Development of a One-Pot Four C-C Bond-Forming Sequence Based on Palladium/Ruthenium Tandem Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b03556

A one-pot four C-C bond-forming sequence has been developed using two distinct transition metal complexes. The sequence entails a double Pd-catalyzed allylic alkylation followed by a Ru-catalyzed ring-closing metathesis and a Pd-catalyzed Heck coupling. The use of various active methylene nucleophiles was examined with yields up to 76% (93% per C-C bond).

Full text of DOI:10.1021/acs.orglett.7b03556

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Development of a One-Pot Four C−C Bond-Forming Sequence Based
on Palladium/Ruthenium Tandem Catalysis
Anne-Doriane Manick, Farouk Berhal,* and Guillaume Prestat*
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR CNRS 8601, Universite
Saints Peres, 75006 Paris, France
́
Paris Descartes, 45 rue des
̀
S
* Supporting Information
ABSTRACT: A one-pot four C−C bond-forming sequence has been
developed using two distinct transition metal complexes. The sequence
entails a double Pd-catalyzed allylic alkylation followed by a Ru-catalyzed
ring-closing metathesis and a Pd-catalyzed Heck coupling. The use of
various active methylene nucleophiles was examined with yields up to 76%
(93% per C−C bond).
erforming successive bond formation in a single vessel
Pwithout any isolation or purification of the intermediates
allows the reduction of waste, cost, and time and is therefore of
prime importance in the context of green or sustainable
chemistry.1 The importance of such step-economical processes
defined as one-pot, tandem, cascade, domino, or pseudodomi-
no has been underlined by Paul Wender as an important means
to reach the ideal synthesis.2,3 The tremendous development of
transition metal (TM) catalysis during the past 50 years has
allowed the emergence of a specific class of one-pot processes
in which all the forming bond events are based on TM-
catalysis.4 Such processes represent a significant step forward
for green chemistry, being both atom and step economical.5
Evidently, the efficiency of a process is measured not only by its
sustainability but also by its ability to allow diversity-oriented
synthesis.6 In order to enhance the chemical space accessible,
one-pot processes catalyzed by a single transition metal
complex must be able to entail, in the desired order, reactions
of various natures.7 The versatility of palladium chemistry8 in
which the same complex is able to catalyze Heck, Suzuki−
Miyaura, and Sonogashira couplings as well as Tsuji−Trost
allylic alkylations has allowed the emergence of these
fascinating sequences.9 In order to access a larger number of
reactions, synthetic chemists envision switching the reactivity of
the initial TM-complex in the course of the process. The switch
of the reactivity may be driven by the evolution of the initial
catalyst in the reaction mixture as developed in ruthenium
catalysis by queuing metathetical and nonmetathetical reac-
tions.10 A trigger may also be used, such as the addition of a
ligand or of a redox active species able to change the oxidation
state of the metal.11 To further expand the range of
transformations accessible, the use of various metal complexes
in a one-pot process is highly appealing. Although successes
were found in heterogeneous catalysis, the homogeneous
version remains highly challenging and scarcely studied.12
Indeed, optimization of such processes is difficult due to ligand
exchange between the various metal centers. In most cases, the
sequence is based on the use of two metal complexes, each one
driving a single transformation. An even more challenging
process is the development of a sequence in which one of the
metal complexes is used for two transformations. Such
processes lead to atom, step, and catalyst economy. In 2002,
Chung reported a Pauson−Khand/Allylic-Alkylation/Pauson−
Khand sequence using Co-nanoparticles and a homogeneous
palladium catalyst (Figure 1, 2002 Chung).13
Figure 1. One-pot procedure with two transition metals and three
catalytic cycles.
Taking advantage of the known compatibility of Cu and Pd,
Hong reported in 2015 a Pd-cat. dehydrogenation/Cu-cat.
oxidation/Pd-cat. oxidative cyclization (Figure 1, 2015
Hong).14 In 2005, one of us together with Poli reported a
sequence queuing two successive Pd-catalyzed allylic alkylation
and a Ru-catalyzed ring-closing metathesis reactions (Figure 1,
2005 Prestat and Poli).15 In order to demonstrate the
potentiality of such one-pot processes mediated by two
Received: November 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
transition metal complexes, we sought to push forward the
complexity of the last sequence. We envision adding to this
sequence a final Pd-catalyzed Heck coupling step taking
advantage of the cyclopentene generated through ring-closing
metathesis (RCM) (Figure 1). More precisely, the one-pot
process targeted will start with a double Pd-catalyzed allylic
alkylation (AA) using an active methylene compound 1 and an
allylic derivative 2 (Scheme 1). The thus generated diene 3 will
complete conversion of 3a to 4a, based on TLC analysis,
reagents required for the Heck coupling step were added in
DMF (Scheme 2). Under these conditions the desired product
5a was isolated in 73% yield using the Hoveyda−Grubbs II
catalyst and 63% yield with the Grubbs II catalyst.
