Bronsted acid-catalyzed nucleophilic substitution of alcohols

Article abstract of DOI:10.1002/adsc.200606183

Simple Bronsted acids such as p-toluene-sulfonic acid monohydrate (PTS) or polymer-bound p-toluenesulfonic acid efficiently catalyze the direct nucleophilic substitution of the hydroxy group of allylic and benzylic alcohols with a large variety of carbon- and heteroatom-centered nucleophiles. Reaction conditions are mild, the process is conducted under an atmosphere of air without the need for dried solvents, and water is the only side product of the reaction.

Full text of DOI:10.1002/adsc.200606183

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DOI: 10.1002/adsc.200606183
Brønsted Acid-Catalyzed Nucleophilic Substitution of Alcohols
Roberto Sanz,a,* Alberto Martínez,a Delia Miguel,a Julia M. Álvarez-Gutiérrez,a
and Félix Rodríguezb
a
Departamento de Química, Área de Química Orgánica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael
Bañuelos, s/n, 09001-Burgos, Spain
Fax: (+34)-947-258-831; e-mail: rsd@ubu.es
Instituto Universitario de Química Organometálica “Enrique Moles”, Universidad de Oviedo, C/Julián Clavería, 8,
b
33006-Oviedo, Spain
Received: April 17, 2006; Accepted: July 13, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Simple Brønsted acids such as p-toluene-
sulfonic acid monohydrate (PTS) or polymer-bound
p-toluenesulfonic acid efficiently catalyze the direct
nucleophilic substitution of the hydroxy group of al-
lylic and benzylic alcohols with a large variety of
carbon- and heteroatom-centered nucleophiles. Re-
action conditions are mild, the process is conducted
under an atmosphere of air without the need for
dried solvents, and water is the only side product of
the reaction.
on the use of transition metal complexes as catalysts.
Remarkable are the Ru-,[3] Re-,[4] and Au-catalyzed[5]
propargylation of nucleophiles with propargylic alco-
hols, the Tsuji–Trost reaction of allylic alcohols with
active methylene compounds,[6] the reaction of secon-
dary benzylic alcohols with different nucleophiles cat-
alyzed by La, Sc, or Hf salts,[7] and the Fe-, or Au-cat-
alyzed arylation of benzylic alcohols.[8] In addition,
InCl3 has emerged as a powerful catalyst to perform
direct nucleophilic substitution of allylic and benzylic
alcohols.[9]
Although the catalytic activation of alcohols is
thought to be difficult due to the poor leaving ability
of the OH group, we have recently found that simple
Brønsted acids like p-toluenesulfonic acid monohy-
drate (PTS) catalyze the direct nucleophilic substitu-
tion of propargylic alcohols.[10] Herein we report a
À
Keywords: alcohols; C C coupling; nucleophilic
substitution; supported catalysts; synthetic methods
À
The construction of C C bonds is a fundamental reac- strategy involving simple Brønsted acid-catalyzed ac-
tion in organic synthesis and coupling reactions be- tivation of allylic and benzylic alcohols as a method
À
À
tween reactive nucleophiles (NuH) and halides (RX) for the direct formation of new C C and C hetero-
or related species are one of the most used strategies. atom bonds from carbon (active methylene com-
In this context, direct substitution of the hydroxy pounds, aromatic and heteroaromatic compounds), ni-
group in alcohols by nucleophiles could be considered trogen, sulfur, and oxygen nucleophiles and alcohols.
as an ideal process because of the wide availability of Surprisingly, the Brønsted acid-catalyzed direct substi-
the starting materials and the generation of H2O as tution of allylic alcohols has not been reported in the
the only side product. However, the main limitation literature and so no systematic study has so far been
of this strategy is that an excess of sulfuric acid, poly- performed. Moreover, in some recent papers this re-
phosphoric acid,[1] or a stoichiometric amount of a action has been reported not to proceed at all.[9b]
Lewis acid[2] is required, and so the range of possible
Despite all these negative forewarnings, we decided
nucleophiles is limited. Therefore, the development of to investigate the reaction of allylic alcohol 1a as a
catalytic versions of this reaction remains as a major model substrate with selected nucleophiles 2–8 under
objective of the modern organic chemistry PTS-catalyzed conditions (Scheme 2). To our surprise,
(Scheme 1). Recent advances in this field are based all nucleophiles coupled very well with 1a when the
reaction was performed with 5 mol% of PTS as cata-
lyst in CH3CN at room temperature, affording the
substitution products 9–15 in high yields (Scheme 2
and Table 1). As shown, not only heteroatom-cen-
tered (2–4) (Table 1, entries 1–3) but also carbon-cen-
tered (5–8) nucleophiles are appropriate partners for
Scheme 1. Ideal reaction for nucleophilic substitution of al-
cohols.
