Efficient and general continuous-flow hydroarylation and hydroalkylation of styrenes

Article abstract of DOI:10.1002/adsc.201000538

A simple and efficient continuous-flow hydroarylation of arenes and heteroarenes using various styrenes in conjunction with a heterogeneous catalyst has been developed. Additionally, this method has been successfully extended to the hydroalkylation of styrenes by employing 1,3-dicarbonyl compounds as the nucleophile. Multigram quantities of diarylmethanes have been prepared using this new flow method. Copyright

Full text of DOI:10.1002/adsc.201000538

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DOI: 10.1002/adsc.201000538
Efficient and General Continuous-Flow Hydroarylation and
Hydroalkylation of Styrenes
Magnus Rueping,a,* Teerawut Bootwicha,a and Erli Sugionoa
a
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-(0)241-8092665; e-mail: Magnus.Rueping@RWTH-Aachen.de
Received: July 8, 2010; Revised: September 3, 2010; Published online: November 17, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000538.
Abstract: A simple and efficient continuous-flow
hydroarylation of arenes and heteroarenes using
various styrenes in conjunction with a heterogene-
ous catalyst has been developed. Additionally, this
method has been successfully extended to the hy-
droalkylation of styrenes by employing 1,3-dicar-
bonyl compounds as the nucleophile. Multigram
quantities of diarylmethanes have been prepared
using this new flow method.
the efficient bismuth-catalyzed hydroarylation[7f] and
hydroalkylation of styrenes[7i] as well as direct benzy-
lation and allylic alkylation of 2,4-pentanediones.[7g]
However, utilizing the advantages of flow technolo-
gy, the development of a continuous variant of these
reactions would be highly desirable as it would offer
an economic and environmentally benign alternative.
Here we report the first example of a flow hydroary-
lation and hydroalkylation of styrenes using a hetero-
geneous catalyst.
Keywords: continuous-flow microwave conditions;
flow reactor; green chemistry; heterogeneous catal-
ysis; polymerization
The experiment was set up according to Scheme 1.
A glass vial (10 mL) filled with the heterogeneous
catalyst (10 g), was inserted into the cavity of a micro-
wave. The inlet tube was connected to peristaltic
pump and the outlet tube was connected to a 250 psi
back-pressure regulator. The reaction mixture was
continuously introduced to the cell under microwave
In recent years the development of continuous-flow irradiation (100 W) and the product was collected
technologies for organic synthesis has attracted a con- from the outlet tube.
siderable amount of attention. Advantages include
Initially our reaction development concentrated on
facile automation, reproducibility, energy efficiency, finding the optimal heterogeneous catalyst for the
improved mixing quality, improved safety, precise continuous-flow reaction of anisole 2c with styrene
control of reaction parameters (temperature, pressure, 1a. From the various catalysts evaluated amberlyst-15
residence time and heat transfer) and the restriction was the most efficient. Further reaction optimization
of by-product formation often caused by prolonged was accomplished by varying the substrate concentra-
heating.[1] Scale-up of the reaction can be achieved by tion, the flow rate and the reaction temperature,
either running a single reactor for extended periods while maintaining the same catalyst (Table 1, en-
of time or by running several reactors in parallel.[2] tries 1–8). The reaction yields remained constant
Moreover, microwave technology has been incorpo- during an increase from 0.05M to 0.1M (Table 1, en-
rated into flow processes providing faster, cleaner and tries 1 and 2). However, when the concentration is
more selective reactions with higher yields as com- above 0.1M the yield decreases (Table 1, entries 3
pared to traditional batch methods.[3–5] Thus, chemists and 4). Thus, the optimal concentration for this reac-
in industry and in academia have begun to focus on tion was found to be 0.1M. Next we examined the
reactor design and the development of new flow pro- flow rate. Increasing the flow rate from 1 mLminÀ1 to
cesses.[6]
2 mLminÀ1 resulted in a significant drop in conver-
Hydroarylation and hydroalkylation reactions are sion, implying that the flow rate should be 1 mLminÀ1
important synthetic methods for the synthesis of di- (Table 1, entries 5 and 6). With regard to the reaction
ACHTUNGTRENNUNGarylmethanes. To date several catalytic approaches temperature 908C is required as decreased tempera-
have been developed, employing a variety of Lewis tures lead to the formation of undesired adducts, in
and Brønsted acids.[7] Recently, our group reported
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Scheme 1. The schematic diagram of the CF-MW reactor.
