Calcium-catalyzed hydroarylation of alkenes at room temperature

Article abstract of DOI:10.1002/chem.201001375

Calcium-catalyst gaining ground: A variety of electron-poor electron-rich and trisubstituted styrene derivatives were reacted to give the desired diarylalkanes within less than an hour at room temperature in the presence of 2.5 mol % of Ca(NTf₂)₂/Bu₄NPF₆ (see scheme). Additionally the highly reactive calcium catalyst was successfully applied for the hydroarylation of dienes and even trisubstituted olefins.

Full text of DOI:10.1002/chem.201001375

DOI: 10.1002/chem.201001375
Calcium-Catalyzed Hydroarylation of Alkenes at Room Temperature
Meike Niggemann* and Nicola Bisek[a]
Elaboration of simple olefins represents one of the most
fundamental transformations for the synthesis of commodity
chemicals and pharmacologically relevant target mole-
cules.[1] In this context, the formal addition of a nucleophile
À
HX across a C C double bond to form a functionalized
alkane is an ideal chemical process, that has attracted con-
Scheme 1. Calcium-catalyzed hydroarylation of olefins.
siderable scientific commitment in the past.[2] Transition-
metal,[3] Brønsted,[4] or Lewis acid[5] catalysts were employed
for hydrofunctionalizations with amine,[6] alcohol,[2,7] and ac-
tivated methylene[8,9] nucleophiles. Reactions of olefinic
double bonds with electron-rich aromatic compounds are es-
pecially interesting,[10–13] as they combine the benefits of
ing an even easier access to synthetically useful aryl-substi-
tuted compounds. The hydroarylation of di- and trisubstitut-
ed styrenes, cyclic and linear dienes as well as cyclic trisub-
stituted alkenes was found to proceed smoothly at room
temperature in the presence of the calcium-based catalyst
system and full conversion was obtained within 30 min to a
few hours. Thus, due to the very mild reaction conditions,
the new catalyst appears suitable to address some of the typ-
ical limitations of hydroarylation reactions, such as low func-
tional group tolerance and narrow substrate scope.
À
olefin hydrofunctionalizations with a C H transformation of
an aromatic compound. Furthermore, these so-called hydro-
arylation processes can be considered as an atom economi-
cal alternative to classical Friedel–Crafts-type alkylations of
arenes.[11]
Nowadays the development of sustainable methods using
abundant and cheap catalysts becomes more and more im-
portant. Precious metals, which still play a fundamental role
as the central metal of homogeneous catalysts, are expensive
and are becoming increasingly rare as we use up the Na-
tureꢀs resources. Surprisingly, the elaboration of main group
metal catalyzed reactions has received very little attention
in the past. Among other alkaline earth metals, calcium
seems to be an ideal candidate,[14] as it is essentially non-
toxic, very cheap, and one of the most abundant elements in
the earth crust. Recently, our group demonstrated the effi-
ciency of a novel calcium-based catalytic system for the ad-
dition of benzylic, allylic, and propargylic alcohols to arenes
and heteroarenes under very mild reaction conditions
(Scheme 1).[15] Herein, we present that the Lewis acidic
properties of the same catalytic system promote the addition
Initially the CaACTHNGUTERNNU(G NTf2)2/Bu4NPF6 catalytic system was ap-
plied to the hydroarylation of styrene 1 with resorcinol di-
methyl ether 2 as model substrates. The comparison with
various other Lewis and Brønsted acids clearly demonstrat-
ed the outstanding catalytic potential of the calcium catalyst
(Table 1). Furthermore, the catalyst loading could be low-
ered to 2.5 mol% without significant loss of catalytic activi-
Table 1. Optimization of the reaction conditions.
Entry[a]
(Lewis-) acid [mol%] Additive [mol%] t [h] Yield[b] [%]
ACHTUNGTRENNUNG
2
3
3
4
5
6
8
10
Mg
G
Bu4NPF6 (5)
Bu4NPF6 (5)
Bu4NPF6 ACTHNGUTERNNU(G 2.5)
Bu4NPF6 (5)
–
Bu4NPF6 (5)
Bu4NPF6 (5)
Bu4NPF6 (5)
16
0.2
0.5
16
16
16
16
16
–
Ca
Ca
Ba
Ca
Ca
N
91
89
15
–
52
45
35
À
of electron-rich arenes across C C double bonds, thus offer-
G
[a] Prof. Dr. M. Niggemann, Dr. N. Bisek
Institut fꢁr Organische Chemie, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
HNTf2 (5)
HOTf (5)
E-mail: niggemann@oc.rwth-aachen.de
[a] 5 mol% Additive and 5 mol% Lewis acid were added at room tem-
perature to the alkene (0.5 mmol) and arene 2 (1.5 mmol) in CH2Cl2
(1 mL) and stirred for the time indicated. [b] Isolated yield.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001375.
11246
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11246 – 11249