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Roberto Sanz et al.
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Scheme 2. PTS-catalyzed substitution reactions of 1a with selected nucleophiles 2–8.
Table 1. Nucleophilic substitution reactions of alcohol 1a.
Entry NuH Product
Yield [%][a]
Table 1. (Continued)
Entry NuH Product
Yield [%][a]
1
2
3
2
3
4
9a
83
81
86
9
7c
8
14ac 72[c]
10a
11a
10
15a
90
[a]
[b]
[c]
Isolated yield based on the starting alcohol 1a.
Isolated yield (7.5 g) from a 30 mmol scale reaction.
Mixture of diastereoisomers (ca. 1:1).
4
5
5a
6a
12aa 75
13aa 84
this reaction. Thus, active methylene compounds 7
(Table 1, entries 7–9) and allylsilane (Table 1,
entry 10) have been successfully used. Moreover, in-
teresting Friedel–Crafts allylations of arenes
8
5
(Table 1, entry 4) or indoles 6 (Table 1, entries 5 and
6) occur with high selectivity and yield. Due to the
high interest in the regioselective alkylation of in-
doles,[11] it is remarkable that this methodology gives
rise selectively to 3-alkylated products without forma-
tion of the corresponding N- or 2-substituted indole
derivatives. It is also important to remark that these
reactions can also be performed using catalytic
amounts (5 mol%) of commercially available poly-
mer-bound p-toluenesulfonic acid. Similar or even
slightly higher yields are obtained under these condi-
tions and, moreover, the isolation of the product by
simple filtration of the solid supported acid is much
easier.[12] Also, a large-scale synthesis of 14aa was suc-
cessful (7.5 grams, 86% yield after filtration of the
solid acid and simple crystallization).
6
6b
13ab 74
7
8
7a
7b
14aa 84 (86)[b]
14ab 80
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Brønsted Acid-Catalyzed Nucleophilic Substitution of Alcohols
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In order to test the scope of the reaction with re- ported PTS in CH2Cl2 at reflux.[14] As shown in
spect to the starting allylic alcohol, we performed a Table 3, the reaction is general for different benzylic
set of experiments using differently substituted alco- alcohols 1g–j and the selected hetereoatom- and
hols 1b–f (Table 2). The reactions of the alcohols 1b carbon-centered nucleophiles.
and 1c afforded in some cases regioisomeric mixtures
Regarding the mechanism, the reactions probably
(Table 2, entries 2,4). Interestingly, alcohol 1c gave proceed through the formation of a stabilized carbo-
rise to the same products, with similar yields and re- nium intermediate and so two pathways are plausible
gioselectivity, as those obtained with 1b (Table 2, en- and probably competitive for the substitution reac-
tries 1, 2, and 4). This fact supports the same allylic tions: a direct substitution of the acid-activated alco-
cation as intermediate for both allylic alcohols. The hol and/or dimerization of the starting alcohol and
same situation is observed with cinnamyl alcohol 1e subsequent substitution.[15] The main decomposition
and a-vinylbenzyl alcohol 1f (Table 2, entries 6 and pathway of secondary benzylic alcohols is via the gen-
7). Again, very similar results were achieved by the eration of olefins as shown by the side products ob-
use of the polymer-supported PTS as catalyst with the tained in the reactions of 1g[16] and 1j (Table 3, en-
advantage of the very simple removal of the catalyst tries 3 and 10).
and the possibility of reusing it.
In summary, we have developed a PTS-catalyzed
We then turned our attention to the catalytic direct method for the direct nucleophilic substitution of hy-
nucleophilic substitutions of simple benzylic alcohols droxy groups by a range of heteroatom- and carbon-
1g–j (Table 3).[13] Several solvents and conditions were centered nucleophiles under mild conditions. The pro-
tried and we have found that optimum results were cess is conducted in an open flask, using analytical
obtained by using 10 mol% of PTS or polymer-sup- grade solvents and water is the only side product of
Table 2. PTS-catalyzed substitution reactions of allylic alcohols 1b–f.
