Highly efficient microwave-assisted CO aminocarbonylation with a recyclable Pd(II)/TPP-β-cyclodextrin cross-linked catalyst

Article abstract of DOI:10.1021/op5003374

The incorporation of the carbonyl moiety into organic molecules using a three-component matrix, including carbon monoxide, an organic halide, and a nucleophilic component, offers a simple and versatile approach to the formation of carboxylic acids, anhydrides, esters, amides, and ketones. The design of a sustainable synthetic protocol for aminocarbonylation can be efficiently accomplished using a multifaceted strategy that combines solid green catalysts and suitable enabling techniques. The safe and synergistic use of carbon monoxide in a microwave reactor under pressure may be able to create a technological breakthrough in aminocarbonylation reactions. Moreover, a new recyclable catalytic system "CβCAT" based on Pd(II)-triphenylphosphine embedded in cross-linked β-cyclodextrin (hexamethylene diisocyanate) has been found to be very efficient in aryl iodide aminocarbonylation reactions.

Full text of DOI:10.1021/op5003374

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Concept Article
Highly efficient microwave-assisted CO aminocarbonylation
with a recyclable Pd(II)/TPP-#-cyclodextrin cross linked catalyst
Emanuela Calcio Gaudino, Diego Carnaroglio, Katia Martina,
Giovanni Palmisano, Andrea Penoni, and Giancarlo Cravotto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op5003374 • Publication Date (Web): 13 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Highly efficient microwaveꢀassisted CO
aminocarbonylation with a recyclable Pd(II)/TPPꢀβꢀ
cyclodextrin cross linked catalyst
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Emanuela Calcio Gaudino , Diego Carnaroglio , Katia Martina , Giovanni Palmisano , Andrea
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Penoni , Giancarlo Cravotto
1
Dipartimento di Scienza e Tecnologia del Farmaco, and NIS ꢀ Centre for Nanostructured
Interfaces and Surfaces, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
2
Dipartimento di Scienza e Alta Tecnologia, University of Insubria, Via Valleggio 11,
22100 Como, Italy.
AUTHOR INFORMATION
Corresponding Author
* eꢀmail: giancarlo.cravotto@unito.it
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ABSTRACT
The incorporation of the carbonyl moiety into organic molecules using a threeꢀcomponent
matrix, including carbon monoxide, an organic halide and a nucleophilic component offers a
simple and versatile approach to the formation of carboxylic acids, anhydrides, esters, amides
and ketones. The design of a sustainable synthetic protocol for aminocarbonylation can be
efficiently accomplished using a multiꢀfaceted strategy that combines solid green catalysts and
suitable enabling techniques. The safe and synergistic use of carbon monoxide in a microwave
reactor under pressure may be able to create a technological breakthrough in aminocarbonylation
reactions. Moreover, a new recyclable catalytic system “CβCAT” based on Pd(II)ꢀ
triphenylphosphine embedded in cross linked βꢀcyclodextrin (hexamethylene diisocyanate) has
been found to be very efficient in aryl iodide aminocarbonylation reactions.
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KEYWORDS
Microwaves; Aminocarbonylation; Carbon Monoxide; Heterogeneous catalysis; Palladium.
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. INTRODUCTION
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The term ‘carbonylation’, coined by Reppe in the ‘30s, includes a plethora of reactions such
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as formylation, hydroformylation, alkoxycarbonylation, aminocarbonylation, carbonylative
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Heck, carbonylative Suzuki Miyaura, carbonylative Sonogashira reactions,
which provide
an easy and practical method for the introduction of a carbonyl group into an organic substrate.
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Since the pioneering work of Heck and coꢀworkers in 1974,
the palladiumꢀcatalyzed
carbonylation of aryl halides or pseudohalides with a suitable nucleophile have emerged as the
most important tool for the production of substituted arenes, which are the main critical
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intermediates for various agrochemicals and pharmaceuticals. The recent advancements in
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aminocarbonylation reactions, that exploit the use of carbon monoxide (CO), are truly
noteworthy. Being a versatile and cost efficient C building block reagent (in combination with
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transition metal catalysis),
CO enables “amide bond formation avoiding poor atom economy
reagents” as voted by The American Chemical Society Green Chemistry Institute in 2007 as the
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top challenge to be fulfilled by organic chemistry.
