Calcium-catalyzed friedel-crafts alkylation at room temperature

Article abstract of DOI:10.1002/anie.200907227

Chemical Equatation Representation A novel calcium catalyst was found to efficiently functionalize electron-rich arenes with secondary and tertiary benzylic, propargylic, and allylic alcohols under very mild reaction conditions. The new catalyst system significantly enlarges the scope of the reaction, which was previously limited except for the few examples with secondary benzylic alcohols.

Full text of DOI:10.1002/anie.200907227

Communications
DOI: 10.1002/anie.200907227
Arene Functionalization
Calcium-Catalyzed Friedel–Crafts Alkylation at Room Temperature
Meike Niggemann* and Matthias J. Meel
Friedel–Crafts reactions are among the oldest and most
systems[3,6,7] were published within the last couple of years.
Transition metal free procedures were realized by the means
of aluminum,[8] indium,[9] bismuth,[10] iodine,[11] and Brønsted
acid[12,13] catalysis. Transformation of propargylic and allylic
alcohols, not activated by an additional aryl substituent in the
a-position to the hydroxy group, has been scarce in inter-
molecular Friedel–Crafts reactions.[7,12,14,15] Palladium-[16] and
molybdenum-catalyzed[17] processes are not included here, as
they proceed through a different mechanism. The trans-
formation of a tertiary allylic alcohol was, to our knowledge,
thus far unsuccessful. Arylation of tertiary benzylic[18] and
tertiary propargylic[14] alcohols have not yet been realized
under mild reaction conditions. A central drawback of
Friedel–Crafts-type additions remains the low functional
group tolerance, because even modern procedures generally
suffer from the necessity of rather harsh reaction conditions.
In the last couple of years sustainable metal catalysis has
emerged, complementing the concept of organocatalysis. An
exponentially growing number of publications have showed
that iron complexes provide efficient alternatives to the
precious transition-metals Pd, Rh, and Au.[19] Bismuth salts
have exhibited growing importance as ecologically benign
Lewis acids.[20] Remarkably, the catalytic activity of the
nontoxic alkaline earth metals is almost unexplored despite
excellent availability and the low cost of these potential,
sustainable metal catalysts.[21] Among the alkaline earth
metals calcium appears particularly promising, as it displays
similarities to the lanthanoids with regard to its chemical
properties.[22] Furthermore, first applications of this main
group metal as a catalyst have been recently realized.[23]
Herein we present a calcium-based catalyst system for the
alkylation of electron-rich arenes using secondary and tertiary
benzylic, allylic, and propargylic alcohols at room temper-
ature (Scheme 2). The new catalyst system allows the general
arylation of allylic and propargylic alcohols, without neces-
À
efficient C C bond-forming processes for the functionaliza-
tion of aromatic compounds.[1] Avivid interest in the synthesis
of polycyclic aromatics, core structures of innumerable,
biologically active natural products having continuing indus-
trial and academic impact, has recently revived the research
field of Friedel–Crafts reactions.[2] Most of the original
Friedel–Crafts procedures have now been replaced by
environmentally more compatible catalytic approaches. An
additional step on the way towards ecologically and econom-
ically beneficial arylations was the use of alcohols as electro-
philes, wherein water is the only by-product accompanying
the transformation of these readily available substrates.[3]
Ideally, a coupled catalytic process as depicted in Scheme 1
would be a conceivable reaction.
Scheme 1. Coupled catalytic arylation of inactivated olefins.
In a first reaction step, an equilibrium between the olefin 1
and the Markovnikov product 2 would be established by a
Lewis acid catalyzed addition of water to an olefinic double
bond.[4] As these equilibria often provide only minor amounts
of the alcohol 2, a coupled catalytic process seems ideal for a
synthetically useful application of this reaction. In the next
step, the same catalyst would then account for the function-
alization of the arene with alcohol 2. Therefore, water would
be no more than a mediator, present only in negligible
amounts, and olefins that were previously unreactive in
Friedel–Crafts reactions may be activated. On the way
towards the envisioned coupled catalysis, we needed to
identify a broadly applicable Lewis acid for the functional-
ization of arenes with alcohols.
On the basis of the lanthanoid-catalyzed transformations
of secondary a-aryl alcohols to diarylmethanes by Ishii and
co-workers,[5] a series of transition metal based catalyst
[*] Prof. Dr. M. Niggemann, Dr. M. J. Meel
Institut fꢀr Organische Chemie, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: niggemann@oc.rwth-aachen.de
Homepage: http://www.oc.rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907227.
Scheme 2. Calcium-catalyzed arylation of alcohols.
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Table 1: Optimization of the reaction conditions.
Table 2: Addition of different secondary alcohols to arene 17.