Scheme 2. One-Pot RCM/Heck Coupling Sequence
Scheme 1. Targeted One-Pot Pd/Pd/Ru/Pd Sequence
The one pot double-AA/RCM/Heck sequence was next
explored (Table 2). Barbituric acid 1a was submitted to the
give rise to a cyclopentene 4 through Ru-catalyzed RCM
followed by a Heck reaction with an aryl derivative leading to
compound 5. Such a one-pot procedure will therefore include
three Pd-catalyzed events of two different kinds, with a Ru-
catalytic cycle in between them, using a single palladium source.
One of the main challenges to face is the stability of the Pd
catalyst all along the procedure.
Table 2. First Attempt toward Targeted One-Pot Pd/Pd/Ru/
a
Pd Sequence
Having already in hand the reaction conditions for the AA/
RCM sequence, we initiated our study by checking the
feasibility of the Heck coupling using barbituric derivative 4a
and p-Tol-I (1.1 equiv) as model substrates. An initial study
(see Supporting Information (SI)) led to the use of Pd(PPh3)4
(5 mol %) and NEt3 (1.2 equiv) as a base in a DCM/DMF
(1:1, v/v) mixture. Under these conditions, the desired product
5a was isolated in a poor 26% yield (Table 1, entry 1). Addition
a
Table 1. Optimization of the Heck Coupling
b
b
b
entry
x (mol %)
y (mol %)
3a (%)
4a (%)
5a (%)
1
2
3
5
0
0
5
0
14
0
78
60
50
8
3
7.5
2.5
43
a
Reaction conditions: substrate 1a (1 equiv), 2a (2.1 equiv),
b
entry
additive
yield (%)
Pd(PPh3)4 (x mol %), and NaH (2.2 equiv) were added in DCM.
The mixture was stirred at rt until complete conversion of 1a. HG-II
catalyst (5 mol %) was added, and the mixture was stirred at reflux.
After complete conversion of 3a, p-Tol-I (1.5 equiv), Pd(PPh3)4 (y
mol %), Et3N (1.2 equiv), and AgBF4 (2.5 equiv) in DMF were added.
1
2
3
4
5
−
LiCl
26
19
15
64
92
Bu4NBr
Ag3PO4
AgBF4
b
The mixture was stirred at 110 °C. Yields refer to isolated product.
a
Reaction conditions: substrate 4a (1 equiv), Pd(PPh3)4 (5 mol %), p-
Tol-I (1.1 equiv), Et3N (1.2 equiv), and additive (2.5 equiv) were
action of allyl acetate (2.1 equiv), NaH (2.2 equiv), and
Pd(PPh3)4 (5 mol %) at rt in DCM. After complete conversion
of the substrate 1a based on TLC analysis, the Hoveyda-
Grubbs II catalyst was added and the reaction was stirred at
reflux for 16 h. Then p-Tol-I (1.5 equiv), Et3N (1.2 equiv), and
AgBF4 (2.5 equiv) were added in DMF to the reaction mixture.
Under these conditions the product 5a was isolated in a poor
8% yield while the product 4a arising from the double AA/
RCM sequence was isolated in 78% yield (Table 2, entry 1).
Having already demonstrated that the Heck step is effective
in the presence of metathesis catalyst, we hypothesized a
deactivation of the palladium catalyst during the process. The
palladium loading was thus raised to 7.5 mol % which led to a
decrease of the yield of both 4a and 5a (Table 2, entry 2). The
lower efficiency of the metathesis step observed under these
conditions might be attributed to the excess of PPh3.20
Decreasing the palladium loading in the first step and adding
added to a sealed tube in DCM/DMF (1:1). The mixture was stirred
b
for 24 h at 120 °C. Yields refer to isolated product.
of a halide source16 such as LiCl or Bu4NBr induced a decrease
of the yield (entries 2 and 3 vs 1, Table 1). The addition of
silver(I) salt was then evaluated.17 To our pleasure, when the
reaction was run in the presence of Ag3PO4 or AgBF4 the
desired coupling product was isolated in respectively 64% and
92% yield (entries 4 and 5, Table 1).
