The first thiadiazolidine 1-oxide system for phosphine-free palladium-mediated catalysis

Article abstract of DOI:10.1002/adsc.200800522

We herein report a highly active catalyst system using for the first time a thiadiazolidine 1-oxide as a ligand for palladium in the Mizoroki-Heck reaction. Excellent yields of stilbenes derived from aryl iodides and bromides have been achieved using as little as 0.00002 mol% catalyst. The ligand/ palladium system can be stored as a stock solution open to air at room temperature with no observable loss of activity for a period of several weeks/months.

Full text of DOI:10.1002/adsc.200800522

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DOI: 10.1002/adsc.200800522
The First Thiadiazolidine 1-Oxide System for Phosphine-Free
Palladium-Mediated Catalysis
Benjamin R. Buckleya,* and Stephen P. Nearya
a
Department of Chemistry. Loughborough University, Ashby Road, Loughborough, Leicestershire LE11 3TU, U.K.
Fax : (+44)-(0)1509-223-925; e-mail: b.r.buckley@lboro.ac.uk
Received: August 20, 2008; Revised: December 11, 2008; Published online: January 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800522.
Abstract: We herein report a highly active catalyst
system using for the first time a thiadiazolidine 1-
oxide as a ligand for palladium in the Mizoroki–
Heck reaction. Excellent yields of stilbenes derived
from aryl iodides and bromides have been achieved
using as little as 0.00002 mol% catalyst. The ligand/
palladium system can be stored as a stock solution
open to air at room temperature with no observable
loss of activity for a period of several weeks/
months.
À
Keywords: catalysis; C C coupling; Mizoroki–Heck
reaction; palladium; thiadiazolidines
There are a wide number of reports utilizing a 1,3-ni-
trogen skeleton as a basis for catalyst/ligand design;
for example, N-heterocyclic carbenes 1,[1] phosphor-
ACHTUNGTRENNUNG
amides 2,[2] and thioureas 3.[3] Indeed 1,3-amines and
imines have themselves been reported as ligands and
catalysts. However, there are very few reports regard-
ing the synthesis of structurally related thiadiazoli- phosphines,[12] diphosphines,[13] cyclometallated phos-
dines 4 or thiadiazolidine oxides 5. The majority of re- phines, and phosphites are particularly good ligands
ports regarding thiadiazolidine 1,1-dioxides 6 relate to for palladium.[14,15] The air-sensitivity of these types of
their pharmacological properties,[4] the zwitterion 7 ligands, however, precludes their use in a variety of
has been used in a Mitsunobu-type reaction[5] and 8 synthetic applications. Therefore, the development of
has been proposed in connection with Oppolzerꢀs phosphine-free palladium catalysis is a topic of enor-
sultam model.[6] Thiadiazolidine 1,1-dioxides have mous interest,[16] with thioureas being amongst the
also been reported as useful polar aprotic solvents[7] most effective systems.[3,17,18] In our continuing pro-
and as key intermediates for the synthesis of con- gramme for the development of nitrogen-sulfur-
strained peptides.[8] We were particularly attracted to oxygen ligands/catalysts we herein report the first use
the thiadiazolidine oxides as we postulated that they of an air-stable thiadiazolidine oxide in the Mizoroki–
may be interesting and useful ligands for metal-cata- Heck reaction.
lysed reactions.
We conjectured that thiadiazolidine 1-oxides might
Traditionally, phosphine ligands have been used to be effective ligands for palladium-mediated processes,
stabilise reactive palladium intermediates, and excel- and in order to test our hypothesis we chose to pre-
lent results have been reported for Pd-catalysed pare the mesityl-derived thiadiazolidine oxide 9. This
Mizoroki–Heck reactions.[9,10,11] Sterically bulky mono- was easily achieved in two steps; mesitylamine and
Adv. Synth. Catal. 2009, 351, 71 – 77
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71

Benjamin R. Buckley and Stephen P. Neary
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glyoxal were reacted neat, and upon formation of the a temperature of 2008C (reactions of other substrates
bright yellow bis-imine, sodium borohydride/ethanol at 1508C resulted in slightly lower yields when com-
was added to furnish the bis-amine 10 in excellent pared to the corresponding reaction at 2008C). Using
yield (Scheme 1). Treatment of a solution of 10 in di- our optimised conditions, we went on to screen a
range of substrates, and were delighted to find that
excellent yields of the corresponding styrenes and
a,b-unsaturated esters could be achieved in reaction
times of only 10 min (Table 2). We have observed that
the reactions are tolerant of both electron-donating
and withdrawing substituents on either the aryl iodide
or the alkene components, with yields generally of
over 95%. For reasons which are unclear at present
the reaction of methyl acrylate and iodobenzene
(Table 2, entry 6) was extremely capricious and over
several runs the yield of product varied significantly
(28–81%). Although these reactions were carried out
under microwave irradiation, we also confirmed that
Scheme 1.