COMMUNICATION
ty. In accordance with our previous findings, the 1:1 stoichi-
ometry of the calcium salt and the hexafluorophosphate was
critical for an efficient conversion. This indicates that an
anion exchange might take place to form a more reactive
CaNTf2·PF6 species.[15,16] Suitable solvents were aprotic and
non-coordinating, such as dichloromethane, dichloroethane
or hexane. As in our previous findings for the reaction of
arenes with alcohols, the observed regioselectivity of the ar-
omatic alkylation was found to be remarkable. Attack of the
olefinic electrophile occurred exclusively in o,p-position to
the residual methoxy groups of resorcinol dimethyl ether
2.[17] We observed insignificant overalkylation in the pres-
ence of three equivalents of the arene.
is known for styrenes bearing an electron-withdrawing sub-
stituent in the 2-position.[13] Electron-rich phenylpropenes,
such as isoeugenol (entry 3), were found to react exclusively
at the a-position. Interestingly, no isomerization of the
double bond in the methyl indenes (entry 7,8) was observed.
Lower yields for entries 3,7, and 8 are due to a background
reaction yielding small amounts of homocoupled products.
Even though a much longer reaction time was required to
achieve full conversion of phenylcyclohexene (entry 9), the
desired product was formed selectively in a good yield. To
our knowledge this is the first time that a substrate with
such a high degree of steric congestion was successfully
transformed in a hydroarylation reaction. Encouraged by
this result we turned our attention toward the transforma-
tion of less reactive alkenes without a-phenyl substituents
(Table 3).
To explore the scope of the reaction a series of differently
substituted styrenes was reacted with resorcinol dimethyl
ether 2 (Table 2). With 2.5 mol% of CaACHTUNGTRNEUNG(NTf2)2/Bu4NPF6 full
Table 2. Reaction of resorcinol dimethyl ether 2 with styrenes.
Table 3. Reaction of resorcinol dimethyl ether 2 with alkenes.
Entry[a]
Alkene
Product[b]
t [h]
Yield[c]
[%]
Entry[a]
Alkene
Product[b]
t [h]
Yield[c]
[%]
1
2
3
13
14
15
0.5
0.5
0.5
72
75
83
1
2
4
5
0.5
2
95
92
3
6
0.5
86
4
16
0.5
87
5
17
18
0.5
2
84
92
4
5
7
8
2
1
78[d]
89
6[d]
7[d]
8[d]
[a] 2.5 mol% Bu4NPF6 and 2.5 mol% Ca
temperature to the alkene (0.5 mmol) and arene 2 (1.5 mmol) in CH2Cl2
(1 mL) and stirred for the time indicated. [b] Ar: o,p-dimethoxyphenyl.
[c] isolated yield. [d] 5 mol% Bu4NPF6 and 5 mol% Ca
used.
19
20
6
2
89
91
6
7
8
9
0.5
0.5
0.5
92
72
76
(NTf2)2 were added at room
10
11
ACHTUNGTERN(NUNG NTf2)2 were
9
12
12
65
The reaction of resorcinol dimethyl ether 2 with cyclic
and acyclic dienes (entries 1–5) proceeded smoothly in the
presence of 2.5 mol% of the calcium-catalyst. Nucleophilic
attack of the arene occurred exclusively at the 3-position of
the cyclic dienes (entry 1,2). In like manner, conversion of
1,3-pentadiene (entry 3) gave the mono-arylated product 15.
A second arylation was not observed for the cyclic dienes or
for 1,3-pentadiene even upon heating of the reaction mix-
tures up to 1308C (microwave irradiation). However, sub-
jecting isoprene or methylpentadiene (entry 4,5) to the reac-
tion conditions gave full conversion to the bisarylated prod-
ucts 16 and 17 after 30 min at room temperature. Attempts
to isolate the monoarylated product by shortening the reac-
tion time or lowering the catalyst loading were unsuccessful.
Changing the stoichiometry, thus lowering the amount of
arene, resulted in the formation of complex mixtures of bis-
[a] 2.5 mol% Bu4NPF6 and 2.5 mol% CaACTHNUTRGNEUNG(NTf2)2 were added at room
temperature to styrene (0.5 mmol) and arene 2 (1.5 mmol) in CH2Cl2
(1 mL) and stirred for the time indicated. [b] Ar: o,p-dimethoxyphenyl.
[c] Isolated yield. [d] 10:1 mixture of regioisomers (o,p-/o,o-substitution).
conversion of the styrene was usually achieved after 30 min
to 2 h and the corresponding diarylalkane products 4–10
were obtained in 72–95% yield. a-Substituted (entry 1,2, 5,
8–9) as well as electron-withdrawing halo-substituents bear-
ing styrenes (entry 4–5) were readily hydroarylated, even
though both substrate groups are considered to be poorly
reactive. Regioselectivities were generally excellent, only
the reaction of 2-fluorostyrene (entry 4) gave a 10:1 mixture
of isomers (o,p- vs o,o-substitution). This drop in selectivity
Chem. Eur. J. 2010, 16, 11246 – 11249
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11247