Importantly the same catalyst was maintained
throughout. In general, the hydroarylation of different
arenes and heteroarenes with styrene provided the
corresponding diarylethanes 3 in good yields as a mix-
ture of o- and p-substituted isomers (Table 2). As
shown in Table 2 various electron-rich arenes with dif-
ferent substitution patterns could be employed. Inter-
estingly even the reactions with thiophene 2h and
methylthiophene 2i proceeded smoothly.
Table 1. The optimization of the flow hydroarylation
reaction.[a]
Having established the hydroarylation of styrene
with arenes and heteroarenes under continuous-flow
conditions, we further demonstrated that this method
can be applied to the reaction of different styrene de-
rivatives with anisole. The results are summarized in
Table 3.
The hydroarylation of halo-substituted styrenes
with anisole was achieved under CF-MW conditions
and the diarylethane products were obtained in good
yields (71–88%; Table 3, entries 2–5). Similarly, the
reaction of 4-methyl-substituted styrene with anisole
2c also proceeded well providing the product in 89%
yield (Table 3, entry 8). Moreover, the transformation
of indene and dihydronaphthalene to the correspond-
ing products, which are useful precursors for biologi-
cally active compounds, proceeded smoothly resulting
in yields of 63% for 3q and 65% for 3n (Table 3, en-
tries 6 and 9). In the case of a-methylstyrene, the hy-
Entry Concentration Flow rate
Temp.
[oC]
Yield
[%][b]
[M]
[mLminÀ1]
1
2
3
4
5
6
7
8
0.05
0.1
0.2
0.3
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
1
2
1
1
90
90
90
90
90
90
80
70
67
68
60
52
66
45
65[c]
66[c]
[a]
Reaction conditions: styrene 1a (1.0 equiv.), anisole 2c
(4.0 equiv.), 100 W, 0.1M solution in MeNO2.
Isolated yield after column chromatography.
Mixture of the diarylmethane and 1,3-diphenylbut-1-ene
(entry 7: 3.2:1; entry 8: 2.6:1)
[b]
[c]
particular the dimerization product of styrene droarylated product 3o containing a quaternary ste-
(Table 1, entries 7 and 8).
reocenter, was only obtained in low yield (37%), de-
Applying the optimal reaction conditions the sub- spite applying a flow rate of 0.5 mLminÀ1 (Table 3,
strate scope of the continuous flow hydroarylation entry 7). However, in general, the method developed
was examined. Initially, different arenes and heteroar- compares favorably with classical batch reactions.
enes 2 were employed in the reaction with styrene 1a
To demonstrate the generality and efficiency even
(Table 2). The reaction mixture of arene and styrene further we decided to extend the methodology to the
was constantly introduced into the flow cell at a flow first continuous-flow hydroalkylation of styrenes with
rate of 1 mLminÀ1 under microwave heating. This was 1,3-dicarbonyl compounds. Thus, acetylacetone 4a and
followed by washing procedure using 20 mL of pyrone 4b were examined (Table 4). In general, under
MeNO2 and then the next substrate was introduced. the optimized conditions, the reaction of acetylace-
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Efficient and General Continuous-Flow Hydroarylation and Hydroalkylation of Styrenes
Table 2. Flow hydroarylation of arenes and heteroarenes
Table 3. Flow hydroarylation of various styrene derivatives
with styrene.[a]
with anisole.[a]
Entry Arene 2
Product 3
Selectivity[b] Yield
[%][c]
1[d]
15:1
7:1[e]
81
41
Entry Product 3
Selectivity[b} Yield [%][c]
1
6:1
66
88
2[f]
2
3
4
19:1
3
4
5
6
6:1
3:1
5:1
7:1
66
76
88
95
4:1
73
71
86
26:1
3:1
5
6
20:1
–
65
37
7
25:1
97
7[d]
8[f]
8:1
63
89
8
7:1
8:1
89
63
9[f]
17:1
9
[a]
Reaction conditions: styrene 1a (1.0 equiv.), arene 2
(4.0 equiv.), 100 W, 908C, 1.0 mLminÀ1, 0.1M solution in
MeNO2.
