Gold-catalyzed etherification and friedel - Crafts alkylation using ortho-alkynylbenzoic acid alkyl ester as an efficient alkylating agent

Article abstract of DOI:10.1021/ol701861d

A gold-catalyzed alkylation of alcohols and aromatic compounds is described. The reaction of ortho-alkynylbenzoic acid alkyl esters with alcohols or aromatic compounds occurs in the presence of catalytic amounts of Ph ₃PAuCl and AgOTf under mild conditions to produce corresponding ethers or Friedel-Crafts alkylation products in good to high yields. The reaction likely proceeds through the gold-induced in situ construction of leaving groups and subsequent nucleophilic attack of alcohols or aromatic compounds.

Full text of DOI:10.1021/ol701861d

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4299-4302
Gold-Catalyzed Etherification and
Friedel Crafts Alkylation Using
−
ortho-Alkynylbenzoic Acid Alkyl Ester
as an Efficient Alkylating Agent
Naoki Asao,*,†,‡ Haruo Aikawa,† Sakie Tago,† and Kazuteru Umetsu†
Department of Chemistry, and Research and Analytical Center for Giant Molecules,
Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
asao@mail.tains.tohoku.ac.jp
Received August 1, 2007
ABSTRACT
A gold-catalyzed alkylation of alcohols and aromatic compounds is described. The reaction of ortho-alkynylbenzoic acid alkyl esters with
alcohols or aromatic compounds occurs in the presence of catalytic amounts of Ph3PAuCl and AgOTf under mild conditions to produce
corresponding ethers or Friedel−Crafts alkylation products in good to high yields. The reaction likely proceeds through the gold-induced in
situ construction of leaving groups and subsequent nucleophilic attack of alcohols or aromatic compounds.
Lewis acid-catalyzed substitution reaction is one of the most
fundamental and useful bond-forming methods in organic
synthesis.1 Generally, Lewis acids activate electrophiles by
their strong affinities toward heteroatoms of the leaving
groups, such as acetal and epoxide. We are interested in the
possibility of applying the alkynophilicity of a gold catalyst
to a substitution reaction.2,3 In this paper, we report a gold-
catalyzed alkylation of alcohols and aromatic compounds by
using ortho-alkynylbenzoic acid alkyl ester 1, leading to ether
and Friedel-Crafts alkylation products in good to high yields
under very mild reaction conditions (Scheme 1).
We have previously reported a gold-catalyzed benzannu-
lation between ortho-alkynylbenzaldehydes and alkynes,
which produced naphthyl ketones in good to high yields.4
On the basis of these results, we envisaged that ortho-
alkynylbenzoic acid alkyl ester might behave as an effective
Scheme 1
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
(1) For reviews, see: Lewis Acids in Organic Synthesis; Yamamoto, H.,
Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vols. 1-2.
(2) For recent reviews on the Au-catalyzed reactions, see: (a) Hoffmann-
Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (b) Zhang, L.;
Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271. (c) Hashmi, A.
S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (d) Jime´nez-
Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (e) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395.
electrophile when it is treated with proper nucleophiles in
the presence of the gold catalyst. Then, we examined the
(4) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J.
Am. Chem. Soc. 2002, 124, 12650. (b) Asao, N.; Nogami, T.; Lee, S.;
Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921. (c) Asao, N.; Aikawa,
H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458. (d) Asao, N. Synlett
2006, 1645.
(3) (a) Georgy, M.; Boucard, V.; Campagne, J.-M. J. Am. Chem. Soc.
2005, 127, 14180. (b) Hotha, S.; Kashyap, S. J. Am. Chem. Soc. 2006,
128, 9620.
10.1021/ol701861d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/20/2007

reaction of ortho-alkynylbenzoic acid benzyl esters 1a,b with
phenethyl alcohol 2a under several conditions, and the results
are summarized in Table 1. To our delight, treatment of 1a
entries 4-7, isocoumarins 5 were formed nearly quantita-
tively in each reaction, which would be generated by the
gold-catalyzed electrocyclization of 1 (vide infra).5 The
reaction also proceeded smoothly when 3 equiv of 1a was
used over 2a (entry 8). In the current catalyst system, TfOH
might be produced. However, no reaction occurred with a
catalytic amount of TfOH (entry 9).