Entry
1
Alcohol
R1
R2
Ph
NuH
Product
Yield [%][a]
77[b]
1b
Me
2
9b
2
3
1b
1b
Me
Me
Ph
Ph
3
10b (70:30)
65[b]
72
5b
12bb
4
5
1c
Ph
Me
7a[c]
14ba (75:25)
79[b]
1d
-(CH2)3-
6a[c]
13da
12ec
55
6
7
1e
1f
H
Ph
Ph
H
5c[c]
5c[c]
58[d]
64[d]
[a]
Isolated yield based on starting alcohol 1.
Independently on using 1b or 1c as starting material, similar results were obtained.
Run at reflux.
[b]
[c]
[d]
Minor amounts of the corresponding ortho-substituted product are observed.
Adv. Synth. Catal. 2006, 348, 1841 – 1845
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Roberto Sanz et al.
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Table 3. PTS-catalyzed substitution reactions of benzylic alcohols 1g–j.
Entry
1
Alcohol
NuH
Product
Yield [%][a]
81
2
9g
2
3
5b
7a
12gb
76
1g
14ga
70[b]
4
5
6
7
7b
2
14gb
9h
64
73
58
84
1h
5b
2
12hb
9i
8
9
5a
12ia
74
1i[c]
7a
3
14ia
10j
85
10
1j
65[d]
[a]
Isolated yield based on the starting alcohol 1.
[b]
[c]
[d]
15% of 1,3-diphenylbut-1-ene was also isolated.[16]
5 mol% of catalyst was used.
10% of 1,2-dihydronaphthalene was also isolated.
the reaction. This metal-free methodology offers a methods is that, in our case, the reaction can be per-
clean, environmentally friendly, synthetically competi- formed using easily available polymer-supported p-
tive, and very cheap alternative to the already estab- toluenesulfonic acid, which allows the easy isolation
lished use of metal complexes.[17] Another important of the final product and the reuse of the catalyst.[18]
advantage over other previously reported catalytic
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Brønsted Acid-Catalyzed Nucleophilic Substitution of Alcohols
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Yoshikawa, M. D. Milton, Y. Nishibayashi, S. Uemura,
Eur. J. Org. Chem. 2006, 881–890.
Experimental Section
[4] See, for instance: a) B. D. Sherry, A. T. Radosevich,
F. D. Toste, J. Am. Chem. Soc. 2003, 125, 6076–6077;
b) R. V. Ohri, A. T. Radosevich, K. J. Hrovat, C.
Musich, D. Huang, T. R. Holman, F. D. Toste, Org.
Lett. 2005, 7, 2501–2504.
[5] M. Georgy, V. Boucard, J.-C. Campagne, J. Am. Chem.
Soc. 2005, 127, 14180–14181.
[6] a) F. Ozawa, H. Okamoto, S. Kawagishi, S. Yamamoto,
T. Minami, M. Yoshifuji, J. Am. Chem. Soc. 2002, 124,
10968–10969; b) Y. Kayaki, T. Koda, T. Ikariya, J. Org.
Chem. 2004, 69, 2595–2597.
[7] M. Noji, T. Ohno, K. Fuji, N. Futaba, H. Tajima, K.
Ishii, J. Org. Chem. 2003, 68, 9340–9347.
[8] a) I. Jovel, K. Mertins, J. Kischel, A. Zapf, M. Beller,
Angew. Chem. 2005, 117, 3981–3985; Angew. Chem.
Int. Ed. 2005, 44, 3913–3917; b) J. Liu, E. Muth, U.
Flörke, G. Henkel, K. Merz, J. Sauvageau, E. Schwake,
G. Dyker, Adv. Synth. Catal. 2006, 348, 456–462; c) K.
Mertins, I. Iovel, J. Kischel, A. Zapf, M. Beller, Adv.
Synth. Catal. 2006, 348, 691–695.
[9] a) M. Yasuda, T. Saito, M. Ueba, A. Baba, Angew.