these reactions can take place under more conven-
ethyl ether/triethylamine with thionyl chloride afford- tional thermal conditions. The Heck reaction of butyl
ed the thiadiazolidine oxide 9 in good yield.
acrylate and iodobenzene achieved complete conver-
With ligand 9 in hand we chose to screen a range of sion within two hours using standard reflux condi-
palladium sources, using 4-methoxyiodobenzene and tions.
styrene, as our test system, and carried out the reac-
For convenience, stock catalyst solutions of the pal-
tions under microwave irradiation.[19] We found that ladium/ligand complex were prepared and we were
the system reported by Yang was particularly applica- surprised to find that the prepared ligand/palladium
ble, and we eventually chose Pd2ACTHNUTRGNEU(GN dba)3 as our stan- complex is extremely air- and moisture-tolerant and
dard source of palladium.[3] Optimisation of the mi- can be stored for months as a stock solution in DMF
crowave system revealed that reactions could be ef- or NMP open to air at room temperature with no ob-
fectively carried out at 1508C in 10 min with servable loss of activity (a similar observation for thi-
0.2 mol% of Pd2ACHTUNGTRENNUNG
(dba)3 and 0.4 mol% of the ligand ourea systems has been reported by Yang[3]).[20] This is
(Table 1). Reactions carried out at 2008C for only in stark contrast to a range of phosphine ligands that
1 min afforded 85% of the desired product. For con- have to be prepared and used under strict inert reac-
venience we settled on a reaction time of 10 min and tion conditions and, therefore, precludes their effec-
tive use in industrial applications.
Following the work on aryl iodides, Heck reactions
Table 1. Microwave optimization studies.[a]
were attempted using aryl bromides as substrates
(Table 3). The conditions used for aryl iodides were
found to be unsuitable for aryl bromides. The solvent
was changed from DMF to N-methylpyrrolidinone
(NMP), and sodium acetate was used as the base.
Some reactions performed at 2008C were prone to
excess pressure build-ups inside the sealed vials used
for irradiation. In these cases, the reaction tempera-
tures were reduced to 1608C. PdACTHNUTRGNEUNG(dba)2 was used as
the palladium source and reaction times were extend-
ed to 30 min.
Entry
Temp [8C]
Time [min]
Conversion [%][b]
Over the course of the initial experiments, with the
bromide-Heck reactions, only two were ever safely
brought to 2008C without incident, the reactions of
bromobenzene with styrene (Table 3 entry 1) and
with butyl acrylate (Table 3 entries 4 and 5). Any at-
tempts to bring reactions involving substituted aryl
bromides, substituted styrenes or methyl acrylate to
2008C in the microwave resulted in shattering of the
sealed vial. Lowering of the temperature to below
1708C prevented shattering of the vial but also result-
ed in a low yield.
1
2
3
4
1008C
1508C
2008C
2008C
10 min
10 min
10 min
1 min
<5%
100%
100%
85%
[a]
Standard conditions: Pd2ACHTGNUTRNE(NUG dba)3 (0.2 mol%), 9 (0.4
mol%), Et3N (1.2 equiv), DMF (0.5 mL), T 8C, in a Biot-
age Initiator Microwave.
Conversions were evaluated using H NMR spectroscopy,
by comparison of the methoxy protons from 4-iodoani-
sole and the product.
[b]
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Thiadiazolidine 1-Oxide System for Phosphine-Free Palladium-Mediated Catalysis
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Table 2. Heck reactions using palladium and ligand 9.[a]
Entry
1
Aryl Iodide
Alkene
Product
Yield [%][b]
97%
2
3
99%
99%
4
99%
5
6
>99%
up to 81%[c]
7
97%
99%
93%
99%
8
9
10
11
98%
[a]
Standard conditions: Pd2CATHUNGTREN(UNGN dba)3 (0.2 mol%), 9 (0.4 mol%), Et3N (1.2 equiv), DMF (0.5 mL), 2008C, 10 min in a Biotage
Initiator Microwave.