Table 1. Gold-Catalyzed Synthesis of Ethersa
To know the scope of the current etherification, we
examined reactions with various combinations of esters 1
and alcohols 2, and the results are shown in Table 2. The
yield (%)b
Table 2. Gold-Catalyzed Synthesis of Ethersa
entry
1
cat.
solvent
time 3a
4
1c
2c
3c
4
5
6
7
8e
9
1a AuBr3
(ClCH2)2 3 h
21
64
0
86
84
81
87
80
0
0d
7
0
7
8
9
6
12
0f
1a Ph3PAuCl-AgOTf (ClCH2)2 3 h
1a Ph3PAuCl (ClCH2)2 3 h
1a Ph3PAuCl-AgOTf (ClCH2)2 12 h
1a Ph3PAuCl-AgOTf C6H6
1a Ph3PAuCl-AgOTf C6H5Cl
1b Ph3PAuCl-AgOTf C6H5Cl
1b Ph3PAuCl-AgOTf C6H5Cl
yield
1 h
1 h
1 h
1 h
1 h
of 3
entry
1
R
R1
2
R2OH
conditions
(%)b
1c
2c
1c Ph
C12H25 2b C12H25OH
80 °C, 5 h 3b 50
80 °C, 12 h 3b 80
80 °C, 18 h 3b 86
1d o-anisyl C12H25 2b C12H25OH
3c,d 1d o-anisyl C12H25 2b C12H25OH
1b TfOH
C6H5Cl
4
5
6
7
8
9
1e Bu
1f Bu
1b Bu
1b Bu
1f Bu
1b Bu
iPr
2a PhCH2CH2OH rt, 12 h
3c 73
3d 92e
3e 70f,g
3f 90
3g 70h
3h 70i
3i 69j
a The reaction was carried out using 1 (1 equiv) and 2a (3 equiv) in the
PMB 2a PhCH2CH2OH rt, 1 h
PhCH2 2c c-C6H11OH
PhCH2 2d t-BuOH
PMB 2e EtOCOCH2OH rt, 1 h
PhCH2 2f AcO(CH2)2OH rt, 1 h
PMB 2g
presence of catalyst (5 mol %) at rt unless otherwise noted. b Determined
rt, 3 h
rt, 1 h
1
by H NMR spectra using p-xylene as an internal standard. c The reaction
was carried out using 1a (1 equiv) and 2a (1.5 equiv) in the presence of
catalyst (10 mol %) at rt. d 1a was recovered in 50% yield. e The reaction
was conducted using 1b (3 equiv) and 2a (1 equiv). f 1b was recovered
nearly quantitatively.
10 1f Bu
rt, 1 h
11 1b Bu
PhCH2 2h NC(CH2)2OH rt, 16 h
3j 75i
a The reaction was carried out using 1 (1 equiv) and 2 (3 equiv) in the
presence of Ph3PAuCl (5 mol %) and AgOTf (5 mol %) in C6H5Cl unless
otherwise mentioned. b Isolated yields. c The reaction was conducted in
C6H6. d The reaction was conducted using 1d (3 equiv) and 2b (1 equiv).
e 6 was obtained in 8% yield. f 4 was obtained in 9% yield. g Determined
by 1H NMR spectra using p-xylene as an internal standard. h 6 was obtained
in 9% yield. i 4 was obtained in 7% yield. j 6 was obtained in 12% yield.
