Palladium-catalyzed addition of disulfides and diselenides to alkynes under solvent free conditions

Article abstract of DOI:10.1039/b312471a

An efficient methodology was developed for performing palladium-catalyzed E-E (E = S, Se) bond addition to alkynes under solvent free conditions. Compared to reaction in solvent significant enhancement of reaction rate, improved efficiency and remarkable

Full text of DOI:10.1039/b312471a

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Palladium-catalyzed addition of disulfides and diselenides to
alkynes under solvent free conditions†
Valentine P. Ananikov*a and Irina P. Beletskaya*b
a Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47,
Moscow, 119991, Russia. E-mail: val@ioc.ac.ru; Fax: ϩ007 (095) 1355328
b Lomonosov Moscow State University, Chemistry Department, Vorob’evy gory, Moscow,
119899, Russia. E-mail: beletska@org.chem.msu.ru; Fax: ϩ007 (095) 9393618
Received 10th October 2003, Accepted 16th December 2003
First published as an Advance Article on the web 19th December 2003
An efficient methodology was developed for performing
palladium-catalyzed E–E (E ؍ S, Se) bond addition to
alkynes under solvent free conditions. Compared to reac-
tion in solvent significant enhancement of reaction rate,
improved efficiency and remarkable catalyst stability were
observed under solvent free conditions. The addition reac-
tions were carried out with high stereoselectivity and yields
in a short reaction time.
Continuing our recent studies we have developed a new
synthetic approach to palladium catalyzed S–S and Se–Se
bond addition to alkynes under solvent free conditions.
Besides economical and ecological advantages the approach is
superior in respect of higher reaction rate and better catalyst
efficiency.
The present study is the first example of a transition metal
catalyzed addition reaction under solvent free conditions.
The key point of the solvent free reaction is the presence
of an excess of phosphine ligand (entries 1, 2; Table 1). In
the absence of an excess of PPh3 rapid polymerization of
Nowadays development of organic synthesis is focused on
environmentally friendly procedures with fewer toxic sub-
stances involved. Special attention is paid to minimize quantity
of organic solvents used in the reaction, since very often
organic solvents are ecologically harmful and flammable. In
addition, using large quantities of solvents gives rise to waste
removal concern.
Table 1 Catalytic Ar2E2 addition to alkynes under solvent free
conditions
Undoubtedly, solvent free organic synthesis is the best eco-
friendly methodology to overcome the above problems.1 Very
often performing the reaction under solvent free conditions
requires applying microwaves to bring additional energy to the
system. Many examples of microwaves assisted solvent free
organic synthesis procedures have already been published.2 In
contrast, transition metal catalyzed solvent free methodology is
at the beginning stage of development and encounters several
difficulties due to the multicomponent nature of the system.
In this case excluding solvents also has an economical benefit,
since transition metal catalyzed transformations usually require
rigorously dried and purified solvents treated under an inert
atmosphere. At the moment solvent free methodology has been
successfully applied to cross-coupling reactions: Suzuki coup-
ling,3 Heck reaction,4 and C–N bond formation.5 However,
to the best of our knowledge no studies have been published
concerning transition metal catalyzed addition reactions to
unsaturated species under solvent free conditions.