Despite the advantages of CO as a high affinity ligand for palladium, (both in 0 and II
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oxidation states, due its dual ability to act as a σꢀdonor and πꢀacceptor), and the high number of
aminocarbonylation protocols described in the literature which use it as a carbonyl group
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source, its true potential has not been fully realised in labꢀscale synthesis due to the
troublesome handling of CO gas.
To overcome the safety problems involved in using CO gas, several groups have developed
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COꢀequivalents such as alkyl formats, formic anhydride and Nꢀsubstituted formamide,
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carbamoylstannanes,
carbamoylsilane,
silacarboxylic acids,
and acid chloride
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derivatives.
However, this approach requires harsh reaction conditions for CO release, such
as the presence of a strong base combined with high temperatures and long reaction times.
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Another class of solid in situ COꢀreleasing reagents are metal carbonyls,
which are
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currently the best alternative to COꢀgas for aminocarbonylation.
These inorganic metal
carbonyls and their derivatives are nevertheless CO releasers and relatively expensive.
Moreover, they require near stoichiometric amounts of an additional transition metal to work,
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which can encumber the purification of the desired amide products. To avoid this problem and
enable the reuse of the highꢀcost catalyst/ligand system, it is necessary to address the
sustainability problems of aminocarbonylation reactions. Under the relentless demand to develop
ever more efficient methods for amide production, in particular in the pharmaceuticals industry,
the synthetic routes which make use of CO gas' high reactivity may offer clear advantages over
the aforementioned alternative COꢀsources despite entailing certain hazards, which can be
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avoided using suitable equipment. The use of inexpensive and easily reusable catalytic systems
combined with the new enabling technologies can make this process costꢀeffective.
In synthetic organic chemistry, one of the most direct ways to pursue green chemistry is the
use of “enabling technologies” that include traditional techniques such as “solid phase synthesis”
and heterogeneous catalysis as well as relatively new ones such as “microwave (MW)ꢀassisted
synthesis”, “continuous flow reactors” etc. which were developed to speed up synthetic
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transformations and ease process workup. Heterogeneous catalysts bring the efficacy of a
highly active immobilized catalyst as well as simplifying reaction workup, as they are often
readily removed by filtration. Our experience has helped us to use crossꢀlinked chitosan Pd(II)
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complexes to give successful results in MWꢀcatalysed Suzuki reactions. Excellent catalytic
activity has been obtained in Heck, Suzuki and Sonogashira reactions with Pd(II)ꢀbased crossꢀ
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linked βꢀcyclodextrin (βꢀCD) catalysts which are obtained via the in situ polymerization of βCD
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with diisocyanates under ultrasound irradiation in the presence of Pd salts and TPP.
Nowadays, there is no doubt that MWꢀassisted chemistry has helped to radically reduce
reaction times, increase product yields, minimize catalyst loading and reagent excess. Under
MW irradiation, reactions are wellꢀtargeted and uniformly heated at extraordinarily high rates
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that cannot be reproduced under classical heating.
However, few publications describe this
technique with gaseous reagents in a closed vessel and in heterogeneous gasꢀphase reactions. To
the best of our knowledge, very few reports deal with the use of CO gas as an
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aminocarbonylation reagent inside a MW oven.
In the course of our quest for aminocarbonylation procedures which are suitable for MWꢀ
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accelerated highꢀspeed chemistry, and using our experience in MW promoted reactions with
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gaseous reagents in a closed pressurized cavity,
we herein describe a fast MWꢀassisted
Pd(II)ꢀcatalysed protocol for the synthesis of amides using CO gas. The aim of the work is to
maximize the advantages of MW technology in the presence of catalytic systems which are
immobilized on other polar matrices. This investigation carries out the optimization of a
heterogeneous phase protocol in the presence of a supported Pd catalyst (CβCAT). The catalyst
was chosen because it combines high metal performance and high MW adsorption efficacy,
while the βCD is able to complex the TPP ligand making the catalyst more effective. The
influence of different substituents on the aryl halides on reaction outcome, and different
nucleophiles on catalyst performance as well as catalyst recycling are also studied in this
investigation.