While these results strongly suggested a cationic mecha-
nism,18 we were surprised to observe that upon use of phenyl
triflate only a trace amount of the Heck product was detected.19
Having in hand the optimized reaction conditions for the Heck
coupling of the spiro derivative 4a, we intend a one-pot RCM/
Heck sequence. The diene 3a was thus submitted to the action
of a ruthenium metathesis catalyst (5 mol %) in DCM. After
B
DOI: 10.1021/acs.orglett.7b03556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a fresh palladium source after the RCM step allowed us to
isolate 4a and 5a in, respectively, 50% and 43% yield. The
deleterious effect of excess Pd(PPh3)4 on the RCM step and the
deactivation of the palladium during the RCM step were thus
confirmed (Table 2, entry 3).
Scheme 3. Scope of the Pd/Pd/Ru/Pd Sequence Using
Various Aryl Iodides
a
In the quest for a more stable palladium(0) complex we
became interested in the superstable Pd(0) catalyst Pd(P[3,5-
(CF3)2C6H3]3) developed by Soos
́
et al.21 This catalyst has
been reported to be stable under air, moisture, and high
temperature. Its efficiency for Suzuki, Heck, and Sonogashira
coupling as well as C−H activation has been reported,21,22 but
to the best of our knowledge its activity in allylic alkylation
remained unexplored. We investigated the one-pot sequence
using this catalyst (Table 3). A first attempt did not allow the
a
Reaction conditions: (i) substrate 1a (1 equiv), 2d (2.1 equiv),
superstable-Pd (5 mol %) in DCE for 24 h at 65 °C, (ii) HG-II cat. (5
mol %) for 4 h at 65 °C, (iii) iodoarene (1.1 equiv), AgBF4 (2.5
equiv), Et3N (1.2 equiv) in DMF for 48 h at 110 °C.
Table 3. Optimization of the One-Pot Pd/Pd/Ru/Pd
Sequence
a
noticeable exception was the sterically demanding ortho-
methoxy-substituted product 5j that was isolated in 24% yield.
The influence of the active methylene derivative was next
evaluated (Scheme 4).
b
entry
2
OR
OAc
yield (%)
1
2
3
2a
2b
2c
2d
2d
2d
2d
0
49
27
73
67
71
56
OCOCF3
Scheme 4. Scope of the Pd/Pd/Ru/Pd Sequence Using
a
OPO(OEt)2
OCO2CH3
OCO2CH3
OCO2CH3
OCO2CH3
Various Nucleophiles
c
4
cd
,
5
6
7
ce
,
cf
,
a
Reaction conditions: substrate 1a (1 equiv), 2 (2.1 equiv),
superstable-Pd (5 mol %), and NaH (2.2 equiv) were added in
DCE. The mixture was stirred at 65 °C until complete conversion of
1a. HG-II catalyst (5 mol %) was added, and the mixture was stirred at
65 °C. After complete conversion of 3a, p-Tol-I (1.5 equiv), Et3N (1.2
equiv), and AgBF4 (2.5 equiv) in DMF (C = 0.1 M) were added. The
b
mixture was stirred at 110 °C. Yields refer to isolated product.
c
e
f
d
Without NaH. Reaction performed with AgOTf instead of AgBF4.
Reaction performed with Grubbs II catalyst instead of HG-II.
Reaction performed with Pd(PPh3)4 instead of superstable-Pd.
a
Reaction conditions: (i) substrate 1a (1 equiv), 2d (2.1 equiv),
superstable-Pd (5 mol %) in DCE for 24 h at 65 °C, (ii) HG II cat. (5
allylic alkylation using 2a (Table 3, entry 1). We reasoned that
the electron-poor catalyst might inhibit the oxidative addition
and therefore envision the use of a more reactive π-allyl
precursor. Indeed, using allyl trifluoroacetate 2b led to a good
result (Table 3, entry 2, 49% yield) while the use of allyl
diethylphosphonate 2c was found to be uneventfully less
efficient (Table 3, entry 3, 27% yield). To our delight, when
allyl methylcarbonate 2d was used, in the absence of NaH, the
desired product was isolated in an excellent 73% yield (92% per
C−C bond formed, Table 3, entry 4).23 Replacement of AgBF4
with AgOTf or the Hoveyda-Grubbs II catalyst with the Grubbs
II catalyst resulted in a limited erosion of the yield (Table 3,
entries 5−6 vs 4). Finally, Pd(PPh3)4 was proven to be less
efficient than the superstable-Pd complex although leading to a
satisfying yield of 56% (86% per C−C bond formed) for the
overall process (Table 3, entry 7).