Chem. 2004, 116, 1438–1440; Angew. Chem. Int. Ed.
2004, 43, 1414–1416; b) M. Yasuda, T. Somyo, A.
Baba, Angew. Chem. 2006, 118, 807–810; Angew.
Chem. Int. Ed. 2006, 45, 793–796.
General Remarks
All reactions were carried out under air atmosphere without
any special precautions. CH3CN and CH2Cl2 were analytical
grade and purchased from SDS. 1H and 13C NMR spectra
were recorded on a Varian Mercury-Plus 300 spectrometer.
1H NMR spectra (300 MHz) were recorded in CDCl3 and
chemical shifts (d) are reported in ppm from TMS with the
residual solvent resonance as internal standard. 13C NMR
spectra (75.4 MHz) were measured using CDCl3 as the sol-
vent and the internal standard. GC-MS was performed on
an HP 6890N/5973. HR-MS was carried out on a Micromass
Autospec spectrometer. p-Toluenesulfonic acid monohy-
drate (PTS) reagent grade (98%), and p-toluenesulfonic
acid, polymer-bound (macroporous, 30–60 mesh, loading:
2.0 mmolgÀ1) were purchased from Aldrich. Other chemi-
cals were purchased from Acros, Fluka and Aldrich and
used as received.
General Procedure for Reaction of Alcohols 1 with
Nucleophiles 2–8 Catalyzed by Polymer-Bound PTS
To a mixture of the corresponding alcohol 1 (1 mmol) and
polymer-bound PTS (25 mg, 0.05 mmol) in CH3CN (5 mL),
or alternatively, polymer-bound PTS (50 mg, 0.1 mmol) in
CH2Cl2 (5 mL), was added the corresponding nucleophile 2–
8 (1.2 mmol for allyl alcohols 1a–f or 2 mmol for benzyl al-
cohols 1g–j). The reaction mixture was stirred at room tem-
perature or at reflux (see reaction conditions noted in the
text) and the completion of the reaction was monitored by
GC-MS. The mixture was filtered and the solvent was re-
moved under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent: hexane/
EtOAc) to afford the corresponding final product.
[10] R. Sanz, A. Martínez, J. M. Álvarez-Gutiérrez, F. Ro-
dríguez, Eur. J. Org. Chem. 2006, 1383–1386.
[11] See, for instance: a) X. Zhu, A. Ganesan, J. Org.
Chem. 2002, 67, 2705–2708; b) M. Bandini, A. Melloni,
A. Umani-Ronchi, Org. Lett. 2004, 6, 3199–3202.
[12] The polymer-bound acid could be reused at least for
three times without observing any loss of its activity.
[13] For a recent example on the use of benzilyc alcohols
and stoichiometric amounts of Brønsted acids for Frie-
del–Crafts reactions, see: F. Mühlthau, O. Schuster, T.
Bach, J. Am. Chem. Soc. 2005, 127, 9348–9349. For a
single example of a Friedel–Crafts reaction of a benzyl-
ic alcohol catalyzed by PTS, see ref.[8b]
Characterization data for 9–15 are listed in the Supporting
Information.
[14] No reaction was observed in DMSO, THF and DMF.
In CH3CN the Ritter-type product N-(1-phenylethyl)-
acetamide was also generated. Details will be given in
a future paper.
[15] In some cases, we have observed by GC-MS analysis
the formation of the corresponding symmetrical ether.
[16] 1,3-Diphenylbut-1-ene should be formed by the reac-
tion of styrene and phenylethyl cation, and subsequent
elimination of a proton, see ref.[7]
Acknowledgements
We gratefully thank the Ministerio de Educación y Ciencia
(MEC) and FEDER (CTQ2004–08077-C02–02/BQU) for fi-
nancial support. A. M. and D. M. thank Universidad de
Burgos and Junta de Castilla y León for predoctoral fellow-
ships. F. R. and J. M. A.-G. are grateful to MEC and the
Fondo Social Europeo (“Ramón y Cajal” contracts).
[17] PTS, reagent grade, 98%:
2 E/mol (Aldrich ref.
161993); indium(III)chloride, 98%: 1084 E/mol (Al-
AHCTREUNG
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here cited in ref.[9b]
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Adv. Synth. Catal. 2006, 348, 1841 – 1845
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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