiety gave the expected cyclo-
pentenones and six of them afforded good to excellent yields
(entries 2, 3, 5, and 8-10 in Table 3).
According to the results, the complexes derived from
thioureas III and IV with PdCl2 in 1:1 ratio gave the desired
product 2 in 72% and 56% yields, respectively (entries 4
and 5 in Table 1). The other Pd(II)-thiourea complexes gave
either low yields (entries 2 and 3) or did not promote the
(11) Dai, M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Org. Lett. 2004,
6, 221.
1658
Org. Lett., Vol. 7, No. 8, 2005

because these substrates are fairly stable under the reaction
conditions, the desired coupling yields could in fact be
improved by increasing the reaction time.
Table 3. Pd-tmtu-Catalyzed PKR of Allylpropargylaminesa
Importantly, contrary to popular thought,12 the alkynes
attached with electron-deficient groups (entries 5, 6, and
8-10 in Table 3) gave better results than other members of
the family. The results, to our knowledge, have not been
reported so far.
Last, it is notable that when substrates 16a and 17a (entries
8 and 9 in Table 3) were employed in the cyclization, only
one diastereoisomer was obtained, and the relative stereo-
chemistry was determined by NOE analysis.
Although the thiourea-Pd complex can significantly speed
up the PKR, its catalytic mechanism is unclear. Based on
the available structural information for PtCl-tmtu,13 we
speculate that catalysis is taking place with the ligand bound
to the metal center in consideration of the requirement of a
1:1 ratio of PdCl2 with tmtu in this PKR. This hypothesis,
once validated, could be useful for the design of chiral
thiourea for the Pd-catalyzed asymmetric PKR.
In summary, we have established that a thiourea-Pd
complex is a novel type of catalyst in the PKR of allylpro-
pargylamine, and the demonstrated chemistry may prove to
be valuable for developing thiuorea as a ligand for the Pd-
catalyzed PKR. Further study regarding the reaction mech-
anism by joint efforts of experimental and computational
chemistry is currently underway in our laboratory, and the
results will be reported in due course.
Acknowledgment. This work is funded by the CNSF
(Grants 20272003 and 20472002), and the authors thank
VivoQuest Inc. for financial support through the sponsored
research program.
Supporting Information Available: Experimental pro-
cedure and NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050410Y
a Reagent and conditions: Enyne (0.05 mmol) in THF (10 mL), 50 °C
under CO (balloon pressure). b Yield of isolated product. The yields in
parentheses are those obtained based on recovery of starting materials.
(12) For a review, see: Rodrigues Rivero, M.; Adrio, J.; Carretero, J.
C. Eur. J. Org. Chem. 2002, 2881.
(13) (a) Gosavi, R. K.; Agarwaia, U.; Rao, C. N. R. J. Am. Chem.
Soc. 1967, 89, 235. (b) Gosavi, R. K.; Rao, C. N. R. J. Inorg. Nucl.
Chem. 1967, 29, 1937. (c) Schafer, M.; Curran, C. Inorg. Chem. 1966, 5,
265.
Although four of the substrates suffered from low conver-
sion to their products (entries 4, 6, 7, and 11 in Table 3),
Org. Lett., Vol. 7, No. 8, 2005
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