Iron (III)-catalyzed intramolecular friedel-crafts alkylation of electron-deficient arenes with π-activated alcohols

Article abstract of DOI:10.1002/adsc.200900441

"Deficient" but "efficient", the first example of a catalytic Friedel-Crafts alkylation of arenes, carrying electron-withdrawing groups, with alcohols is reported. The optimized iron(III) chloride (97%) catalyzed allylation, benzylation and propargylation

Full text of DOI:10.1002/adsc.200900441

UPDATES
DOI: 10.1002/adsc.200900441
Iron(III)-Catalyzed Intramolecular Friedel–Crafts Alkylation of
G
Electron-Deficient Arenes with p-Activated Alcohols
Marco Bandini,a,* Michele Tragni,a and Achille Umani-Ronchia
a
Dipartimento di Chimica “G. Ciamician”, Universitꢀ di Bologna, Via Selmi 2, 40126 Bologna, Italy
Fax : (+39)-051-209-9456; phone: (+39)-051-209-9509; e-mail: marco.bandini@unibo.it
Received: June 25, 2009; Revised: August 17, 2009; Published online: October 1, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900441.
Abstract: “Deficient” but “efficient”, the first exam-
ple of a catalytic Friedel–Crafts alkylation of
arenes, carrying electron-withdrawing groups, with
alcohols is reported. The optimized ironACTHNURGTNE(NUG III) chlo-
ride (97%) catalyzed allylation, benzylation and
propargylation procedures open an access to a
range of tetrahydronaphthalenes, tetrahydroisoqui-
nolines and tetrahydrobenzo[d]azepines featuring
tertiary benzylic stereocenters in excellent yields
(up to 92%) and short reaction times.
Figure 1. Catalytic Friedel–Crafts alkylations of electron-de-
ficient arenes: a still unsolved synthetic task.
Keywords: alcohols; aromatic compounds; electron-
deficient compounds; Friedel–Crafts alkylation;
iron
The aim of the present update is to describe the
first example of the catalytic FC alkylation of elec-
tron-“deficient” arenes with alcohols.
Intramolecular allylic alkylation[5] of 1 type arenes
is a practical synthetic route to 1-vinyltetrahydro-
Friedel–Crafts (FC) alkylations are probably the most naphthalenes 2, that are valuable building blocks for
ubiquitous protocols for the functionalization of aro- the synthesis of cadinene-type sesquiterpenoids.[6] The
matic compounds.[1] Owing to the great structural di- process has been previously employed by us[7a] and
versity of naturally occurring benzenes, it is not sur- others,[7b] as a benchmark of new FC catalytic systems.
prising that for well over 130 years FC alkylations In order to address the lack of deactivated arenes in
continued to impact synthetic method development catalytic FC alkylations, we considered the readily
with noticeable recent advances in catalytic regio- prepared allylic alcohol 1a, as the model substrate. A
and stereoselective variants.[2] However, in the realm survey of organic/inorganic Brønsted acids, and metal
of FC reactions, the development of mild and efficient s-/p-acids was undertaken and a collection of results
catalytic alkylations of aromatics, carrying electron- is reported in Table 1.
withdrawing substituents, is an ongoing challenge still
to be solved.[3] This lack is still more pronounced if cently emerged in FC alkylations with alcohols and
we consider p-activated alcohols as environmentally halides[8] [i.e., InCl3, Zn
(OTf)2, Sc(OTf)3, Bi(OTf)3,
benign alkylating sources (Figure 1). AgOTf, and Au(I) complexes] gave mean yields of 2a,
As expected, most of the catalytic species, that re-
A
R
ACHTUNGTRENNUNG
The use of alcohols in FC alkylation reactions has with the occasional or predominant formation of lac-
been long known.[1] Deactivation of the catalytic spe- tone 2a’. On the contrary, the cheap and environmen-
cies via irreversible coordination to the hydroxy tally acceptable FeCl3 (10 mol%)[9] catalyzed the FC
group or to the molecules of water released during ring closure at acceptable rate and promising yield
the process, led to stoichiometric amounts of Lewis (37%, entry 11).[10]
acids (LAs) to be required. As a result, the suitability
With the aim to optimize the chemical outcome of
of alcohols in catalytic FC chemistry, has been suc- the process, several reaction parameters were
cessfully discovered only recently.[4]
screened. Interestingly, the combination of FeCl3·
Adv. Synth. Catal. 2009, 351, 2521 – 2524
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Marco Bandini et al.