(1 equiv) with 2a (1.5 equiv) in the presence of 10 mol %
of AuBr3 at rt for 3 h resulted in the formation of the desired
benzyl phenethyl ether 3a in 21% yield. Besides 3a,
isocoumarin 5a (R ) Ph) and the recovered starting material
1a were obtained in 28 and 50% yields, respectively (entry
1). The chemical yield of 3a was improved significantly by
cationic gold catalyst, derived from Ph3PAuCl and AgOTf,
and 3a was obtained in 64% yield along with a small amount
of dibenzyl ether 4 (entry 2). To know the effect of the
alkynyl group of 1a, the reaction of benzyl benzoate, having
no alkynyl group at the ortho-position, with 2a was
examined. As we anticipated, no reaction occurred, and the
benzyl ester was recovered nearly quantitatively. These
results clearly indicate that the alkynyl group of 1a is
essential for the current etherification. Other silver additives,
such as AgBF4 and AgSbF6, were less effective. Without
silver catalysts, no reaction took place (entry 3). While the
use of 3 equiv of 2a and 5 mol % of catalyst increased the
chemical yield, a longer reaction time was needed for
completion (entry 4). Interestingly, when the solvent was
changed from (CH2Cl)2 to benzene or chlorobenzene, the
reaction was dramatically accelerated and 3a was obtained
in high yields within a shortened period (1 h) (entries 5 and
6). Besides 1a, ortho-hexynylbenzoic acid benzyl ester 1b
works well as an effective alkylating agent (entry 7). In
reaction of primary alkyl ester 1c with dodecanol 2b did
not give any products in benzene at rt. However, when the
reaction was conducted at 80 °C for 5 h, etherification
proceeded to give didodecyl ether 3b in 50% yield (entry
1). Interestingly, the chemical yield was increased up to 86%
by changing the substituent at the terminus of the alkynyl
moiety of 1 from a phenyl group to an ortho-anisyl group
(entries 2 and 3). Other examined reactions proceeded
smoothly at rt to give the corresponding ether products in
good to high yields (entries 4-11). The reactions with
p-methoxybenzyl (PMB) ester 1f afforded the corresponding
ethers in good to high yields together with a small amount
of 4-(4-methoxybenzyl)-3-butyl-1H-isochromen-1-one 6 (en-
tries 5, 8, and 10).6 It is noteworthy that ester, ketone, and
nitrile groups in 2e-h were inert during the reaction and
the corresponding products 3g-j were obtained in good
yields, respectively (entries 8-11). A large number of
(5) Electrocyclization of ortho-alkynylbenzoic acid alkyl ester has been
reported for synthesis of isocoumarin. For examples, see: (a) Oliver, M.
A.; Gandour, R. D. J. Org. Chem. 1984, 49, 558. (b) Rossi, R.; Carpita,
A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron 2003, 59, 2067. (c)
Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936.
4300
Org. Lett., Vol. 9, No. 21, 2007

catalytic etherification methods have been reported on the
basis of the substitution reactions.7 Dehydration of alcohols
with metal catalysts is a direct approach for the synthesis of
ethers, and such protocols have been recently studied.8
Transition-metal-catalyzed allylic and propargylic etherifi-
cation reactions are also attractive.9 However, there are still
limitations on substrates and drawbacks such as the require-
ment of elevated temperature and long reaction time in the
known procedures. In contrast, neither severe reaction
conditions nor highly reactive electrophiles are necessary in
the current catalytic system.
Scheme 3
excess was 37%, which suggests that the reaction between
1g and 2i involves SN1 mechanism having some SN2
character.
On the basis of these results, a plausible mechanism is
illustrated in Scheme 4. The coordination of the triple bond
The current etherification was applied to the synthesis of
cyclic ether compounds. Treatment of 7a with the gold
catalyst resulted in the formation of the corresponding six-
membered cyclic ether product 8a in 86% yield. On the other
hand, no reaction occurred with 7b, which has no alkynyl
group at the ortho-position. The reactions of 7c and 7d also
gave the corresponding products 8b and 8c in 90 and 100%
yields, respectively (Scheme 2).
Scheme 4
Scheme 2
of 1 to the gold catalyst enhances the electrophilicity of
alkyne, and the subsequent nucleophilic attack of the
carbonyl oxygen to the electron-deficient alkyne would form
the zwitterionic intermediate 10.11,12 Due to the enhanced
leaving ability of the isocoumarin moiety, the nucleophilic
attack of alcohol 2 to 10 would occur to give ether compound
3 together with isocoumarin 5.