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. RESULTS AND DISCUSSION
The influence of critical reaction parameters (i.e., temperature, time, CO pressure, base, ligand
and solvent) on the MW aminocarbonylation of 4ꢀiodoanisole (1 mmol scale), using tꢀ
butylamine (2 equiv) as a nucleophile, has been investigated as the model reaction for
optimization. Our initial efforts were directed at performing comparison experiments in the
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presence of triethylamine (Et N) and TPP, as a base and ligand, using palladium acetate (0.1 %)
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instead of the heterogeneous CβCAT as reaction catalyst, carrying out the aminocarbonylations
in a multimode MW reactor (Scheme 1, Table 1 and Table 2). This MW device was equipped
with a pressure control system and a multiple position rack, which enables multiple gas loading
(inert and/or reactive gas) and simultaneous reaction runs.
It was observed that performing the aminocarbonylation of (1) in the presence of 2 equiv of
nucleophile (2), a 82 % amide yield (3a) could be achieved at 125 °C in toluene after 90 min of
MW irradiation (average power: 55 W) using 1 bar of CO pressure (diluted up to 10 bar with N2)
in the presence of Et N (3.5 equiv) and TPP ligand (0.1%) (Table 1, entry 4). No improvements
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were detected when the MW irradiation time was increased to 2 h (Table 1, entry 6). Several
nucleophile to aryl iodide molar ratios were tested in toluene in order to maximize the
conversion and selectivity of 3a with respect to the ketoamide side product (3b) (Table 1, entries
2, 3, 4 and 5). A ratio of 2:1 furnished the best results, giving 96% conversion and 82% yield.
The influence of CO pressure on MW aminocarbonylation was also investigated. Raising CO
pressure from 1 to 2.5 bar did not give any improvement in 3a product yield (Table 1, entries 4,
and 7), but, as expected, a slight increase in ketoamide (3b) formation (up to 25%) was observed
when the reaction was carried out over 5 bar of CO (Table 1, entry 8). The reaction was repeated
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under conventional conditions, and on the basis of published results , the amount of Pd(OAc)
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was increased to 5%. Complete conversion was obtained after 8 h of heating at 100 °C and the
desired product was collected in a 69% yield (Table 1, entry 9).
Scheme 1. MWꢀassisted aminocarbonylation of 4ꢀiodoanisole.
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Table 1. Optimisation conditions for the MWꢀassisted aminocarbonylation of 4ꢀiodoanisole (1)
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with tꢀbutylamine (2) to 3a in the presence of Pd(OAc)2.
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Entry
Reaction conditions
Conversion (%) Yield (%)
t
Solvent
H N Bu (equiv) CO (bar) Time (h)
(3a) (3b)
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Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
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5
1
1
1
71
89
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96
75
96
95
97
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62
71
82
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64
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1.5
1.5
1.5
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Toluene
MeCN
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>99
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THF
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Dioxane
Dioxane:H O (8:2)
<5
<5
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Dioxane:H O (2:8)
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DMF
a Reaction conditions: 4ꢀiodoanisole (1, 1 mmol), tꢀbutylamine (2), 0.01% of Pd(OAc) , 0.1%
of TPP and Et N (3.5 mmol) in 5 mL of solvent, 125 °C (55 W average MW power) in the
presence of a CO and N (9 bar) atmosphere b Determined by GC–MS; c The reaction was
performed under conventional conditions. 5% Pd(OAc) , TPP (0.1 mmol), Et N (3.5 mmol) in 10
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mL toluene, 1 bar CO. The solution was heated at 100°C for 8 h.
A reduction in reaction yields was noticed (Table 1, entries 10, 11, 12, 15) as we moved from
toluene to more polar nonꢀnucleophilic solvents (such as MeCN, THF, dioxane or DMF). As
expected, a benzoic acid derivative was detected as the main reaction product when a mixture of
dioxane:H O (8:2 or 2:8) was used as greener reaction solvent (Table 1, entries 13, 14).
