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M. Bandini, A. Umani-Ronchi and A. Melloni

Stereoselective Alkylations

New Catalytic Approaches in the Stereoselective


FriedelCrafts Alkylation Reaction**
Marco Bandini,* Alfonso Melloni, and Achille Umani-Ronchi*
Keywords:
alkylation aromatic substitution asymmetric
catalysis Lewis acids synthesis design

fter more than 125 years, the FriedelCrafts alkylation is still one of
the most studied and most utilized reactions in organic synthesis. What
is the secret of this astonishing success? Perhaps the great versatility in
scope and applicability continues to justify its crucial role in the
synthesis of more and more complex molecules. However, it has taken
more than a century for asymmetric catalytic versions of this reaction
to be developed and subsequently extended to a range of aromatic
compounds and alkylating agents. Herein we review recent developments in the design and use of catalytic and stereoselective strategies
for the alkylation of aromatic systems and synthesis of a wide range of
polyfunctionalized enantiomerically enriched compounds.

prompted several groups to develop


new stereoselective and catalytic strategies.[6] Herein, a brief overview of the
most recent asymmetric protocols of
the metal- and organocatalyzed electrophilic alkylation of aromatic compounds is presented. We found it
convenient to gather the FC alkylations into three sections: ring-opening reactions of epoxides
by aromatic compounds (Scheme 1 a), enantioselective 1,2-

1. Introduction
The FriedelCrafts (FC) reaction is one of the oldest
organic transformations to employ Lewis acids as promoters,
and since the pioneering study by Charles Friedel and
James M. Crafts[1] it has been one of the most powerful C C
bond-forming processes in organic synthesis.[2] The original
procedure (for which stoichiometric amounts of a Lewis acid
were required) has subsequently been replaced by milder and
more environmentally friendly conditions.[3] The ever-increasing number of catalytic procedures reported in the literature
over the past decade for the catalytic alkylation and acylation
of aromatic and heteroaromatic compounds is striking
(Figure 1).[4]
In the mid-1980s the first examples of the asymmetric
addition of aromatic C H bonds to carbonyl compounds
appeared in the literature.[5] Since then the synthetic relevance of the formation of benzylic carbon stereocenters

Figure 1. The increasing number of catalytic FriedelCrafts procedures


published from 1991 to date.

[*] Dr. M. Bandini, A. Melloni, Prof. Dr. A. Umani-Ronchi


Dipartimento di Chimica G. Ciamician, Universit/ di Bologna
Via Selmi, 2, 40126 Bologna (Italy)
Fax: (+ 39) 051-209-9456
E-mail: marco.bandini@unibo.it
umani@ciam.unibo.it
[**] We thank Progetti FIRB, Consorzio C.I.N.M.P.I.S. (Bari),
M.U.R.S.T. (Rome) Progetto Stereoselezione in Chimica Organica.
Metodologie ed Applicazioni, and the University of Bologna (funds
for selected research topics) for the financial support of this
research.

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Scheme 1. Possible approaches in the asymmetric FriedelCrafts


alkylation of aromatic compounds.

DOI: 10.1002/anie.200301679

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FriedelCrafts Alkylations

additions of aromatic systems to carbonyl groups (Scheme 1 b), and 1,4-conjugate additions of aromatic systems to
a,b-unsaturated carbonyl compounds (Scheme 1 c).

2. Catalytic Stereocontrolled Ring-Opening of


Epoxides by Aromatic Compounds
The ring-opening of epoxides by aromatic compounds in
the presence of Lewis acids, bases, and solid acids is widely
recognized as an effective step in the synthesis of polyfunctionalized compounds.[7] Moreover, the ready availability of
enantioenriched cis and trans epoxides by means of various
stereoselective epoxidations makes this approach an attractive candidate for use as a tool in the synthesis of optically
active aromatic compounds. The main drawbacks encountered in this strategy are the occurrence of polyalkylation and
the frequent absence of regioselectivity. Only a few examples
involving enantiomerically enriched epoxides have been
described. In particular, Kotsuki et al. reported the regioand stereoselective alkylation of indole (2) with (R)-(+)styrene oxide (1) promoted by high pressure or catalyzed by
silica gel (Scheme 2).[8] Although both approaches guaran-

Scheme 2. High-pressure and silica-gel-catalyzed stereoselective ringopening of (R)-(+)-styrene oxide.

teed satisfactory yields of 3, partial racemization of the


enantiomerically pure starting epoxide was observed (high
pressure: 92 % ee, SiO2 : 88 % ee).
The use of Lewis acids represents a valuable way to
promote and control the reactivity of oxiranes toward
nucleophiles. Furthermore, the electronic features of the
Lewis acid must be considered carefully to prevent the
formation of carbocation intermediates. In this context, the
mild Lewis acidity of indium(iii) salts and their relatively low

oxophilicity[9] make them suitable candidates for the promotion of stereoselective alkylations of aromatic compounds by
the ring-opening of enantiomerically pure epoxides.
Our research group reported a highly stereoselective
alkylation of functionalized indoles with enantiomerically
pure aryl epoxides in the presence of anhydrous InBr3
(1 mol %).[10] The reaction, which proceeds exclusively
through a regio- and stereoselective SN2-type pathway at
the benzylic position of the epoxide, allows a number of b-3indolyl alcohols 3 to be isolated in high yields and with
99 % ee (Scheme 3).