Isolated yield over an average of 3 runs.
Capricious reaction: variable yields over 3 runs: 28%, 50% and 81%.
[b]
[c]
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Benjamin R. Buckley and Stephen P. Neary
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Table 3. Heck reactons of aryl bromides.[a]
Table 4. Heck reactions performed by conventional reflux.[a]
Entry R
Alkene
Temp. Time Yield
[8C]
Entry R
Alkene
Temp. Time Yield
[min] [%][b]
[8C]
[h]
[%][b]
complex
mixture
1
200
30
30
99%
85%
1
2
200
24
2[c]
160
140
140
24
24
37%
18%
3[c]
4
160
200
200
160
30
85%
14
3
[a]
30
Standard conditions: PdACTHNUTRGNE(UNG dba)2 (0.1 mol%), 9 (0.4 mol%),
NaOAc (1.5 equiv), NMP (0.5 mL), T8C.
[b]
Isolated yield.
5
180
30
28
6[c]
N.R.
Table 5. Heck reactions of aryl bromides in the presence of
TBAB under microwave conditions.[a]
7[c]
160
160
30
30
27
24
8[c]
[a]
Standard conditions: PdACTHNUTRGNE(UNG dba)2 (0.1 mol%), 9 (0.4 mol%),
NaOAc (1.2 equiv), NMP (0.5 mL), T 8C, in a Biotage
Initiator Microwave.
Isolated yield.
Reaction vial shattered at temperatures above 1808C.
Entry R
Alkene
Temp. Time Yield
[8C]
[b]
[c]
[min] [%][b]
1
2
3
4
200
30
30
99%
99%
In light of this, Heck reactions using bromides were
attempted using conventional heating under reflux
conditions. In these cases, temperatures exceeding
1808C resulted in a complex mixture of products.
Keeping temperatures below 1508C was sufficient to
achieve crude yields consisting only of the expected
product and its starting materials. Unfortunately the
isolated product yields were still low (Table 4).
However, we have found that the addition of tetra-
butylammonium bromide (TBAB) to the reactions
has allowed them to proceed smoothly at 2008C in
the microwave apparatus. The synthesis of various
stilbene products with both electron-donating and
-withdrawing groups is possible in excellent yields.
The addition of TBAB has also made it possible to in-
crease the yield of the reaction of bromobenzene and
butyl acrylate to 73% (Table 5, entry 5).
200
200
200
200
30
30
30
98%
89%
73%
5
[a]
Standard conditions: PdACTHNUTRGNE(UNG dba)2 (0.1 mol%), 9 (0.8 mol%),
NaOAc (1.5 equiv), NMP (0.5 mL), TBAB (0.4 equiv),
T8C, in a Biotage Initiator Microwave.
Isolated yield.
[b]
After successful conversion of these aryl bromides range of catalyst loadings (Table 6). Our experiments
and iodides to stilbene products we turned our atten- have shown that the system was still effective at ex-
tion to the effectiveness of this ligand system over a tremely low catalyst loadings; for lower loadings the
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Thiadiazolidine 1-Oxide System for Phosphine-Free Palladium-Mediated Catalysis
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Table 6. Catalyst/ligand loading study.[a]
we observed a maximum of up to 40% conversion to
the desired Heck product (compared to 76% conver-
sion when using the ligand 9). Indicating that the
active catalytic species must require the ligand for
high turnover and product yield.
In summary, we have developed a highly active,
easily prepared and air-stable thiadiazolidine 1-oxide
ligand, which in conjunction with palladium effective-
ly catalyses the Mizoroki–Heck reaction of activated
and unactivated iodides and bromides. Remarkably,
the prepared ligand/palladium complex can be stored
(months) as a stock solution in DMF or NMP open to
air at room temperature with no observable loss of
activity. Further investigations into the ligand struc-
ture to identify an even more reactive system are cur-
rently in progress as is the development of these sys-
tems for other metal-catalysed reactions.
Entry X Pd
9
Time
TON
Conv.