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Product yields generally increased slightly (7%) at higher catalyst loading (from 0.01% to
0.1% (Table 2, entry 1ꢀ4). Meanwhile, without the TPP ligand, only a poor (3a) yield was
obtained and no reaction product was detected when Et N was omitted even when 0.1% Pd was
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employed. Various other organic bases, including pyridine, 2,6ꢀlutidine, and 4ꢀ
dimethylaminopyridine (DMAP), were investigated and were all found to be less effective than
Et N (Table 2, entries 7ꢀ9). Lower reaction temperatures, from 125 °C to 85 °C, were then
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investigated (Table 2, entries 10ꢀ12). The reported results show that yields increase with reaction
temperature, while ketoamide selectivity was much higher at lower temperature (Table 2, entries
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0ꢀ12).
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Table 2. Optimisation of conditions for the MWꢀassisted aminocarbonylation reaction.
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b
Entry
Reaction condition
Conversion(%)
Yield (%)
(3a)
Base (equiv)
Pd(OAc) (%) Temp. (°C)
(3b)
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Et N (3.5)
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115
100
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89 (29) (0)
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Et N (3.5)
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Et N (3.5)
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Et N (1.5)
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Pyridine (3.5)
2,6ꢀlutidine (3.5)
DMAP (3.5)
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Et N (3.5)
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Et N (3.5)
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Et N (3.5)
3
a
Reactions performed under MW irradiation (90 min) on a 1 mmol scale of (1), using 2
b
equiv of amine (2), in presence of CO (1 bar) and N (9 bar) atmosphere Determined by GC–
MS. Reaction performed without TPP ligand. Reaction performed without Et N.
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c
d
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The recovery and recycling of the Pd catalyst from the product mixture is still a big challenge.
Heterogeneous catalysts can simplify workup procedures without contaminating desired products
with heavy metals and can be reused. Therefore, Pd(AcO) was entrapped in the presence of the
2
TPP ligand on a βꢀCD crossꢀlinked polymer, thus forming the CβCAT catalyst.
CβCAT was simply obtained via the sonochemical reticulation of (βꢀCD) with hexamethylene
diisocyanate (HDI) in a solution containing Pd(II) salts and triphenylphosphine (TPP). Metal
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content was measured by ICP and a 0.65% average was obtained. Moreover, ICP analysis
indicated negligible metal leaching, while the absence of TPP of TPPO in the reaction filtrate
demonstrated the potential of this catalyst for recycling. Based on our experience, this crossꢀ
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linked catalyst is particularly efficient owing to the intense MW adsorption.
Having optimised the MWꢀassisted reaction conditions for the synthesis of Nꢀ(tꢀbutyl)ꢀ4ꢀ
methoxybenzamide (3a), the above protocol was subsequently applied to different
aminocarbonylations using CβCAT (Scheme 2).
Scheme 2. MWꢀassisted aminocarbonylations using CβCAT.
O
X
R1
C
β
CAT (Pd 0.01%)
H
N
R
+
N
+ COgas
R
R1
R2
R
MW, EtN , solvent
2
3
1, 4-12
2, 13-20
3a, 21-34
As depicted in Table 3, numerous solvents were preliminarily tested for the
aminocarbonylation of (1) with (2) in the presence of CβCAT to achieve the best catalytic
performance. The great results obtained previously lead us to performing the reaction under MW
irradiation. Compared to Pd(OAc) , better results were obtained with polar solvents and
2
acetonitrile was selected as the optimal choice (Table 3, entry 2). The reaction in acetonitrile was
repeated in a Parr reactor (80 mL), with the aim of verifying method feasibility under
conventional heating, but worse results were obtained (Table 3, entry 3.