The addition reactions are performed with 100% atom effi-
ciency with no waste materials formed. In particular, E–E bond
addition to alkynes is a recognized tool for modern organic and
element-organic synthesis.6 A very efficient palladium catalyzed
S–S and Se–Se bond addition reaction to alkynes has been
developed leading to Z-substituted alkenes with high stereo-
selectivity.7 The addition reaction represents a convenient single
stage way of two carbon-element bond formations and leads to
important products required in synthetic organic chemistry8
and materials science.9 Recently we have studied the mechanism
of the E–E (E = S, Se) addition reaction to alkynes and have
found that the catalytic cycle involves dinuclear palladium
complexes (Scheme 1).10
Entry
1
Ar2E2
Ph2S2
Alkyne
Conditionsa
Yieldb, %
0c
1-A
80 ЊC, 8 h
2
3
Ph2S2
Ph2S2
1-A
1-B
80 ЊC, 8 h
80 ЊC, 8 h
99 (90)
99 (90)
4
5
6
Ph2S2
Ph2S2
Ph2S2
1-C
1-D
1-E
80 ЊC, 8 h
80 ЊC, 8 h
80 ЊC, 8 h
98 (85)
97 (80)
96 (85)
7
8
9
10
11
12
13
14
15
Ph2S2
Ph2S2
Ph2S2
Ph2S2
Ph2S2
Ph2 Se2
Ph2Se2
(p-MePh)2Se2
(p-FPh)2Se2
1-A
1-B
1-C
1-D
1-E
1-B
1-C
1-B
1-B
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
100 ЊC, 2 h
99 (90)
99 (90)
99 (85)
98 (80)
97 (85)
96 (87)
97 (80)
95 (85)
95 (85)
a The reactions were performed in 1 mmol scale.11 b Determined with
NMR spectroscopy, the isolated yield is given in parentheses;12 in all
cases Z/E > 97 : 3 was observed. c The reaction was carried out with
1 mol% of Pd(PPh3)4 without addition of PPh3.
† Electronic supplementary information (ESI) available: full experi-
mental details of synthetic procedure, compound separation and purifi-
cation, details of spectroscopic studies, kinetic measurements and
compound characterization. See http://www.rsc.org/suppdata/ob/b3/
b312471a/
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 8 4 – 2 8 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
284

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Scheme 1
Table 2 Catalytic Ph2S2 addition to 1-B under solvent free conditions
and in solventa
the palladium catalyst is observed resulting in a dark brown
precipitate insoluble in common organic solvents (6, Scheme 1).
Under the reaction conditions at 80 ЊC (or higher) both Ph2S2
and PPh3 are molten and Pd(PPh3)4 can be easily dissolved in
the Ph2S2/PPh3 melt. An excess of PPh3 prevents precipitate
formation and results in a homogeneous melt. Therefore, stir-
ring is no longer needed for the system. The addition process
was performed under very simple reaction conditions in a
sealed tube. Excellent yields were obtained for various alkynes
(entries 2–5; Table 1). No difference in the product yield was
observed in the reactions performed under an inert atmosphere
or under air. Due to quantitative conversion and the absence of
solvent product separation is much simplified as well. In fact,
filtering out palladium complex and PPh3 on silica or a rapid
flash chromatography13 suits very well for most of the cases
studied.
Total reaction
volume, ml
Solvent
Entry
added,b ml
Yield,c %
t1/2,d h
1
2
3
0.6
2.0
5.0
—
1.4
4.4
66
25
14
1.5
4.2
7.6
a The reactions were performed in 1 mmol scale at 80 ЊC with 1 mol%
of Pd(PPh3)4 and 15 mol% PPh3. b Toluene was used as a solvent.
c Measured with NMR spectroscopy after 2 h of reaction. d Time
needed for 50% conversion of Ph2S2.
Table 3 Temperature dependence of the yields of 2-B under solvent
free conditionsa
With 1 mol% of the catalyst and 15 mol% of PPh3 heating at
80 ЊC for 8 h results in quantitative product yields for several
alkynes with various functional groups (entries 2–5; Table 1).
Under these conditions two equivalents of Ph2S2 can be added
to hepta-1,6-diyne with 96% product yield (entry 6; Table 1).