We next turned our attention to the Friedel-Crafts
alkylation.13 Generally, alkylation of π-rich heteroaromatics,
such as furan, is difficult under the traditional Friedel-Crafts
conditions because of catalyst-promoted polymerization and
polyalkylation.14 Recently, some effective catalysts, such as
lanthanide triflates15 and transition metal catalysts,16 have
From a mechanistic point of view, we investigated the
reaction of (S)-1g (99% ee) with MeOH 2i (Scheme 3). The
reaction proceeded smoothly at rt for 1 h in CH2Cl2, and the
corresponding ether 3k was obtained in 78% yield. The
absolute configuration of 3k was determined to be R by
comparison of the observed optical rotation to a literature
value for (R)-(1-methoxyethyl)benzene.10 The enantiomeric
(6) PtCl2-catalyzed cyclization of benzoic acid ester through car-
boalkoxylation of the alkyne has been reported; see: Fu¨rstner, A.; Davies,
P. W. J. Am. Chem. Soc. 2005, 127, 15024. For recent other examples of
metal-catalyzed intramolecular carboalkoxylation of alkynes, see: (a)
Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127,
15022. (b) Dube´, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 12062.
(7) For examples of catalytic etherifications, see: (a) Kashman, Y. J.
Org. Chem. 1972, 37, 912. (b) Doyle, M. P.; DeBruyn, D. J.; Kooistra, D.
A. J. Am. Chem. Soc. 1972, 94, 3659. (c) Tsunoda, T.; Suzuki, M.; Noyori,
R. Tetrahedron Lett. 1979, 20, 4679. (d) Iversen, T.; Bundle, D. R. J. Chem.
Soc., Chem. Commun. 1981, 1240. (e) Kato, J.; Iwasawa, N.; Mukaiyama,
T. Chem. Lett. 1985, 743. (f) Olah, G. A.; Yamato, T.; Iyer, P. S.; Prakash,
G. K. J. Org. Chem. 1986, 51, 2826. (g) Olah, G. A.; Shamma, T.; Prakash,
G. K. S. Catal. Lett. 1997, 46, 1. (h) Gray, W. K.; Smail, F. R.; Hitzler, M.
G.; Ross, S. K.; Poliakoff, M. J. Am. Chem. Soc. 1999, 121, 10711. (i)
Mahrwald, R.; Quint, S.; Scholtis, S. Tetrahedron 2002, 58, 9847. (j) Rai,
A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267. (k) Aoki, H.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 2006, 79, 1255. (l) Kuethe, J. T.; Marcoux, J.-F.;
Wong, A.; Wu, J.; Hillier, M. C.; Dormer, P. G.; Davies, I. W.; Hughes,
D. L. J. Org. Chem. 2006, 71, 7378.
(8) For examples of metal-catalyzed dehydration of alcohols, see: (a)
Nishibayashi, Y.; Wakiji, I.; Hidai, M. J. Am. Chem. Soc. 2000, 122, 11019.
(b) Sherry, B. D.; Radosevich, A. T.; Toste, F. D. J. Am. Chem. Soc. 2003,
125, 6076. (c) Miller, K. J.; Abu-Omar, M. M. Eur. J. Org. Chem. 2003,
1294. (d) Shibata, T.; Fujiwara, R.; Ueno, Y. Synlett 2005, 152. (e) Bustelo,
E.; Dixneuf, P. H. AdV. Synth. Catal. 2007, 349, 933. (f) Corma, A.; Renz,
M. Angew. Chem., Int. Ed. 2007, 46, 298.
(9) For reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003,
103, 2921. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (c) Miyabe, H.;
Takemoto, Y. Synlett 2005, 1641.
(10) Yoshida, M.; Weiss, R. G. Tetrahedron 1975, 31, 1801.
(11) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed.
2004, 43, 1239.
(12) Kusama, H.; Iwasawa, N. Chem. Lett. 2006, 35, 1082.
(13) (a) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley: New
York, 1963. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem.,
Int. Ed. 2004, 43, 550.