[a]
Reaction conditions: styrene derivative 1 (1.0 equiv.), ani-
sole 2c (4.0 equiv.), 100 W, 908C, 1.0 mLminÀ1, 0.1M so-
lution in MeNO2.
Determined by H NMR of the crude products.
Isolated yields after column chromatography.
[b]
[c]
[d]
[e]
[f]
1
Determined by H NMR of the crude products.
Isolated yields after column chromatography.
The arene was used as a solvent.
1,3-Diphenylbut-1-ene.
[b]
[c]
[d]
1
The reaction was carried out at
a flow rate of
The reaction was carried out at
a flow rate of
0.5 mLminÀ1.
0.5 mLminÀ1.
tone 4a with different styrene derivatives resulted in yields. (Table 4, entries 1–4). Gratifyingly, the better
the corresponding products 5a–d in moderate to good results were achieved by use of pyrone 4b as the nu-
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Table 4. Flow hydroalkylation of 1,3-dicarbonyl compounds
cleophile. Again the corresponding products 5e–h
were isolated in good to excellent yields (Table 4, en-
tries 5–8).
with styrenes.[a]
Having established the successful hydroarylation on
a small-scale, we decided to scale up this continuous-
flow procedure to multigram quantities. Thus, the hy-
droarylation of 2-naphthol 2g with styrene 1a was
conducted on a 10 and a 40 mmol scale to provide the
diarylmethane 3g (Scheme 2). A good yield was ob-
tained if the reaction was performed under the estab-
lished reaction conditions. However, increasing the
substrate concentration resulted in a decrease in
yield.
In conclusion, we have developed a simple and effi-
cient continuous-flow hydroarylation of arenes and
heteroarenes using various styrenes and employing a
heterogeneous catalyst. The reactions were sequen-
tially introduced into the flow cell and performed sev-
eral times without having to change the catalyst. This
procedure provided a series of valuable 1,1-diarylal-
kanes in good yields. Additionally, this method has
been efficiently applied to the hydroalkylation of styr-
enes with 1,3-dicarbonyl compounds. Scale up of this
method was readily achieved providing an efficient
method for the preparation of diarylmethanes in mul-
tigram quantities. The technology presented is benefi-
cial compared to classical batch reactions in particular
with regard to continuously harvesting product, the
fast optimization of reaction parameters, and restric-
tion of by-product formation, in particular styrene di-
merization and polymerization.
Entry
1
4
Product 5
Yield [%][b]
60
2
3
4
85
55
90
5
6
7
90
94
98
85
Experimental Section
Typical Procedure for Flow Hydroarylation and
Hydroalkylation of Styrenes: Preparation of 1-
Methoxy-4-(1-phenylethyl)benzene (3c)
A
solution of styrene 1a (0.5 mmol) and anisole 2c
(2.0 mmol) in nitromethane (5.0 mL) was pumped through
the flow cell filled with amberlyst-15 resin (10.0 g) at a flow
rate of 1.0 mLminÀ1. During this period the flow reactor
was irradiated in a microwave cavity at 908C (100 W). In
order to wash the system nitromethane (20.0 mL) was
pumped through the flow cell after the reaction was com-
pleted. For the larger scale experiments more solvent had to
8
[a]
Reaction conditions: styrene derivative 1 (1.0 equiv.), 1,3-
dicarbonyl compound
4
(4.0 equiv.), 100 W, 908C,
1.0 mLminÀ1, 0.1M solution in MeNO2.
Isolated yields after column chromatography.
[b]
Scheme 2. Preparation of diarylmethanes on a larger scale.
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Efficient and General Continuous-Flow Hydroarylation and Hydroalkylation of Styrenes
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The authors acknowledge the Fonds der Chemischen Indus-
trie for the generous support.
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