A significant acceleration of the reaction under solvent free
conditions makes it possible to achieve quantitative yields with
1 mol% of catalyst in 8 h (entries 2–6; Table 1), while the same
reaction in solvent requires 12–16 h of heating and 2–3 mol%
of the catalyst.7,10 Increasing the temperature to 100 ЊC allows
quantitative yields to be achieved after 2 h of reaction time. We
have shown that Se–Se is less reactive toward alkynes in the
palladium catalyzed reaction in solvent compared to the S–S
bond.10 However, the difference in reactivity is less apparent
under solvent free conditions, both S–S (entries 7–11) and
Se–Se bonds (entries 12–15, Table 1) quantitatively adding to
alkynes. In all cases studied, the addition proceeds in a syn-
manner with high stereoselectivity leading to Z-configuration
of the products (entries 2–15; Table 1).14
Entry
Temperature, ЊC
Time, min
Yield,b %
1
2
3
4
5
6
7
8
80
80
80
100
100
100
120
140
120
270
450
15
30
60
66
91
99
63
92
99
99
99
5
<3
a The reactions were performed in 1 mmol scale with 1 mol% of
Pd(PPh3)4 and 15 mol% of PPh3. b Measured with NMR spectroscopy;
in all cases Z/E > 97 : 3 was observed.
Table 2). Adding as little as 1.4 and 4.4 ml of solvent dram-
atically decreases the reaction rate by factors of approximately
3 and 5, respectively (entries 2, 3; Table 2). Obviously, reaction
rate enhancement under solvent free conditions originates from
the concentration effect.
The rate of catalytic Ar2E2 addition to alkynes in solvent
cannot be substantially improved at higher temperatures due to
rapid catalyst decomposition. We found that the palladium
catalyst is much more stable in the solvent free conditions. For
the Ph2S2 addition across a triple bond in 1-B increasing the
temperature to 100 ЊC allows the reaction time to be shortened
to 1 h (Table 3). With the temperature increased to 120 ЊC
or higher no longer than 5 min of reaction time is required
(Table 3).
For complete utilization of sulfur- and selenium-containing
species Ar2E2 : alkyne = 1 : 1.5 ratio should be used. Changing
the color of reaction mixture from dark-brown to orange or
yellow indicates the completion of the reaction. In this case
Pd(PPh3)4 is released at the end of the addition process.
A detailed NMR study of the catalytic reaction has shown a
significant acceleration of Ph2S2 addition to the triple bond of
1-B in the solvent free conditions (Table 2).
A typical 1 mmol scale setup11 results in a reaction volume
of about 0.6 ml under the solvent free conditions (entry 1;
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Table 4 Catalytic Ph2S2 addition to alkynes with different reaction scale and amount of catalyst useda
Entry
Alkyne
Reaction scale, mmol
Pd(PPh3)4, mol %
Time, min
Yield,b %
1
2
3
4
5
6
7
1-A
1-A
1-A
1-A
1-A
1-B
1-B
1
1
10
10
10
1
1.0
0.1
0.1
0.01
0.001
0.1
<3
30
30
60
300
30
97
97
97
97
70
98
98
10
0.1
30
a The reactions were performed at 140 ЊC with 15 mol% of PPh3. b Measured with NMR spectroscopy.
To check the scope of the catalytic reaction at high temper-
ature we have repeated Ph2E2 addition to alkynes 1-A–1-D at
140 ЊC (entries 2–12, Table 1). In all cases after 5 min of
heating 96–99% product yields were obtained with high stereo-
selectivity (Z/E > 97/3). It is known that long heating at
high temperatures could lower overall stereoselectivity of E–E
addition due to noncatalytic thermal reaction or double bond
isomerisation.6 However, this was not the case for the studied
solvent free system, since reaction time at high temperature is
very short.
Reaction rate enhancement and remarkable catalyst stability
at high temperature give an opportunity to perform addition
reactions with a rather small amount of catalyst (entries 1–5,
Table 4). Particularly, 97% product yield was observed with
only 0.01 mol% of catalyst (entry 4, Table 4). Even with as low
as 0.001 mol% of catalyst a 70% yield was observed after 5 h of
reaction at 140 ЊC (entry 5, Table 4).
Performing reactions with 0.1 mol% of catalyst requires
about 1 mg of Pd(PPh3)4 for the synthesis of ∼3 g of the addi-
tion products (entries 3, 7; Table 4).