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Table 3. MWꢀassisted aminocarbonylation of (1) with (2) in the presence of CβCAT.
a
b
c
Entry
Solvent
Conversion (%)
Yield (%)
(3a)
1
2
Toluene
MeCN
MeCN
THF
98
100
30
73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
94
28
82
85
75
23
81
d
3
4
5
6
7
8
98
Dioxane
98
Dioxane:H O (8:2)
100
100
98
2
Dioxane:H O (2:8)
2
DMF
a
Reactions were performed under MW irradiation (125 °C, 90 min) on a 1
mmol scale of (1), using 2 equiv of amine (2), 0.01 % of CβCAT and 3.5
b
equiv of Et N, CO (1 bar) and N (9 bar) atmosphere. Determined by GC–
3
2
c
MS. Ketoamide (3b) yield: always lower than 2%. d) the reaction was
performed in a Parr reactor
A wide range of substrates were tested as simultaneous MW reactions were performed under
CO pressure and interesting results were achieved (Tables 4 and 5). All the products were
synthesized and the efficiency of homogeneous and heterogeneous conditions compared.
Table 4. CO aminocarbonylations of different aryl halides with tꢀbutylamine using CβCAT.
a
Entry
ArylꢀX
Product
Yield (%)
CβCAT
94
Yield (%)
Pd(OAc)2
74
1
1
3a
2
100
79
4
21
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2
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2
2
2
2
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75
61
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22
0
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9
0
1
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9
0
1
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8
9
0
1
2
3
4
5
6
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8
9
0
74
23
5
6
41
25
60
24
83
8
9
25
7
8
78
58
2
26
Br
b
b
3
25
3
29 (35)
13 (21)
O
1
0
9
0
11
b
10
0 (0)
0
1
2
a
Twenty reactions were performed simultaneously in the SynthWAVE reactor
multiꢀrack position on a 2 mmol aryl halide scale (1ꢀ12), using 2 equiv of (2), 0.01 %
of CβCAT and 3.5 equiv of Et N in presence of CO (1 bar) and N (9 bar)
3
2
b
atmosphere (125 °C, 90 min). Reactions performed at 150 °C (3 h).
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It was possible to perform twenty simultaneous reactions (2 mmol scale x 20 tubes) at very low
CO pressures (1 bar) in the MW reactor (SynthWAVE, Milestone Srl ꢀ MLS Gmbh) which was
equipped with a multiꢀposition rack and a fine pressure control. Moreover, 1 bar CO was loaded
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and the inert and cheaper N was added to achieve 10 bar of total pressure, thanks to a multipleꢀ
2
gas loading system.
As shown in Table 4, different aryl iodides were converted to the corresponding tꢀbutylamides
using our optimal MW condition in MeCN, including orthoꢀsubstituted compounds, even if in
moderate yields (Table 4, entries 4, 5). Aryl bromides give lower product yields, while aryl
chloride proved to be completely inactive even when the temperature was increased to 150 °C
and MW irradiation up to 3 h (Table 4, entries 8ꢀ10).
As 4ꢀiodoanisole was found to produce one of the best amide yields, it was chosen as the
standard electrophile for the screening of various commercially available amines such as
benzylamine, pꢀtoluidine, pꢀanisidine, dicyclohexylamine and morpholine, etc. The primary
amines were found to be more reactive (Table 5, entries 1ꢀ3), and gave good results. The more
demanding substrates, including the sterically disfavoured secondary amine (19), were then
investigated. They only gave incomplete conversion and consequently lower isolated product
5
6ꢀ59
yields (Table 5, entry 6ꢀ7). As already reported in the literature,
we confirmed that solid
supported Pd showed better results than homogeneous phase conditions for the same amount of
catalyst. The biggest advantage of the βꢀCD system is the very low metal leaching and the total
capture of TPP and the TPPꢀoxide formed during the reaction. This greatly simplifies the
purification step and resulted in quantitative yields, without TPP and Pd impurities in the
products.