mol %) for 4 h at 65 °C, (iii) iodoarene (1.1 equiv), AgBF4 (2.5
b
equiv), Et3N (1.2 equiv) in DMF for 48 h at 110 °C. (i) and (ii) at 90
c
°C. Pd source: Pd(PPh3)4 (5 mol %).
First, a range of various N,N′-disubstituted barbituric acids
were submitted to the sequence. The desired products 5k−n
were isolated in yields between 26% and 47%. The use of 1,3-
diphenylpropane-1,3-dione and cyclohexane-1,3-dione afforded
5o and 5p in, respectively, 65% and 50% yield. We observed
that superstable-Pd was ineffective to promote the allylic
alkylation upon use of cyclopentane-1,3-dione, acetylacetone,
methylacetoacetate, and dimethylmalonate. Gratifyingly, for
these carbon nucleophiles the use of Pd(PPh3)4 allowed the
isolation of products 5q−t in yields between 26% and 71%
(Scheme 4).
To conclude, we have successfully developed a one-pot
procedure allowing the formation of four C−C bonds through
four successive catalytic cycles. This sequence is based on three
different reactions catalyzed by two different transition-metal
complexes. Palladium catalysis allowed two allylic alkylations
and a Heck coupling reaction, while ruthenium catalysis
The scope of the one-pot sequence was next explored.24
First, various substituted phenyl iodides were tested using the
optimized conditions (Table 3, entry 4) with superstable-Pd
(Scheme 3). The reaction conditions were found to be highly
tolerant to electronic and steric effects with yields typically
ranging between 50% and 76% (compounds 5a−i). The only
C
DOI: 10.1021/acs.orglett.7b03556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Handbook of Organopalladium Chemistry for Organic
Synthesis, Negishi, E., Ed.; Wiley: New York, 2002. (b) Gildner, P.
G.; Colacot, T. J. Organometallics 2015, 34, 5497−5508.
(9) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56,
5959−5989.
(10) (a) Schmidt, B. Pure Appl. Chem. 2006, 78, 469−476.
(b) Dragutan, V.; Dragutan, I. J. Organomet. Chem. 2006, 691,
5129−5147. (c) Kotha, S.; Misra, S.; Sreevani, G.; Babu, B. V. Curr.
Org. Chem. 2013, 17, 2776−2795. (d) Al-Caide, B.; Almendros, P.;
Luna, A. Chem. Rev. 2009, 109, 3817−3858.
(11) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004, 248,
2365−2379.
(12) (a) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
Rev. 2005, 105, 1001−1020. (b) Lee, J. M.; Na, Y.; Han, H.; Chang, S.
Chem. Soc. Rev. 2004, 33, 302−312. (c) Robert, C.; Thomas, C. M.
Chem. Soc. Rev. 2013, 42, 9392−9402. (d) Lohr, T. L.; Marks, T. J.
Nat. Chem. 2015, 7, 477−482.
(13) Son, S. U.; Park, K. H.; Chung, Y. K. J. Am. Chem. Soc. 2002,
124, 6838−6839.
allowed a ring-closing metathesis. The RCM step is inserted
between two different Pd-catalyzed reactions demonstrating the
stability of the palladium source during the whole process. The
reaction conditions developed allowed yields up to 93% per
C−C bond formed. This study illustrates, in the context of
sustainable chemistry and diversity-oriented synthesis, the
potentiality of transition metal catalysis to queued reactions
of completely different nature in a one-pot process.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03556.
Experimental procedures, characterization details, and
spectral data (PDF)
(14) Jeong, Y.; Moon, Y.; Hong, S. Org. Lett. 2015, 17, 3252−3255.
(15) Kammerer, C.; Prestat, G.; Gaillard, T.; Madec, D.; Poli, G. Org.