The developed solvent free methodology provides the same
quantitative yields for 1 and 10 mmol of reaction scale (entries
2–3 and 6–7; Table 4). For the alkyne 1-A this corresponds to
0.33 and 3.32 g of the final product, respectively (2-A).
Recently we have shown that the mechanism of Pd(PPh3)4
catalyzed Ar2E2 (E = S, Se) addition to alkynes in toluene or
benzene solutions involves dinuclear complexes10 formed after
the E–E bond oxidative addition to zero valent palladium (4, 5;
Scheme 1).15 It was shown that the concentration of dinuclear
complexes in solution is increased in the presence of excess of
PPh3.10 Most likely, triphenylphosphine prevents catalyst poly-
16
merization leading to insoluble [Pd(EAr)2]n (6) and ensures
homogeneous reactions conditions.
To clarify the reaction mechanism under solvent free condi-
tions we have performed a 31P{1H} NMR study directly in the
molten Ph2S2/PPh3. Adding Pd(PPh3)4 to the melted Ph2S2/PPh3
at 80 ЊC results in the appearance of two major resonances at
δ = 30.4 and 29.0 ppm (Fig. 1A) corresponding to dinuclear
complexes 4 and 5 (Scheme 1).17 Similar complexes were
detected in toluene in the oxidative addition reaction of Ph2S2
Fig. 1 31P{1H} NMR spectra of the dinuclear complexes trans-, cis-
[Pd2(SPh)4(PPh3)2] (4, 5): A – in the melted Ph2S2/PPh3 without solvent;
B – in a toluene solution in the presence of a 15 fold excess of PPh3; C –
in a toluene solution in the presence of twofold excess of PPh3; D – in a
toluene solution.
to Pd(PPh3)4 (δ = 30.8 and 29.4 ppm).10,15 The small difference
in the chemical shifts of dinuclear complexes in the molten
Ph2S2/PPh3 and in the toluene solution indicates rather similar
solvation properties of both media. This is one of the key
factors for developing a successful synthetic procedure under
solvent free conditions.
isolated compound shows several lines in the region of 29.5–
31.0 ppm (Fig. 1D). Adding an excess of PPh3 increases the
intensity of the signals corresponding to dinuclear complexes 4,
5 (δ = 30.8 and 29.4 ppm) simultaneously decreasing the
intensity of the other lines (Fig. 1C). In a 15 fold excess of
the ligand only two signals of 4 and 5 are detected (Fig. 1B).
The NMR study confirms the suggestion made earlier: an
excess of the ligand prevents catalyst oligomerization and shifts
the equilibrium toward dinuclear complexes.19
31P{1H} NMR monitoring of the catalytic reaction in the
molten Ph2S2/PPh3 confirmed the presence of the dinuclear
complexes 4, 5 (Fig. 1A). The observation indicates that the
catalytic process under solvent free conditions, involves di-
nuclear complex [Pd2(EAr)4(PPh3)2] (4, 5) formation. The pres-
ent study suggests the same mechanism of the catalytic reaction
under solvent free conditions and in solvent.
Remarkable catalyst stability provides the necessary condi-
tions for recycling. Indeed, we have found that palladium
catalyst can be easily separated by flash chromatography after
completing the reaction.18 The 31P{1H} NMR spectrum of the
Recycled catalyst shows the same catalytic activity and stereo-
selectivity in the Ar2E2 addition reaction under solvent free
conditions compared to the initial Pd(PPh3)4. The recycling
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 8 4 – 2 8 7
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Table 5 Catalytic Ph2S2 addition to alkynes using recycled catalysta
Synthesis, 1998, 1213; (c) R. S. Varma, Green Chem., 1999, 1, 43;
(d ) S. A. Galema, Chem. Soc. Rev., 1997, 26, 233.
Cycles
Alkyne
Yield,a %
3 (a) G. W. Kabalka, L. Wang, R. M. Pagni, M. C. Hair and V. Nam-
boodiri, Synthesis, 2003, 217; (b) L. M. Klingensmith and N. E.