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2
2
2
2
2
2
2
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3
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3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
Table 5. MWꢀassisted CO aminocarbonylations of 4ꢀiodoanisole (1) with different amines using
CβCAT.
a
Entry
Amine
Product
Yield (%)
Yield (%)
CβCAT
Pd(OAc)2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H N
2
1
6
93
89
72
70
65
51
1
3
27
28
29
2
3
14
1
5
4
5
6
76
82
65
50
64
46
16
30
1
1
7
8
31
O
N
O
32
7
59
31
1
9
33
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73
49
20
34
a
Sixteen reactions were performed simultaneously in the SynthWAVE reactor with a multiꢀ
position rack on a 2 mmol scale of (1), using 2 equiv of amine (13ꢀ20), 0.01 % of CβCAT and
.5 equiv of Et N in the presence of CO (1 bar) and N (9 bar) atmosphere (125 °C, 90 min).
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
30
31
32
33
34
35
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37
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53
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59
60
3
3
2
The optimized protocol was tested over 10 simultaneous reactions which ranged from 1 to 10
mmol aryl iodide levels (1) (1, 2.5, 5, 7.5 and 10 mmol, respectively) in presence of amine (2) or
(
14) using 0.01% CβCAT. We flushed the MW reactor chamber first with the CO amount
needed for the five reactions run simultaneously (56 mmol scale) (2 bar) and added up to 10 bar
using N . During the course of the reaction, a drop in pressure to 2 bar was observed, this clearly
2
indicated CO consumption. Upon reaction completion, the reactor cavity was cooled down to 40°
C, before the residual pressure was released into a wellꢀventilated hood. Amide products (3)
were obtained in yield ranges of 75ꢀ94% and 68ꢀ89%, which are in accordance with results
obtained in our previous smaller–scale trials.
Table 6. Scaling up of the MWꢀassisted CO aminocarbonylation reactions in the presence of
CβCAT.
a
Entry
Amine
(2)
mmol
1
Yield (%)
1
2
3
4
94
90
89
83
(2)
2.5
5
(2)
(2)
7.5
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
3
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4
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5
5
5
5
5
5
6
5
6
7
8
9
(2)
10
1
78
89
86
85
78
68
(14)
(14)
(14)
(14)
(14)
2.5
5
0
1
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9
0
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9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.5
10
10
a
Ten reactions were run simultaneously in the SynthWAVE reactor with a multiꢀposition
rack, using the noted quantity of aryl iodide (1), 2 equiv of amine (2) or (14), 0.01% of
CβCAT, and 3.5 equiv of EtN in the presence of MeCN. (Reaction condition: 125 °C, 90
3
min, CO (1.5 bar) and N (8.5 bar).
2
2
.1. CβCAT recycling
Key features of heterogeneous catalysts are recovery and reuse; essential considerations for
green chemistry which looks to both the ecologic and economic. We also evaluated the activity
and recycling of CβCAT in the MWꢀassisted aminocarbonylation of (1) with (2) in the presence
of CO gas (reactions performed in MeCN at 125 °C for 90 min in the presence of CO (1.5 bar)
and N (8.5 bar). It should be pointed out that the CβCAT used was easily recovered by filtration
2
after the completion of the reaction and washed with a Petroleum Ether 40ꢀ60/EtOAc (1:1)
mixture, dried under vacuum and reused under the same reaction conditions. The recovered
catalyst was reused at least five times and gave consistent isolated amide yields (3a) (83%, 75%,
70% and 64%, respectively) (Figure 1). The slight change may be due to a loss of catalyst during
handling of the βꢀCD catalytic system.
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Figure 1. CβCAT recycling.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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52
53
54
55
56
57
58
59
60
In this context, it is worth noting that the βꢀCD network serves as an efficient metal chelator
which encapsulates the organic ligand as well.
3. CONCLUSION
A highly efficient and reusable catalyst (CβCAT) has been applied to MWꢀassisted
aminocarbonylation reactions under mild CO pressure for the first time. Several amide
derivatives have been synthesized from an aryl iodide/nucleophilic amine 1:2 ratio in good
yields, using a CO/N mixture. This novel catalyst is well suited to MWꢀassisted reactions, an
2
alternative to common palladium complexes based homogeneous catalytic systems, has
competitive advantages, including easy recyclability with no significant loss in activity and
selectivity and negligible entrapped metal catalyst leaching. This inexpensive and effective
catalyst should have a bright future in industrial applications and enable the MW production of
multiꢀkg quantities of amides from CO gas in a safe manner.