UPDATES
Table 1. Optimization of the reaction conditions for the in-
tramolecular Friedel–Crafts allylic alkylation of 1a.[a]
Table 2. Scope of the reaction.[a]
Entry Alcohols
Y
Time [min] Yield of 2 [%][b]
1
2
3
4
5
6
7
8
(Z)-1b
(E)-1b
(Z)-1c
(Z)-1d
(Z)-1e
(Z)-1f
(Z)-1g
(Z)-1h
(Z)-1i
(Z)-1j
4-F
4-F
4-Cl
4-Br
3-F
4-CN
4-CO2Me 15
4-CO2Et 60
4-NO2
2-NO2
30
15
30
30
15
15
88
85
71
89
Entry Cat
Solvent/
t [h]
Yield 2a Yield 2a’
[%][b]
[%][b]
1[c]
2[c]
3[c]
4[c]
5
6
7
8
9
10
11
12[c]
13[e]
14
15
16
(RO)2P(O)OH[d] DCE/16
HCl (1M, Et2O) DCE/16
–
–
–
–
–
–
–
–
78 (66:33)[c]
71
75
75
45
43
InCl3
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Al(OTf)3
Bi(OTf)3
AgOTf
(PPh3)AuOTf
FeCl3·A(97%)
FeCl3·A(97%)
FeCl3·A(97%)
DCE/16
DCE/16
DCE/16
DCE/16
DCE/16
DCE/16
DCE/16
DCE/16
DCE/16
CH3CN/16
N
E
traces
traces
traces
traces
traces
traces
37
38
35
70
84
64
76
10
–
<5
traces
traces
–
9
10
60
60
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a]
All the reactions were carried out in reagent grade
MeNO2 under no moisture restriction.
After flash chromatography.
ACHTUNGTRENNUNG
[b]
[c]
ACHTUNGTRENNUNG
1
The ratio was determined by GC-MS and H NMR on
CHTUNGTRENNUNG
C
C
the reaction crude (see Supporting Information for de-
tails).
–
MeNO2/0.2 81
MeNO2/0.5 65
MeNO2/32 50
FeCl3 (99.99%)
FeCl2
FeACHTUNGTRENNUNG(OTf)2ACHTUNGTRENNUNG(ACN)4 CH3CN/24 65
Halogen atom-containing arenes (1b–e) cyclized
smoothly leading to the corresponding tetrahydro-
[a]
The reactions were carried out under nitrogen atmos-
phere with anhydrous solvents, unless otherwise speci- naphthalenes in excellent yields (71–89%, entries 1–5)
fied.
and moderate selectivity in the case of 3-fluoro-substi-
tuted compound 1e. Here, a mixture of 8-fluoro-1-
vinyl- and 6-fluoro-1-vinyltetrahydronaphthalene in a
33:66 ratio was obtained (see Supporting Information
for details).
[b]
[c]
[d]
[e]
After flash chromatography.
Unreacted 1a (>90%) was recovered.
(S)-1,1’-Binaphthyl-2,2’-diyl hydrogen phosphate.
Reagent grade MeNO2 was used with no moisture re-
striction.
Tolerance toward numerous electron-withdrawing
substituents was highlighted by performing the cyclo-
ACHTUNGTRENNUNG(97%) and reagent grade MeNO2 (808C) worked as alkylation of compounds 1f–j. Here, both cyano and
the best reaction conditions, leading to 2a in 81% ester moieties provided the corresponding bicyclic
yield, within 15 min reaction time (entry 13, Table 1). compounds in good yields. Also nitroarenes (1i and
Interestingly, both metal purity (entry 14) and oxi- 1j), that are commonly targeted as electrophilic re-
dation state (entries 15 and 16) of the iron source agents,[13] underwent nucleophilic allylic cyclization in
proved to be crucial for optimal chemical outcomes. decent yields (entries 9 and 10). Finally, the configura-
In particular, when highly pure FeCl3 (99.99% metal tion of the carbon-carbon double bond did not signifi-
purity, Aldrich) was employed in anhydrous nitrome- cantly influence the chemical output of the process
thane, 2a was formed to a lower extent (65% yield, (compare entries 1 and 2), calling for the presence of
30 min). Such a finding could be rationalized in terms positively charged intermediates during the reaction
of a synergic Lewis-Brønsted[11] acid co-catalysis course.