Scheme 3. Regio- and stereoselective ring-opening of optically active


epoxides catalyzed by InBr3.

As a natural extension of the ring-opening of enantiomerically pure epoxides, we recently developed the first catalytic
asymmetric resolution of racemic internal aromatic oxiranes
through a carboncarbon bond-forming reaction. It was found
that 2-methylindole reacts smoothly and regioselectively with
( )-styrene oxide (1) in the presence of a catalytic amount
(5 mol %) of the commercially available [Cr(salen)Cl] complex 4 a (salen = N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine) to afford both the unreacted styrene oxide
and the indolyl derivative 5 with moderate enantiomeric
excess (55 and 56 % ee, respectively, Scheme 4 a).[11] By careful tuning of the conversion of the kinetically controlled step,
the protocol allowed functionalized internal cis and trans
epoxides to be prepared in enantiomerically pure form (up to
99 % ee) and in moderate yields (Scheme 4 b). Moreover, the
[Cr(salen)Cl] 4 a was also found able to promote the
desymmetrization of meso stilbene oxide in the presence of
variously substituted indoles. The desired b-indolyl alcohols 5
were isolated in excellent chemical yields and optical purities
(up to 98 % yield, up to 98 % ee, Scheme 5).

Marco Bandini was born in Faenza (Italy)


in 1973. He received his BSc degree
(Laurea) in 1997 from the University of
Bologna. In 1999 he spent a period in the
research group of Prof. M. R. Gagn) at
North Carolina University, Chapel Hill. In
2000 he received his PhD under the supervision of Prof. Umani-Ronchi and was appointed assistant professor at the University
of Bologna. He was the recipient of the
G.I.C.O. Junior Award of the Italian Chemical Society in 2002. His current scientific interests are focused on asymmetric synthesis
mediated by homogeneous organometallic
catalysts.

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Alfonso Melloni, born in Padova (Italy) in


1973, received his BSc in chemistry from
the University of Bologna in 1999. In 2000
he joined Prof. P. Bravo (Politecnico of Milan), working on the total synthesis of fluorinated pheromones. He is currently a PhD
student in the research group of Prof.
A. Umani-Ronchi. His research is focused on
the synthesis of optically active compounds
by employing chiral organometallic catalysts.

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the intrinsic instability of many aminomethyl and hydroxymethyl aromatic systems, polysubstitution reactions to give
bisaryl compounds of the type 6 are commonly encountered
both under homogeneous and heterogeneous catalysis
(Scheme 6).[13] After the first catalytic asymmetric addition

Scheme 6. Bisindolyl compounds 6 as side products in Lewis acid


(LA) mediated additions of indoles to carbonyl compounds.

of 1-naphthol (7) to pyruvic esters 8 mediated by the chiral


zirconocene complex 9 (Scheme 7),[5b] a considerable breakthrough in this area was made independently by Johannsen[14a]
Scheme 4. Asymmetric kinetic resolution of cis and trans epoxides
catalyzed by [Cr(salen)X] complexes. TBDMS = tert-butyldimethylsilyl,
TBME = tert-butyl methyl ether.

Scheme 7. The use of a chiral zirconocene complex 9 as the catalyst


for the addition of 1-hydroxynaphthalene (7) to the pyruvic esters 8.

Scheme 5. Enantioselective desymmetrization of meso stilbene oxide


catalyzed by [Cr(salen)X] complexes.

3. Catalytic Asymmetric Addition of Aromatic


Compounds to C=O and C=NR Groups
The addition of electron-rich aromatic compounds to
aldehydes, ketones, and imines leads to the formation of
versatile functionalized compounds.[12] However, because of
Achille Umani-Ronchi graduated in
chemistry in 1960 from the University of
Rome. He was an assistant at the Politecnico of Milan (Italy) from 1961 to 1969, then
an assistant professor at the University of
Bari. He spent one year (196465) as a
postdoctoral fellow at the ETH in Z=rich
(Prof. D. Arigoni) and six months as a postdoctoral fellow at the University of Cambridge (Prof. J. Lewis). Since 1980 he has
been a full professor of organic chemistry at
the University of Bologna. In 2002 he received the Award of the Italian Chemical
Society for his contributions to organic synthesis.