Leadbeater, Tetrahedron Lett., 2003, 44, 765; (c) C. R. LeBlond,
A. T. Andrews, J. R. Sowa and Y. Sun, Org. Lett., 2001, 3, 1555;
(d ) G. W. Kabalka, V. Namboodiri and L. Wang, Chem. Commun.,
2001, 775.
4 (a) A. Diaz-Ortiz, A. de la Hoz and F. Langa, Green Chem., 2000, 2,
165; (b) R. J. Morphy, Z. Rankovic and M. York, Tetrahedron Lett.,
2002, 43, 5973; (c) A. Diaz-Ortiz, P. Prieto and E. Vasquez, Synlett,
1997, 269.
1
2
3
1-A
1-B
1-D
98
96
97
a The reactions were performed in 1 mmol scale with 1 mol% of initial
Pd(PPh3)4 and 15 mol% of PPh3 at 140 ЊC.20 b Measured with NMR
spectroscopy after 8 h.
5 (a) F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 5, 793;
(b) B. Basu, S. Jha, N. K. Mridha and M. H. Bhuiyan, Tetrahedron
Lett., 2002, 43, 7967; (c) J. P. Wolfe and S. L. Buchwald, J. Org.
Chem., 2000, 65, 1144.
6 I. P. Beletskaya and C. Moberg, Chem. Rev., 1999, 99, 3435.
7 H. Kuniyasu, A. Ogawa, S.-I. Miyazaki, I. Ryu, N. Kambe and
N. Sonoda, J. Am. Chem. Soc., 1991, 113, 9796.
8 (a) T. Wirth (Ed), Organoselenium Chemistry: Modern Develop-
ments in Organic Synthesis, Springer Verlag, Berlin, New York, 2000;
(b) T. G. Back (Ed), Organoselenium Chemistry : A Practical
Approach, Oxford University Press, New York, 1999;
(c) C. Paulmier, Selenium Reagents and Intermediates in Organic
Synthesis, Pergamon Press, Oxford, 1986; (d ) S. Patai and
Z. Rappoport (Eds), The Chemistry of Organic Selenium and Tellur-
ium Compounds, John Wiley & Sons, New York, 1986, Vol. 1–2.
9 (a) P. I. Clemenson, Coord. Chem. Rev., 1990, 190, 171;
(b) C. Lauterbach and J. Fabian, Eur. J. Inorg. Chem., 1999, 1995
(and references therein).
10 (a) V. P. Ananikov, I. P. Beletskaya, G. G. Aleksandrov and
I. L. Eremenko, Organometallics, 2003, 22, 1414; (b) V. P. Ananikov,
D. A. Malyshev, I. P. Beletskaya, G. G. Aleksandrov and I. L.
Eremenko, J. Organomet. Chem., 2003, 679, 162; (c) V. P. Ananikov,
M. A. Kabeshov, I. P. Beletskaya, G. G. Aleksandrov and
I. L. Eremenko, J. Organomet. Chem., 2003, 687, 451.
sequence being repeated three times does not substantially
effect the reaction yield (Table 5).
For catalyst recycling the optimal Ar2E2 : alkyne ratio is 1 : 1.
In this case the dark-brown complex [Pd2(EAr)4(PPh3)2] is the
final form of the catalyst, which can be easily recycled under
regular conditions in air. As mentioned above, in the case of
an excess of alkyne air-sensitive Pd(PPh3)4 is formed, which is
hardly possible for recycling.
The present article reports the first example of a transition
metal catalyzed E–E bond addition reaction to unsaturated
molecules in the absence of solvent. Two key-factors are of
great importance for the reaction: 1) solvation properties of
Ar2E2/PPh3 are similar to those of aromatic solvents; and 2) the
excess of PPh3 ligand effectively blocks polymerization of
palladium complexes and keeps the active form of the catalyst
in the melt. In the present case the solvent free reaction was
performed as a simple thermal process without microwave
irradiation.