4. EXPERIMENTAL
All chemicals were purchased from SigmaꢀAldrich (solvents from Carlo Erba SpA) and used
without further purification. βꢀCD was kindly provided by Wacker Chemie (Munich, Germany).
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59
CβCAT was prepared following a previously reported procedure.
Reactions were monitored by TLC on Merck 60 F254 (0.25 mm) plates, which were visualized
by UV inspection and/or by heating after a spraying with 5% H SO in ethanol or
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
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2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
phosphomolybdic acid. MWꢀpromoted reactions were carried out in a multimode MW reactor
SynthWAVE (Milestone Srl, Italy; MLS Gmbh, Germany).
This instrument is equipped with a highꢀpressure stainless steel reaction chamber which can
work up to a maximum of 300 °C and 199 bar and enables microwave reactions both on a
simultaneous smallꢀscale (mL) and a large scale (L). Moreover, integrated reactor sensors
continuously monitored the internal pressure, temperature and power applied inside the reactor
cavity during all runs and adjusted the applied microwave power in real time to follow a
predefined temperature profile.
Product purification was performed via flashꢀchromatography (CombiFlash RfsTeledyne
ISCO) on appropriate silica cartridges. NMR spectra were recorded on a Bruker Avance 300
(
operating at a magnetic field strength of 7T) at 25 °C; chemical shifts were calibrated to the
residual proton and carbon resonance of deuterated solvents: CDCl (δ H=7.26, δ C=77.16). GCꢀ
3
MS analyses were performed in a GC Agilent 6890 (Agilent Technologies ꢀ USA) that was fitted
with a mass detector Agilent Network 5973, using a 30 m long capillary column, i.d of 0.25 mm
and film thickness 0.25 ꢁm. GC conditions were: injection split 1:20, injector temperature 250
°C, detector temperature 280 °C. Gas carrier: helium (1.2 mL/min), temperature program: from
7
0 °C (2 min) to 300 °C at 5 °C/min. HRMS was determined using a MALDIꢀTOF mass spectra
(
Bruker Ultraflex TOF mass spectrometer). The metal content in solution was determined by
ICPꢀMS on a QuadrupoleꢀICPꢀMS X Series II (Thermo Fisher Scientific) after sample digestion
in HNO and aqua regia. The oxidation state of the adsorbed palladium or copper was measured
3
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by Xꢀray photoelectron spectroscopy (XPS) with a Quantum 2000 (PHI Co., Chanhassen, MN,
USA) with a focused monochromatic Al K source (1486.7 eV) for excitation.
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13
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4.1. GENERAL PROCEDURES
Single MWꢀassisted aminocarbonylation procedures using Pd(OAc)2
In a typical experiment, 4ꢀiodoanisole (1) (1 mmol) was reacted in the SynthWAVE reactor
with tꢀbutylamine (2) (2 mmol), 0.01% of Pd(OAc) , 0.1% of TPP and Et N (3.5 mmol) in
2
3
toluene or MeCN (5 mL), at 125 °C for 90 min (55 W average MW power) in the presence of
CO (1 bar ) and N (9 bar) atmosphere. The reaction mixture was magnetically stirred throughout
2
the run. Upon completion of the heating stage, the reaction chamber was cooled to 35 °C and
then slowly vented and opened, before the slow release of the internal residual pressure. The
reaction solvent was removed under vacuum; the residue was dissolved in EtOAc (20 mL) and
washed with HCl (2 x 20 mL, 1N), saturated NaHCO (2 x 20 mL) and brine (2 x 20 mL). The
3
organic phase was finally dried over Na SO and the solvent removed by distillation. Product
2
4
purification was performed by flashꢀchromatography (CombiFlash RfsTeledyne ISCO) on
appropriate silica cartridges (petroleum ether 40ꢀ60/EtOAc = 8:2 v/v) yielding amide (3a) and
ketoamide (3b).