during the reaction course. On the contrary, the metal
contamination co-catalysis (generally copper), fre- shortcut for 4-vinyltetrahydro-isoquinolines 4.[14] In
quently encountered in iron(III)-promoted cross-cou- particular, the readily accessible primary alcohols 3a
plings[12] did not seem to be present in our FC-type al- and b (see supporting information for details), carry-
lylic alkylation. ing CO2Me, and CO2H groups, underwent cycloalky-
The method proved to be also a suitable synthetic
AHCTUNGTRENNUNG
Next, to prove the generality of the methods, best lation in satisfactory yields (75–86%) when treated
reaction conditions were applied to a variety of allyl with catalytic amounts of FeCl3 (10 mol%) in MeNO2
alcohols 1b–j bearing electron-deactivating groups on (Scheme 1).[15] Interestingly, the methodology has
the aromatic ring. Typical results are shown in been efficiently applied also to the construction of 7-
Table 2.
membered rings, leading to pharmacologically rele-
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Adv. Synth. Catal. 2009, 351, 2521 – 2524

IronACHTUNGTRENNUNG(III)-Catalyzed Intramolecular Friedel–Crafts Alkylation of Electron-Deficient Arenes
UPDATES
Scheme 3. Intramolecular iron-catalyzed FC benzylation and
propargylation of alcohols 3d and e.
in good yield (79%) under Fe-catalyzed FC-propargy-
lation of 3e.
In conclusion, an environmentally benign iron-cata-
lyzed Friedel-Crafts alkylation of electron-deficient
arenes with alcohols is described. Intramolecular, ally-
Scheme 1. Synthesis of tetrahydroisoquinolines and substi-
tuted tetrahydro-3-benzoazepines through iron-catalyzed in-
tramolecular Friedel–Crafts alkylation with alcohols.
vant 1-vinyltetrahydro-3-benzoazepines.[16] In this lation, benzylation and propargylation reactions were
case, the model allylic alcohol 3c, deriving from 2-(4- efficiently investigated leading to a variety of synthet-
fluorophenyl)ethylamine, smoothly underwent ring- ically useful functionalized tetrahydronaphthalenes,
closure to 4c in 69% yield after 16 h reaction time -isoquinolines and -benzo[d]azepines. Studies toward
(Scheme 1).
the application of such a methodology for the synthe-
The synthetic versatility of the protocol was under- sis of complex naturally occurring aromatic com-
lined further by considering benzylation and propar- pounds are ongoing in our laboratories.
gylation FC-type reactions. To this aim, benzylic and
propargylic alcohols 3d and e were synthesized from
readily available N-Tos-(2,2-dimethoxyethylamine) Experimental Section
5.[17] Here, initial alkylation with 4-fluorobenzyl bro-
mide followed by hydrolysis under acid conditions led Typical Procedure for the FeCl3-Catalyzed
the desired aldehyde
6 in 77% overall yield Intramolecular Friedel-Crafts Alkylation
(Scheme 2). Finally, the corresponding secondary ben-
zylic and propargylic alcohols 3d and e were obtained
in good yields (73–92%) through the condensation of
A Shlenk tube was charged with alcohol 1/3 (60 mmol) dis-
solved in 1 mL of reagent MeNO2, and 1 mg of hydrated
FeCl3 (10 mol%) dissolved in 1 mL of MeNO2. The yellow-
orange mixture was heated up to 808C for the indicated
time, then cooled to room temperature and the volatiles
evaporated under reduced pressure. The crude was directly
purified by flash chromatography (eluent: c-Hex:AcOEt,
see Supporting Information for details).
ꢀ
6 with PhMgCl or PhC CLi, respectively.
4-Phenyl-substituted tetrahydroisoquinolines are
important medicinal leads that found unprecedented
applications in the treatment of ADHD through in-
hibition of the neuronal uptake of cathecolamines.[18]
Satisfyingly, the present methodology provided a
rapid access to such a molecular architecture, in fact,
secondary benzylic alcohol 3d underwent smoothly
the FeACHTUNGTRENNUNG(III)-catalyzed ring-closing reaction leading to
4d in excellent yields (92%, Scheme 3). 4-(2-Phenyle-
thynyl)-tetrahydroisoquinoline 4e was also accessible
Acknowledgements
Acknowledgement is made to the MIUR (Rome), FIRB Proj-
ect (Progettazione, preparazione e valutazione biologica e
farmacologica di nuove molecole organiche quali potenziali
farmaci innovativi), and University of Bologna. Fondazione
del Monte di Bologna e Ravenna and NewChem S.p.A. are
kindly acknowledged for the financial support and a special
mention goes to Stefano Troisi for part of the experimental
work.