Entry[a]
Alcohol
Product[b]
t [h]
Yield [%][c]
1
1
87
Entry[a]
Catalyst (mol%)
Additive
(mol%)
t [h]
Yield [%][b]
2
3
1
4
83
76
1
2
3
4
5
6
7
8
LiNTf2 (10)
Mg(NTf2)2 (5)
Ca(NTf2)2 (5)
Ca(NTf2)2 (5)
Ba(NTf2)2 (5)
Ca(NTf2)2 (5)
Ca(OTf)2 (5)
Ca(BF4)2 (5)
HNTf2 (5)
Bu4NPF6 (5)
Bu4NPF6 (5)
Bu4NPF6 (5)
NH4PF6 (5)
Bu4NPF6 (5)
–
Bu4NPF6 (5)
Bu4NPF6 (5)
Bu4NPF6 (5)
Bu4NPF6 (0.1)
Bu4NPF6 (5)
16
16
1
68
–
85
82
22
–
47
25
5
2
16
16
16
16
20
23
23
4
5
5
5
68
77
9
10
11
HNTf2 (0.1)
HOTf (5)
–
3
[a] Reaction conditions: Alcohol 16 (0.5 mmol) and arene 17 (1.5 mmol)
were dissolved in CH2Cl2 (1 mL). Both the additive and (Lewis-) acid
were added at room temperature and then stirred for the time indicated.
[b] Yield of isolated product.
6
7
4
4
80
88
sitating activation of the alcohol by an additional aryl
substituent in a-position (R1) to the hydroxy group.
Our investigations began with the optimization of the
reaction conditions for the model reaction shown in Table 1.
A catalyst loading of 5 mol% Ca(NTf2)2 in the presence of
5 mol% Bu4NPF6 afforded the desired product 18 within one
hour at room temperature. Multiple functionalizations of the
arene were suppressed in the presence of just three equiv-
alents of this reaction partner. The regioselectivity of the
transformation was found to be remarkable; substitution of
the arene was observed exclusively in o,p-position relative to
the two methoxy groups of resorcinol dimethyl ether (17).[24]
The reaction succeeded only in aprotic, noncoordinating
solvents such as dichloromethane, 1,2-dichloroethane, or n-
hexane. LiNTf2, Mg(NTf2)2, Ba(NTf2)2, Ca(OTf)2, and Ca-
(BF4)2 displayed none or very little catalytic activity (Table 1,
entries 1, 2, 5, 7, and 8). No transformation of the model
substrates occurred with any of the examined Lewis acids in
the absence of the hexafluorophosphate salt. Similar to the
observations made by Shibasaki for a Bi(OTf)2/MPF6-based
catalyst system,[25] the choice of the counter cation to the
hexafluorophosphate additive had little to no influence upon
the reaction outcome (Table 1, entry 4). This finding possibly
[a] Reaction conditions: The alcohol (0.5 mmol) and arene 17
(1.5 mmol) were dissolved in CH2Cl2 (1 mL). 5 mol% Bu4NPF6 and 5
mol% Ca(NTf2)2 were added at room temperature and then the reaction
mixture was stirred for the time indicated. [b] Ar=o,p-dimethoxyphenyl;
regioselectivity determined by NMR and GC analysis. [c] Yield of isolated
product.
secondary alcohols (Table 2). The secondary benzylic alco-
hols 19 and 20 were arylated within one hour in excellent
yields. Conversion of the propargylic alcohol 21, as well as the
cyclic alcohols 22 and 23, occurred readily to give the
corresponding products 28–30. As far as we know substrates
21–23 have never been transformed in a reaction of this type
employing any of the previously published catalyst systems.
Likewise, linear allylic alcohols 24 and 25 were arylated
smoothly. The reaction times were significantly longer when
there were no a-aryl substituents to activate the alcohol for
the ionization step (Table 2, entries 3–7). Nevertheless, the
high reactivity of the catalyst system accounted for full
conversion of the alcohlol in just 4–5 hours at room temper-
ature. As observed for the transformation of phenylethanol 16
(Table 1), substitution of the arene occurred exclusively in
o,p-position to the two methoxy groups of the resorcinol
dimethyl ether (17) in all cases.[25]
Using the same very mild reaction conditions, the trans-
formation of tertiary alcohols resulted in high product yields
and good selectivity (Table 3). Notably, reaction times were
generally shorter compared to those observed for conversion
of secondary alcohols. Benzylic (Table 3, entry 1) and prop-
argylic alcohols (Table 3, entries 2–5) gave branched reaction
products 44 and 45–48, respectively. In contrast, allylic
alcohols reacted to give the linear products 49–53 (Table 3,
entries 6–11). A tertiary allylic alcohol such as 39 displayed no
reactivity because the substituent in the allylic position might
.
points towards the formation of a more reactive CaNTf2 PF6
species.