In the developed solvent free methodology quantitative
yields of stereoselective Ar2E2 addition to alkynes can be
achieved in very simple reaction conditions, followed by a
significantly simplified product separation procedure. The
developed methodology combines several advantages: 1) atom
efficiency of the addition reaction; 2) high stereoselectivity of
the transition metal catalyzed transformation; and 3) econom-
ical and ecological benefits of the solvent free conditions. In
addition, significant acceleration of the reaction was observed,
as a result reaction time was decreased from several hours to a
few minutes with less catalyst used. An important advantage of
the solvent free methodology is the ability for catalyst recycling.
The NMR study has shown the formation of dinuclear
intermediate complexes [Pd2(EAr)4(PPh3)2] in the catalytic reac-
tion performed under solvent free conditions, therefore, sug-
gesting the same catalytic reaction mechanism as in solution.
11 Typical synthetic procedure was used, see electronic supporting
information for details†.
12 Compounds 2-A–2-B were isolated using flash chromatography;
2-D and 2-E were isolated with regular column chromatography;
2-C was isolated as an oxalate salt. A detailed description of separ-
ation procedure is given in the electronic supporting information†.
13 (a) D. S. Pedersen and C. Rosenbohm, Synthesis, 2001, 2431;
(b) L. M. Harwood, Aldrichimica Acta, 1985, 18, 25.
14 The Z-configuration of the products was confirmed with NOESY
NMR experiments.
15 For X-ray structures of [Pd2(EAr)4(PPh3)4] see: (a) R. Oilunkaniemi,
R. S. Laitinen and M. Ahlgren, J. Organomet. Chem., 2001, 623, 168;
(b) R. Oilunkaniemi, R. S. Laitinen and M. Ahlgren, J. Organomet.
Chem., 1999, 587, 200; (c) I. Nakanishi, S. Tanaka, K. Matsumoto
and S. Ooi, Acta Crystallogr., Sect. C., 1994, 50, 58.
16 Polymers of general formula [Pd(ER)2]n (E = S, Se) were isolated as
insoluble dark-brown solids: (a) S. Dey, V. K. Jain and B. Varghese,
J. Organomet. Chem., 2001, 623, 48; (b) A. Ogawa, J. Organomet.
Chem., 2000, 611, 463.
17 The complexes were identified by comparison with authentic sam-
ples synthesized in toluene and dissolved in the molten Ph2S2/PPh3.
18 Flash chromatography was used (see ref. 13). After eluting PPh3 and
product palladium complexes remained adsorbed on the silica (dark
brown ring). The complexes were eluted with hexane : EtOAc =
1 : 1 solvents mixture and dried in vacuum (brown oil, estimated
yield 90–95% based on initial palladium complex). See electronic
supporting information for more details.
Acknowledgements
The work was carried out with partial support from the
Chemistry and Material Science Branch of the Russian
Academy of Sciences (Program: “Theoretical and experimental
investigations of the nature of chemical bonding and mechan-
isms of the most important chemical reactions and processes”).
19 In the toluene solution increasing PPh3 concentration results in
the appearance of two additional minor resonances at δ = 25.0 and
Notes and references
1 For recent reviews on solvent free synthesis see: (a) K. Tanaka and
F. Toda, Chem.Rev., 2000, 100, 1025; (b) J. O. Metzger, Angew.
Chem., Int. Ed., 1998, 37, 2975.
2 For recent reviews on microwave assisted solvent free synthesis see:
(a) R. S. Varma, Pure Appl. Chem., 2001, 73, 193; (b) A. Loupy,
A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault and D. Mathe,
24.1 ppm. The former was assigned as O᎐PPh3 by comparison with
᎐
an authentic sample, while the latter could, in principle, be attri-
buted to the mononuclear complex [Pd(SPh)2(PPh3)2]. However, at
the moment it cannot be unambiguously proved.
20 Typical procedure was followed (see electronic supporting inform-
ation) except 1 : 1 alkyne : Ph2S2 ratio was used.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 8 4 – 2 8 7
287