References
[1] a) Friedel–Crafts and Related Reactions, Vols. I-IV,
(Ed.: G. A. Olah), Wiley-Interscience, New York,
1963–1965; b) Friedel–Crafts Chemistry, (Ed.: G. A.
Olah), Wiley, New York, 1973; c) H. Heaney, in: Com-
prehensive Organic Synthesis, Vol. 2, (Ed.: B. M. Trost),
Pergamon Press: Oxford, 1991, p 733; d) Electrophilic
Scheme 2. Synthetic scheme for the preparation of the ben-
zylic and propargylic alcohols 3d and e.
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asc.wiley-vch.de
2523

Marco Bandini et al.
UPDATES
Aromatic Substitution, (Ed.: R. Taylor), Wiley, Chiches-
ter, 1990.
[9] a) C. Bolm, J. Legros, J. Le Paih, L. Zani, Chem. Rev.
2004, 104, 6217–6254; b) A. Fꢂrstner, R. Martin,
Chem. Lett. 2005, 34, 624–629; c) J. Kischel, K. Mer-
tins, I. Jovel, A. Zapf, M. Beller, in: Iron Catalysis in
Organic Chemistry, (Ed.: B. Plietker), Wiley-VCH,
Weinheim, 2008.
[2] For general reviews: a) K. A. Jørgensen, Synthesis
2003, 1117–1125; b) M. Bandini, A. Melloni, A.
Umani-Ronchi, Angew. Chem. 2004, 116, 560–566,
Angew. Chem. Int. Ed. 2004, 43, 550–556; c) T. B. Poul-
sen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–
2915; d) Y.-F. Sheng, A.-J. Zhang, X.-J. Zheng, S.-L.
You, Chin. Org. Chem. 2008, 28, 605–616; e) Catalytic
Asymmetric Friedel–Crafts Alkylations, (Eds.: M. Ban-
dini, A. Umani-Ronchi), Wiley-VCH, Weinheim, 2009.
[3] a) W.-B. Yi, C. Cai, J. Fluorine Chem. 2005, 126, 831–
833; b) R. Hayashi, G. R. Cook, Org. Lett. 2007, 9,
1311–1314.
[4] For general reviews see: a) N. Ljungdahl, N. Kann,
Angew. Chem. 2009, 121, 652–654, Angew. Chem. Int.
Ed. 2009, 48, 642–644; b) M. Bandini, M. Tragni, Org.
Biomol. Chem. 2009, 7, 1501–1507.
[5] Z. Lu, S. Ma, Angew. Chem. 2008, 120, 264–303,
Angew. Chem. Int. Ed. 2008, 47, 258–297.
[10] For representative examples of iron-catalyzed FC-alky-
lations see: a) I. Iovel, K. Mertins, J. Kischel, A. Zapf,
M. Beller, Angew. Chem. 2005, 117, 3981–3985;
Angew. Chem. Int. Ed. 2005, 42, 3919–3927; b) Z.
Zhan, J. Yu, H. Liu, Y. Cui, R. Yang, W. Yang, J. Li, J.
Org. Chem. 2006, 71, 8298–8301; c) T. Itoh, H. Uehara,
K. Ogiso, S. Nomura, S. Hayase, M. Kawatsura, Chem.
Lett. 2007, 36, 50–51; d) U. Jana, S. Maiti, S. Biswas,
Tetrahedron Lett. 2007, 48, 7160–7163; e) D. Stadler, T.
Bach, Angew. Chem. 2008, 120, 7668–7670, Angew.
Chem. Int. Ed. 2008, 47, 7557–7560; f) Z. Wang, X.
Sun, J. Wu, Tetrahedron 2008, 64, 5013–5018; g) S. En-
thaler, K. Junge, M. Beller, M. Angew. Chem. 2008,
120, 2531–2535, Angew. Chem. Int. Ed. 2008, 47, 3913–
3917; h) W. Huang, L.-C. Hong, P.-Z. Zheng, R.-T. Liu,
X.-G. Zhou, Tetrahedron 2009, 65, 3603–3610.