Org. Lett., Vol. 9, No. 21, 2007
4301

been reported for functionalization of aromatic compounds
based on the substitution reactions. However, they still have
drawbacks such as the necessity of high temperature and long
reaction time. In this context, we examined the gold-catalyzed
alkylation of furan, and the results are summarized in Table
3.17 When esters 1a,h were treated with furans 11a,b in the
1i with 11b gave a mixture of 12da and 12db in 61% yield
with a 7:3 ratio (entry 4).
Intramolecular Friedel-Crafts alkylation reaction is well-
known as a useful synthetic method of cyclic compounds.18
However, only a few examples have been known for the
synthesis of tetralines from primary alkyl halides, alcohols,
and their derivatives.19 It is worth mentioning that the gold-
catalyzed reaction of 13a proceeded at 100 °C for 7 h and
14a was obtained in 70% yield. The introduction of a
methoxy group on the phenyl group accelerated the reaction,
and the corresponding product 14b was obtained in 81%
yield under 100 °C for 2 h (Scheme 5).
Table 3. Gold-Catalyzed Friedel-Crafts Alkylation of Furana
Scheme 5
yield of
12 (%)b
entry
1
R1
PhCH2
PhCH2
PMB
11
R2
1c
2
3
1a
1a
1h
1i
11a
11b
11b
11b
H
12a
12b
12c
12d
70
80
72
61 (7:3)d
Me
Me
Me
4
PhCHdCHCH2
a The reaction was carried out using 1 (1 equiv) and 11 (5 equiv) in the
presence of Ph3PAuCl (5 mol %) and AgOTf (5 mol %) in C6H5Cl at rt
within 1 h unless otherwise noted. b Isolated yields. c The reaction was
conducted with 10 equiv of 11a. d The ratio of 12da and 12db.
In summary, we have developed a new catalytic, practical
etherification method of alcohols with a designed ortho-
alkynylbenzoic acid alkyl ester 1 as an effective alkylating
agent. The reaction likely proceeds through the gold-induced
in situ construction of leaving groups and subsequent
nucleophilic attack of alcohols. The synthetic utility of the
current protocol is further enhanced by its ability to promote
the Friedel-Crafts alkylation under mild conditions. Further
studies to extend the scope of synthetic utility are in progress
in our laboratory.
presence of the gold catalyst at rt for 1 h, the alkylations
occurred smoothly at C2-position of the furan rings and the
corresponding products 12a-c were obtained in good yields,
respectively (entries 1-3). The reaction of cinnamyl ester
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Exploratory Research (No. 18655009)
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
(14) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd
ed.; Chapman and Hall: London, 1995; p 278.
(15) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem.
ReV. 2002, 102, 2227.
(16) For selected examples of transition-metal-catalyzed Friedel-Crafts
alkylations, see: (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell,
W. L.; Kocˇovsky´, P. J. Org. Chem. 1999, 64, 2751. (b) Nishibayashi, Y.;
Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002,
124, 11846. (c) Kennedy-Smith, J. J.; Young, L. A.; Toste, F. D. Org. Lett.
2004, 6, 1325. (d) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964. (e)
Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 13596. (f) Iovel, I.; Mertins,
K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913.
(g) Choudhury, J.; Podder, S.; Roy, S. J. Am. Chem. Soc. 2005, 127, 6162.
(h) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. AdV. Synth. Catal.
2006, 348, 691.
Supporting Information Available: Characterization
data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL701861D
(18) Bandini, M.; Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J. Org.
Chem. 2006, 3527.
(17) (a) Peter, H.; Rodriguez, H.; Muller, B.; Sibral, W.; Bickel, H. HelV.
Chim. Acta 1974, 57, 2024. (b) Cottineau, B.; Chenault, J.; Guillaumet, G.
Tetrahedron Lett. 2006, 47, 817.
(19) (a) Bogert, M. T.; Davidson, D. J. Am. Chem. Soc. 1934, 56, 185.
(b) Kropp, P. J.; Breton, G. W.; Craig, S. L.; Crawford, S. D.; Durland, W.
F., Jr.; Jones, J. E., III; Raleigh, J. S. J. Org. Chem. 1995, 60, 4146.
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