4.1.1. Single MWꢀassisted aminocarbonylation procedure using CβCAT.
In a typical experiment 4ꢀiodoanisole (1) (1 mmol) was reacted in the SynthWAVE reactor
with tꢀbutyl amine (2) (2 mmol), 0.01% of CβCAT and Et N (3.5 mmol) in toluene or MeCN
3
(7.5 mL) at 125 °C for 90 min in the presence of CO (1 bar) and N (9 bar) atmosphere. The
2
reaction mixture was magnetically stirred throughout the run. Upon completion of the heating
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stage, the reaction chamber was cooled to 35 °C and then slowly vented and opened, before the
slow release of the internal residual pressure. The CβCAT was filtered off on a sinteredꢀglass
Buchner funnel and washed twice with EtOAc. Organic solvents were removed under vacuum
and the residue was dissolved in EtOAc (20 mL) and washed with HCl (2 x 20 mL, 1N),
saturated NaHCO (2 x 20 mL) and brine (2 x 20 mL). The organic phase was dried over Na SO
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
and the solvent removed by distillation. Product purification was performed by flashꢀ
chromatography (CombiFlash RfsTeledyne ISCO) on appropriate silica cartridges (petroleum
ether 40ꢀ60/EtOAc = 8:2 v/v) yielding amide (3a) and ketoamide (3b). The crude products did
not require further purification for metal contamination as shown by ICPꢀMS analysis (Pd
content < 6ꢀ8 ppm in all cases).
4.1.2. Simultaneous MWꢀassisted aminocarbonylation of aryl iodides with different amines
with CβCAT.
All reagents and catalyst were added to each of twenty reaction vessels (15 mL capacity)
equipped with a magnetic stir bar and placed into a multipleꢀposition rack: aryl halide (1 or 4ꢀ12)
(2 mmol), CβCAT (0.01%), 0.1 % of TPP, Et N (3.5 mmol) and the corresponding amine (2 or
3
13ꢀ20) (2 mmol) in MeCN (7.5 mL). The multipleꢀposition rack was immersed in a few cm of
®
ethylene glycol (250 mL) present in the reactor cavity (1L Teflon vessel) as a moderating fluid.
The vessel was loaded and purged three times with N then loaded with 1 bar CO (a nearꢀ
2
stoichiometric amount based on the twenty reactions tubes) and further pressurized by N (9 bar),
2
giving a total pressure of 10 bar. An identical heating program was used as in previous single
experiments (MW heating at 125 °C for 90 min). After reaction completion, each product
mixture was worked up individually using the same protocol as previously described in the
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single reaction procedure, thus giving amides (21ꢀ34) in good to excellent yields. The crude
products did not require further purification for metal contamination, as shown by ICPꢀMS
analysis (Pd content < 6ꢀ8 ppm in all cases).
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41
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43
44
45
46
47
48
49
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52
53
54
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56
57
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59
60
4.2. CβCAT recycling
In a typical experiment, 4ꢀiodoanisole (1) (1 mmol) was reacted in the SynthWAVE reactor
with tꢀbutyl amine (2) (2 mmol), 0.01% of CβCAT and Et N (3.5 mmol) in MeCN (7.5 mL) at
3
125 °C for 90 min in the presence of a CO (1.5 bar) and N (8.5 bar) atmosphere.
2
The previous reaction procedure was followed and the CβCAT was filtered off on a sinteredꢀ
glass Buchner funnel and washed with a petroleum ether 40ꢀ60/EtOAc (1:1) mixture (3 x 20
mL), dried under vacuum and reused in the next run under the same reaction conditions. Using
the same work up protocol, the amide (3a) was obtained in 83%, 75%, 70%, 64%, 43% and 21%
yields, respectively, after each recycle.
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ACKNOWLEDGEMENTS
This work is funded by the EU project MAPSYN: Microwave, Acoustic and Plasma
SYNtheses, under grant agreement No. CPꢀIP 309376 of the European Community’s Seventh
Framework Program.
0
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ASSOCIATED CONTENT
The product characterization is reported in the supporting information. This material is available
free of charge via the Internet at http://pubs.acs.org.
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CβCAT
Pd(II)/TPP b-cyclodextrin
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cross-linked catalyst
MW
MW
Table of Contents Graphic
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