Lett. 2008, 10, 405−408.
AUTHOR INFORMATION
Corresponding Authors
■
(16) (a) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41,
26−47. (b) Negishi, E. In Handbook of Organopalladium Chemistry for
Organic Synthesis, Negishi, E., Ed.; Wiley: New York, 2002; Vol. 1, pp
127−145. (c) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−
321. (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991,
113, 8375−8384. (e) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek,
S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488−
6499.
*E-mail: farouk.berhal@parisdescartes.fr.
*E-mail: guillaume.prestat@parisdescartes.fr.
ORCID
Guillaume Prestat: 0000-0002-3948-1476
Notes
(17) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985,
50, 3896−3900.
The authors declare no competing financial interest.
(18) (a) Cabri, W.; Candiani, I.; DeBernardinis, S.; Francalanci, F.;
Penco, S. J. Org. Chem. 1991, 56, 5796−5800. (b) Ozawa, F.; Kubo, A.;
Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417−1419. (c) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2−7.
ACKNOWLEDGMENTS
■
This work was supported by the CNRS, the Universite
́
Paris
e de l’Education Nationale de
́
ieur et de la Recherche (PhD grant for A.-
Descartes and the Minister
l’Enseignement Super
D.M.).
̀
(19) Jutand, A.; Mosleh, A. Organometallics 1995, 14, 1810−1817.
(20) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1993, 115, 9858−9859. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J.
Am. Chem. Soc. 1997, 119, 3887−3897.
REFERENCES
■
(21) (a) Dalicsek, Z.; Soos
Kft., Chinoin Gyogyszeres
2012/093271 A1, 2012. (b) Jakab, A.; Dalicsek, Z.; Soos
Chem. 2015, 2015, 56−59. (c) Jakab, A.; Dalicsek, Z.; Holczbauer, T.;
Hamza, A.; Papai, I.; Finta, Z.; Timari, G.; Soos, T. Eur. J. Org. Chem.
2015, 2015, 60−66.
́
, T.; Finta, Z.; Timar
́
i, G.; Vlad
ek Gyara Zrt. WO
, T. Eur. J. Org.
́
, G. H4Sep
(1) (a) Green Chemistry: Theory and Practice; Oxford University
Press: Oxford, U.K., 2000. (b) Introduction to Green Chemistry; Marcel
Dekker: New York, 2001.
́
́
Vegyeszeti Termek
́
́
́
́
(2) For general reviews on one-pot processes, see: (a) Tandem
Organic Reactions; Wiley: New York, 1992. (b) Bunce, R. A.
Tetrahedron 1995, 51, 13103−13159. (c) Tietze, L. F. Chem. Rev.
1996, 96, 115−136. (d) Domino Reactions in Organic Synthesis; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2006. (e) Nicolaou, K.
C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134−7186. (f) Behr, A.; Vorholt, A. J.; Ostrowski, K. A.;
Seidensticker, T. Green Chem. 2014, 16, 982−1006. (g) Hayashi, Y.
Chem. Sci. 2016, 7, 866−880.
(3) (a) Wender, P. A.; Croatt, M. P.; Witulski, B. Tetrahedron 2006,
62, 7505−7511. (b) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow,
T. H. Acc. Chem. Res. 2008, 41, 40−49. (c) Wender, P. A.; Miller, B. L.
Nature 2009, 460, 197−201.
(4) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
́
́
́
(22) Mirallai, S. I.; Koutentis, P. A. J. Org. Chem. 2015, 80, 8329−
8340.
(23) (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y. Tetrahedron Lett.
1982, 23, 4809−4812. (b) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.;
Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523−1529.
(24) Attempt to perform the reaction under domino conditions failed
(see SI).
2006; pp 359−493. (b) Metal Catalyzed Cascade Reactions; Muller, T.
̈
J. J., Ed.; Topics in Organometallic Chemistry; Springer: Berlin
Heidelberg, 2006.
(5) (a) Trost, B. M. Science 1991, 254, 1471−1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259−281.
(6) (a) Schreiber, S. L. Science 2000, 287, 1964−1969. (b) Galloway,
W. R. J. D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1,
1081.
(7) (a) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43,
3754−3760. (b) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem. - Eur. J.
2009, 15, 12168−12179.
D
DOI: 10.1021/acs.orglett.7b03556
Org. Lett. XXXX, XXX, XXX−XXX