Alternative calcium sources such as Ca(OiPr)2, Ca(OAc)2,
Ca(TFA)2, or calcium halogenides showed no reactivity even
in the presence of the hexafluorophosphate. By using 5 mol%
of either HNTf2 or HOTf (Tf = CF3SO2; Table 1, entries 9–
11) full conversion of phenylethanol 16 was achieved in the
presence of the additive, but the reactions were sluggish.
Reaction did not occur either in the absence of Bu4NPF6, or
when a catalyst loading as little as 1 or 0.1 mol% of the acid/
additive pair was applied (Table 1, entry 10).
Having the optimized reaction conditions in hand, resor-
cinol dimethyl ether (17) was reacted with a series of
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Table 3: Addition of different tertiary alcohols to arene 17.
The reaction with both alcohols (22 and 34) resulted in similar
regioselectivity as that seen in the reaction with resorcinol
dimethyl ether (17). The electrophilic attack of the cation,
generated from the secondary allylic 22, upon the arene
substrates 55, 58, and 59 resulted in poorer regioselectivity
than that seen with 17 (Table 4, entries 2, 5 and 6). In these
cases the substituents on the arene were less directing than
those in 17. The tertiary propargylic alcohol 34 reacted with
all the tested aromatic compounds in the same high regiose-
lectivity as previously observed (Table 4, entries 8–11).
We have developed a general calcium-catalyzed function-
alization that allows the selective alkylation of arenes using
Entry[a]
Alcohol
Product[b]
t [h]
Yield [%][c]
90
1
1
2
3
2
2
87
79
4
5
2
2
71
82
Table 4: Addition of arenes to allylic alcohol 22 (entries 1–7) and
propargylic alcohol 34 (entries 8–11).
Entry[a]
Arene
Product[b]
t [h]
Yield [%][c]
1
5
81
6
7
8
2
–
2
72
–
–
2
3
5
5
74
80
88
9
1
1
4
70
81
70
4
5
82
10
11
5
6
5
5
81
89
[a] Reaction conditions: Alcohol (0.5 mmol) and arene 17 (1.5 mmol)
were dissolved in CH2Cl2 (1 mL). 5 mol% Bu4NPF6 and 5 mol%
Ca(NTf2)2 were then added at room temperature and the resulting
reaction mixture was stirred for the time indicated. [b] Ar=o,p-dime-
thoxyphenyl; regioselectivity determined by NMR and GC analysis.
[c] Yield of isolated product.
7
5
90
8
9
2
2
2
93
86
78
sterically hamper an attack by the nucleophile (Table 3,
entry 7). The successful transformation of propargylic alcohol
36 demonstrated once more the mildness of the reaction
conditions employed, as the acid labile TBS ether in 36
remained intact. Interestingly, the exocyclic double bond
generated during the arylation of the allylic alcohol 43
isomerized under the reaction conditions to form the
endocyclic double bond in 53. This rearrangement goes to
50% at full conversion of the alcohol 43 and is then complete
after an additional three hours.
Furthermore, we were interested in the reactivity towards
different arenes and heteroarenes (Table 4). A series of
electron-rich aromatic compounds (54–60) was alkylated
readily, at room temperature with the allylic alcohol 22 and
the tertiary propargylic alcohol 34, respectively. The data
show that the electron-rich arenes were alkylated at room
temperature, resulting in good to excellent product yields.
10
11
2
91
[a] Reaction conditions: Alcohol (0.5 mmol) and the arene (1.5 mmol)
were dissolved in CH2Cl2 (1 mL). 5 mol% Bu4NPF6 and 5 mol%
Ca(NTf2)2 were added at to the reaction mixture at room temperature and
then stirred for the time indicated. [b] Yield of isolated product;
regioselectivity determined by NMR and GC analysis.
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Chemie
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alcohols. The scope of the reaction was broadened signifi-
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sufficient to overcome the long standing limitation of this
reaction to benzylic alcohols. Typical reactions proceed at
room temperature, with no added strong acids or bases, and
special precautions for exclusion of moisture or air are
unnecessary. Functional groups such as phenolic hydroxy
groups, primary TBS ethers, furans, and thiophenes are
tolerated under the mild reaction conditions. Hence, calcium
was identified as a suitable Lewis acid for the catalysis of our
proposed arylation reaction. Additional developments in this
transformation are currently underway in our laboratories.
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Experimental Section
All reactions were carried out with no precautions taken for the
exclusion of moisture and air. Arylation of phenylethanol: Com-
pounds 16 (0.5 mmol) and 17 (1.5 mmol) placed in a reaction flask
and dissolved in dichloromethane (1 mL). Bu4NPF6 (5 mol%) and
Ca(NTf2)2 (5 mol%) were then added, and the reaction mixture for
1 h at RT. For the isolation of the product, 5 mL sat. NaHCO3 solution
was added to the reaction mixture, the aqueous phase was then
extracted with dichloromethane, and the combined organic phases
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Received: December 22, 2009
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Keywords: allylic compounds · arylation · alcohols · calcium ·
Friedel–Crafts reaction
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