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and Mikami and co-workers.[14b] They described the synthesis


of heteroaromatic N-tosyl-a-amino acids catalyzed by tolbinap/CuPF6 (the Lectka catalyst (10), Scheme 8) and the
preparation of organofluoro compounds by the addition of
electron-rich arenes to fluoral (11) in the presence of a chiral
substituted binoltitanium complex 12 (Scheme 9), respec-

Scheme 8. Enantioselective FriedelCrafts alkylation of indoles catalyzed by the tol-binapCuI complex 10. Ts = p-toluenesulfonyl, tol-binap = bis[2,2-(di-p-tolylphosphanyl)-1,1-naphthyl].

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Scheme 9. Use of a binoltitanium complex 12 as the catalyst for the


asymmetric addition of electron-rich arenes to fluoral (11).
binol = 1,1-bis(2-naphthol).

tively. In the latter case, a notable improvement in the


catalytic effectiveness was observed when biphenols were
added as activators (asymmetric activation) to the chiral
titanium-based Lewis acid.[15]
The range of accessible enantiomerically enriched aheteroarene a-amino acids, starting from a variety of
substituted benzenes and furans, was improved remarkably
by utilizing the catalytic system 10 and a-imine esters 14 as
electrophiles.[16] In this study, several N-protecting groups
were tested, and the highest chemical yields and ee values
were observed when a readily removable N-carbamate group
was used (Scheme 10).

Scheme 11. Stereoselective syntheses of substituted mandelic esters


and heteroaromatic trifluoromethyl-substituted esters through FC
alkylations catalyzed by boxCuII complexes.

Scheme 10. Enantioselective addition of electron-rich aromatic


compounds to imines catalyzed by 10.

The synthetic versatility of the catalytic FC alkylation


was further emphasized by Jrgensen and co-workers, who
were able to obtain aromatic mandelic esters 18[17a] and
heteroaromatic hydroxytrifluoromethyl esters 20[17b] by asymmetric FC reactions of aromatic compounds to ethyl
glyoxylate (16, Scheme 11 a) and ethyl trifluoropyruvate
(19 a, Scheme 11 b), respectively. The cationic tBu-boxcopper(ii) triflate complex 17 (box = bisoxazoline) and chelating
substrates were used in these catalytic approaches to give high
stereoselectivity. Under these conditions aromatic amines,
anisoles, and heteroaromatic compounds were all found to
undergo highly enantioselective FC reactions, thus showing
the wide applicability of the catalytic system. However, lessreactive substituted furans required a higher catalyst loading
(40 mol %) for satisfactory chemical yields to be observed.[18]
Corma et al. recently studied the first example of heterogeneous catalytic asymmetric FC alkylation, in the reaction
of 1,3-dimethoxybenzene with methyl 3,3,3-trifluoropyruvate
(19 b) in the presence of a chiral Ph-boxcopper(ii) complex
covalently anchored to silica or mesoporous MCM-41 (21,
Scheme 12).[19] The use of supported catalysts furnished the
Angew. Chem. Int. Ed. 2004, 43, 550 556

Scheme 12. Chiral copper catalyst anchored to solid supports (silica,


MCM-41) as a mediator of the asymmetric alkylation of 1,3-dimethoxybenzene. conv. = conversion.

same levels of stereoselectivity (8292 % ee, 7277 % conversion) as observed in the homogeneous process
(86 % ee),[17a] and the heterogeneous catalysts could be
recovered easily by filtration. The reusability of the chiral
catalyst 21MCM-41 was also investigated, and the second
catalytic reaction afforded the same level of enantioselectivity
(84 % ee) and only a slight decrease in conversion (73 %).

4. Catalytic Asymmetric Michael-Type Addition of


Aromatic Compounds to a,b-Unsaturated Carbonyl
Compounds
a,b-Unsaturated carbonyl compounds are suitable substrates for FC alkylations, and in fact numerous acidcatalyzed Michael-type additions of aromatic compounds
have been described.[20] Nevertheless, stereoselective variants
have been less explored. The first example of highly

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enantioselective catalytic 1,4-addition of electron-rich aromatic compounds to b,g-unsaturated-a-keto esters 22, in the
presence of the chiral box-copper(ii) complex 17, was
described by Jrgensen et al. (Scheme 13).[21] Later, Zhou
and Tang demonstrated the effectiveness of the pseudo-C3-

lidinoneHX salts 27 a,b derived from (l)-phenylalanine as


organic catalysts for the 1,4-addition of pyrroles, indoles, and

aniline derivatives to a,b-unsaturated aldehydes (Scheme 15).