[11] The formation of HCl during the catalytic cycle, from
partial hydrolysis of FeCl3 cannot be ruled out.
[12] S. L. Buchwald, C. Bolm, Angew. Chem. 2009, 121,
5694–5695, Angew. Chem. Int. Ed. 2009, 48, 5586–
5587, and references cited therein.
[6] L. F. Tietze, T. Raschke, Synlett 1995, 597–598, and ref-
erences cited therein.
[7] a) M. Bandini, A. Eichholzer, P. Kotrusz, M. Tragni, S.
Troisi, A. Umani-Ronchi, Adv. Synth. Catal. 2009, 351,
319–324; b) K. Namba, H. Yamamoto, I. Sasaki, K.
Mori, M. Nishizawa, Org. Lett. 2008, 10, 1767–1770.
[8] For representative examples: a) T. Tsuchimoto, K.
Tobita, T. Hiyama, S. Fukuzawa, J. Org. Chem. 1997,
62, 6997–7005; b) A. V. Malkov, P. Spoor, V. Vinader,
[13] S. Błaz˙ej, M. Ma˛kosza, Chem. Eur. J. 2008, 14, 11113–
11122.
ˇ
P. Koc ovsky, J. Org. Chem. 1999, 64, 5308–5311; c) M.
[14] a) A. R. Katritzky, S. Rachwal, B. Rachwal, Tetrahe-
dron 1996, 52, 15031–15070; b) M. Chrzanowska, M. D.
Rozwadowska, Chem. Rev. 2004, 104, 3341–3370;
c) E. L. Larghi, T. S. Kaufman, Synthesis 2006, 187–
220.
[15] Attempts to extend the protocol to the preparation of
isochromans, failed, leading to decomposition of the
starting material.
[16] a) Y. Shimada, N. Taniguchi, A. Matsuhisa, K. Sakamo-
to, T. Yatsu A. Tanaka, Chem. Pharm. Bull. 2000, 48,
1644–1651; b) U. Wirt, R. Frçhlich, B. Wꢂnsch, Tetra-
hedron: Asymmetry 2005, 16, 2199–2202, and referen-
ces cited therein; c) M. V. Dorogov, S. A. Ivanovsky,
M. Y. Khakhina, D. V. Kravchenko, S. E. Tkachenko,
A. E. Ivachtchenko, Synth. Commun. 2006, 36, 3525–
3535; d) S. Nakagawa, K. Suzuki, T. Mukai, PCT Int.
Appl. WO 2008156217, 2008.
Kimura, M. Futamata, R. Mukai, Y. Tamaru, J. Am.
Chem. Soc. 2005, 127, 4592–4593; d) J. Choudhury, S.
Podder, S. Roy, J. Am. Chem. Soc. 2005, 127, 6162–
6163; e) K. Mertins, I. Iovel, J. Kischel, A. Zapf, M.
Beller, Angew. Chem. 2005, 117, 242–246 Angew.
Chem. Int. Ed. 2005, 42, 238–242; f) B. M. Trost, J.
Quancard, J. Am. Chem. Soc. 2006, 128, 6314–6315;
g) A. B. Zaitsev, S. Gruber, P. S. Pregosin, Chem.
Commun. 2007, 4692–4693; h) H. Matsuzawa, Y.
Miyake, Y. Nishibayashi, Angew. Chem. 2007, 119,
6608–6611, Angew. Chem. Int. Ed. 2007, 46, 6488–
6491; i) H. Matsuzawa, K. Kanao, Y. Miyake, Y. Nishi-
bayashi, Org. Lett. 2007, 9, 5561–5564; j) W. Rao,
P. W. H. Chan, Org. Biomol. Chem. 2008, 6, 2426–
2433; k) A. B. Zaitsev, S. Gruber, P. A. Plꢂss, P. S. Pre-
gosin, L. F. Veiros, M. Wçrle, J. Am. Chem. Soc. 2008,
130, 11604–11606; l) I. Usui, S. Schmidt, M. Keller, B.
Breit, Org. Lett. 2008, 10, 1207–1210; m) Y.-L. Liu, L.
Liu, Y.-L. Wang, Y.-C. Han, D. Wang, Y.-J. Chen,
Green Chem. 2008, 10, 635–640.
[17] N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450–
451.
[18] B. F. Molino, B. Berkowitz, M. Cohen, U.S. Pat. Appl.
Publ. US2006111385, 2006.
2524
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2521 – 2524