[%][b]
[mol%] [mol%]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
0.2
0.02
0.4
10 min 485
97
100
58
0.04
0.004
0.004
10 min 5000
10 min 29,000
30 min 48,500
0.002
0.002
0.0002
0.0002
0.0002
97
0.0004 10 min 160,000 32
0.0004 30 min 205,000 41
0.0004 60 min 490,000 98
0.00002 0.00004 30 min 1,050,000 21
9
10
11
Br 0.0001
Br 0.0001
Br 0.0001
0.0008 30 min 600,000 60
0.0008 60 min 640,000 64
0.0008 120 min 740,000 74
Experimental Section
General Procedure for the Mizoroki–Heck Reaction
using Aryl Iodides
[a]
[b]
Standard conditions for aryl iodides: Pd2ACTHUNTRGNE(UGN dba)3, 9, Et3N
(1.2 equiv.), DMF (0.5 mL), 2008C, in a Biotage Initiator
Microwave; standard conditions for aryl bromides:
PdACHTUNGTRENNUNG(dba)2 (0.1 mol%), 9 (0.8 mol%), NaOAc (1.5 equiv.),
Pd2ACHTUNGTENR(NUG dba)3 (2.3 mg, 0.0025 mmol) and 9 (4 equiv.) were
stirred in DMF (0.5 mL) for 0.5 h at room temperature. Io-
dobenzene (0.28 mL, 2.5 mmol, substrate/catalyst ratio=
500:1) and styrene (0.32 g, 3.0 mmol) and triethylamine
(0.42 mL, 3.0 mmol) were then added. The flask was crimp-
ed and heated at 2008C under microwave irradiation for
10 min. After the indicated time, the solution was diluted
with ethyl acetate (20 mL) and washed with water and
brine. Ethyl acetate was removed under reduced pressure
and the product isolated by crystallisation from dichlorome-
thane/diethyl ether or by flash column chromatography.
NMP (0.5 mL), TBAB (0.4 equiv.), 2008C.
1
Conversions were evaluated using H NMR spectroscopy,
by comparison of the methoxy protons from 4-iodoani-
sole or 4-bromoanisole and the product.
reaction times could be extended to give conversions
>95% (aryl iodides). After some optimisation it ap-
pears that we can achieve highly effective conversions
to the stilbenes from 4-iodoanisole (98%) and 4-bro-
moanisole (79%) with as little as 0.0002 mol% palla-
dium and 0.0004/0.0008 mol% of the ligand (TON of
490,000 and 740,000, respectively). Although low con-
versions can be somewhat increased by irradiating for
a second or third time in the microwave reactor, it is
far more effective to irradiate the reaction mixture
for a longer single run.
The activity of our system appears to be highly de-
pendent on the presence of anionic ligands for palla-
dium, like halide or acetate ions. The “halide effect”
has been thoroughly studied by, for example, Ama-
tore and Jutand.[21] Computational studies of the ef-
fects of halides or acetates have been published by
Shaik[22] and by Norrby.[23] Some very interesting re-
sults showing high activity of palladium in the pres-
ence of acetate anions were published by Reetz[24]
and by de Vries.[25] In view of these reports, we decid-
ed to run the same experiments in the absence of any
ligand, as it is plausible that the active palladium spe-
cies does not contain the ligand. However, when
using 1 mol% Pd systems for the conversion of aryl
General Procedure for the Mizoroki–Heck Reaction
using Aryl Bromides
PdACTHUNTRGENNG(U dba)2 (1.5 mg, 0.0025 mmol), ligand (8 equiv.), TBAB
(1 mmol) and sodium acetate (0.33 g, 3.8 mmol were stirred
in NMP (1.5 mL) for 1 h at room temperature. Aryl bromide
(2.5 mmol, substrate/catalyst ratio=1000:1) and olefin
(2.5 mmol) were then added. The flask was crimped and
heated at 2008C under microwave irradiation for 30 min.
After the indicated time, the solution was diluted with ethyl
acetate (20 mL) and washed with water and brine. Ethyl
acetate was removed under reduced pressure. The product
was isolated by flash column chromatography.
Acknowledgements
The authors would like to thank Loughborough University
for funding a PhD studentship (SPN), Research Councils
UK for a RCUK fellowship (BRB) and Professor Philip C.
B. Page for proof reading this manuscript. We would also
like to thank the referees who made some very interesting
iodides and aryl bromides in the absence of ligand 9 points regarding the nature of the active palladium complex.
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Benjamin R. Buckley and Stephen P. Neary
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