The LUMO-lowering activation of aldehydes by reversible
formation of chiral intermediate iminium salts 28

Scheme 13. Enantioselective conjugate addition of indoles to b,g-unsaturated a-ketoesters in the presence of the cationic tBu-boxcopper(ii)
complex 17.

symmetric trisoxazoline 25 complexed with Cu(ClO4)26 H2O


in promoting (both under anhydrous and non-anhydrous
conditions) the enantioselective addition of indole to arylidene malonates 24 (R = Ar) at 20 8C (Scheme 14).[22] The
data collected by the authors show that the presence of an
aromatic group bonded to the malonate C C double bond is
crucial for high enantioselectivity to be observed. When the
FC reaction was carried out with an alkylidene malonate (24,
R = Me), the enantioselectivity dropped to 60 % ee for the
product 26 b. Comparison of the results obtained in the
analogous reaction by Jrgensen and co-workers with the
classic bidentate C2-symmetric tBu-box ligand (maximum
ee value: 69 %)[23] shows the influence of the sidearm present
in the tridentate ligand 25.
The use of chelating substrates in combination with chiral
cationic Lewis acids is a well-known strategy to ensure high
levels of stereoselectivity. However, it also represents a
significant restriction in applicability. A Michael-type reaction between aromatic compounds and nonchelating a,bunsaturated carbonyl compounds was first reported by the
research group of MacMillan,[24] and more recently by our
research group.[25] MacMillan and co-workers elegantly
designed and employed the chiral tailored benzyl imidazo-

Scheme 15. Examples of enantioselective organocatalyzed Friedel


Crafts Michael-type addition of pyrroles, indoles, and anilines to a,bunsaturated aldehydes.

(Scheme 16) is responsible for the modulation of both


reactivity and stereoselectivity in these FC reactions. This
new metal-free approach for the catalytic and stereoselective
alkylation of electron-rich arenes proved to be general in
scope, and polyalkylation, which is the main type of side
reaction in the metallocatalyzed addition of arenes to
aldehydes, was not observed. Finally, the stereoselective 1,4-addition of indoles to crotonaldehyde
in the presence of 27 b led to a very useful synthetic
application of this strategy, allowing the synthesis of
indolobutyric acid 29 (COX-2 inhibitor) in good
yield and good optical purity (Scheme 17).
The aforementioned organocatalysis protocol is
ineffective toward the stereoselective addition of
aromatic compounds to a,b-unsaturated ketones,
which are less reactive than the corresponding
aldehydes. We recently investigated the use of the
chiral [Al(salen)Cl] complex 31 in the presence 2,6lutidine as the catalyst for the first enantioselective
addition of indoles to a,b-unsaturated aryl ketones
Scheme 14. Versatility of new chiral trisoxazoline ligands in the Michael addition of indole to
(up to 89 % ee, Scheme 18). Experimental evidence
alkylidene and arylidene malonates. The sidearm effect.
suggests that a new catalytic species, formed by

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Scheme 16. The LUMO-lowering activation of a,b-unsaturated


aldehydes by formation of chiral iminium salts 28.

Scheme 17. Organocatalyzed FriedelCrafts alkylation for the synthesis


of the COX-2 inhibitor 29.

Scheme 18. Enantioselective Michael-type addition of indoles to a,bunsaturated aryl ketones catalyzed by an [Al(salen)Cl]/2,6-lutidine complex.

complexation of the aluminum complex with the amine,


operates in the enantiodiscrimination step of the FC
alkylation.

5. Summary and Outlook


As we have seen herein, the design and development of
new catalytic and stereoselective strategies for the alkylation
of aromatic compounds have received a great deal of
attention in recent years. These strategies, which overcome
the historical drawbacks of a lack in regio- and chemoselectivity associated with FriedelCrafts alkylations, allow
easy access to several classes of polyfunctionalized enantiomerically enriched compounds, which are valuable building
blocks in organic synthesis.[26] These reactions are undergoing
continuous development. The attempt to extend the applicability of catalytic stereoselective protocols to less reactive
aromatic compounds is only one of the challenges that engage
researchers on a daily basis in one of the oldest reactions of
modern organic synthesis.
Received: July 10, 2003 [M1679]
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Chem. 2002, 67, 3700 3704; d) M. Bandini, P. Melchiorre, A.

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Melloni, A. Umani-Ronchi, Synthesis 2002, 1110 1114; e) M.


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[24] a) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123,


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[26] Some b-indolyl esters and b-indolyl aldehydes are currently
commercially available in enantiomerically pure form; see:
www.materia-inc.com.

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