M. Niggemann and N. Bisek
ACHTUNGTRENNUNGarylated and cyclized products, formed by intramolecular re-
action pathways.
When cyclic trisubstituted alkenes were treated with re-
sorcinol dimethyl ether, hydroarylation products 18–20 were
obtained selectively. Due to the inferior reactivity of these
compounds
a slightly higher catalyst concentration of
5 mol% was required to achieve full conversion.
To further evaluate the scope of the hydroarylation reac-
tion, a series of different arenes and heteroarenes was
added to a-methylstyrene (Table 4). This substrate was
chosen as general investigations of its reactivity toward dif-
ferent coupling partners are scarce, due to its rather unreac-
tive nature in this type of reaction. We were pleased to find
that hydroarylation occurred readily with electron-rich aro-
matic compounds at room temperature giving the desired
products in good to excellent yields with exceptionally high
p-selectivity in all cases.[17]
Figure 1. Conversion of phenylethanol with resorcinol dimethyl ether 2 in
[a]
^
the presence of styrene 1 ( : consumption of phenylethanol; ꢀ: con-
[a]
sumption[a] of styrene; : formation of diarylmethane 3; [a] determined
~
by GC analysis).
ble in the reaction mixture by GC and NMR analysis at any
time. Further investigations are currently in progress in our
laboratories to elucidate the mechanism of the reaction.
In conclusion, a highly efficient calcium-catalyzed inter-
molecular hydroarylation reaction of aryl and aliphatic al-
kenes has been developed. A variety of electron-poor, elec-
tron-rich, and trisubstituted styrene derivatives was convert-
ed into the desired diarylalkanes within less than an hour at
room temperature. Additionally, dienes and even trisubsti-
tuted olefins were readily arylated, due to the high reactivity
Table 4. Hydroarylation of a-methylstyrene with different arenes and
heteroarenes.
Entry[a]
Arene
Product[b]
t [h]
Yield[c]
[%]
1
2
21
22
0.5
0.5
91
82
of the of CaACHTNUTRGNEG(UN NTf2)2/Bu4NPF6 catalytic system. Free phenolic
hydroxyl groups, acetates, furans, and thiophenes are tolerat-
ed under the very mild reaction conditions. Typical reactions
proceed at room temperature and no special precautions for
exclusion of moisture or air are necessary.
3
23
0.5
87
4
5
24
25
0.5
0.5
75
81
Experimental Section
Synthesis of compound 3: Styrene (52 mg, 0.5 mmol) and resorcinol di-
methyl ether (207 mg, 1.5 mmol) were dissolved in dichloromethane
(1 mL). Bu4NPF6 (5 mg, 2.5 mol%) and CaACHTNUTRGEN(UNG NTf2)2 (7.5 mg, 2.5 mol%)
6
26
1
86
were added at room temperature and the reaction mixture is stirred for
30 min. For the isolation of the product, a satd. NaHCO3 solution (5 mL)
was added, the aqueous phase was extracted with dichloromethane, the
combined organic phases dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by column chromatography (107 mg,
89%).
[a] 2.5 mol% Bu4NPF6 and 2.5 mol% CaACTHNUTRGNEUNG(NTf2)2 were added at room
temperature to the alkene (0.5 mmol) and arene 17 (1.5 mmol) in CH2Cl2
(1 mL) and stirred for the time indicated. [b] Ar: o,p-dimethoxyphenyl.
[c] Isolated yield.
Preliminary mechanistic investigations were undertaken
to address the question whether the reactive carbocationic
intermediate is generated directly by the reversible addition
of a Lewis acid to the olefinic double bond or proceeds via
a carbinol formed in situ through the addition of adventi-
tious water as envisioned in our previous publication.[17]
Competition experiments showed that an alcoholic sub-
strate, such as phenyl ethanol, is consumed with high prefer-
ence in the presence of a corresponding olefin such as sty-
rene (see Figure 1). Additionally, the model reaction of sty-
rene 1 with resorcinol dimethyl ether 2 was inhibited when
run under strictly moisture free conditions. These findings
suggest that the reaction proceeds via the formation of the
carbinol, even though such an intermediate was undetecta-
Keywords: alkenes
alkylation · hydroarylation
· arenes · calcium · Friedel–Crafts
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COMMUNICATION
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Received: May 19, 2010
Revised: June 25, 2010
Published online: August 20, 2010
Chem. Eur. J. 2010, 16, 11246 – 11249
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11249