A new practical method for regioselective nucleophilic aromatic alkylation of ortho- or para-methoxy-substituted aromatic esters with Grignard reagents

Article abstract of DOI:10.1016/S0040-4039(00)02330-3

A new practical method for the regioselective nucleophilic aromatic alkylation of o- or p-methoxy-substituted aromatic carboxylic acids via their triethylcarbinyl ester derivatives by conducting the reactions with alkyl/aryl Grignard reagents in toluene has been developed.

Full text of DOI:10.1016/S0040-4039(00)02330-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1709–1712
A new practical method for regioselective nucleophilic aromatic
alkylation of ortho- or para-methoxy-substituted aromatic esters
with Grignard reagents
Tomoyuki Kojima,a Takeshi Ohishi,a Izumi Yamamoto,a Tatsuomi Matsuokab and
Hiyoshizo Kotsukia,*
aDepartment of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
bDepartment of Biology, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Received 1 November 2000; revised 27 November 2000; accepted 15 December 2000
Abstract—A new practical method for the regioselective nucleophilic aromatic alkylation of o- or p-methoxy-substituted aromatic
carboxylic acids via their triethylcarbinyl ester derivatives by conducting the reactions with alkyl/aryl Grignard reagents in toluene
has been developed. © 2001 Elsevier Science Ltd. All rights reserved.
Since the discovery of blepharismins, which exhibit an
interesting photodynamic behavior in the unicellular
organism Blepharisma,1 we have been attempting to
determine their mode of action.2 Structurally, blepharis-
mins are closely related to the naturally occurring poly-
cyclic quinones such as hypericin and stentorin, and these
compounds are now being given considerable attention
by scientists in several fields due to their characteristic
biological activities, including anti-retroviral activity.3
However, thelimitedquantitiesofbothblepharisminsand
their related quinone pigments available from natural
sourcespromptedustotrytosynthesizethesecompounds.
Scheme 1.
* Corresponding author. Tel.: +81-88-844-8298; fax: +81-88-844-8359; e-mail: kotsuki@cc.kochi-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02330-3

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T. Kojima et al. / Tetrahedron Letters 42 (2001) 1709–1712
The general utility of this procedure was further
demonstrated by using several combinations of aryl
esters and Grignard reagents (Table 2). Although cyclo-
hexylmagnesium bromide reacted quite smoothly with
3b to afford the adduct 10 in 90% yield (Run 1),
PhMgBr and n-BuMgBr furnished the products 11 and
12 in 57 and 65% yields, respectively.10 Interestingly,
whereas 2,6-dimethoxy compound 7 gave the mono-
ortho-alkylated compound 13 as the major product,
2,4,6-trimethoxy homolog 8 gave mainly the 2,6-dialky-
lated product 16. In the latter case, no para-substitu-
tion was observed. This method is particularly useful
for achieving regioselective alkylation of 1-methoxy-2-
naphthoic acid derivative 9 to produce sterically con-
gested molecules 17–19 in high yields (Runs 6–8).11
As target molecules we chose blepharismin-3 (1) and
stentorin-C (2),4 since these compounds both possess a
highly symmetrical structure and an isopropyl group on
the chromophore as a common structural unit. In pur-
suing this project, we required a facile method to obtain
p-isopropylbenzoic acid derivative A as a starting sub-
strate. Since our initial attempts based on the Friedel–
Crafts-type alkylation of 3,5-dimethoxybenzoic acid
derivatives, i.e. route B“A, did not give enough of the
product,5 we adopted a completely different strategy
using nucleophilic aromatic substitution (SNAr) toward
methoxy-substituted aryl esters, i.e. route C“A
(Scheme 1). In this paper, we describe the realization of
this idea by introducing a new protective group for
carboxylic acid.
In conclusion, we have developed a practical and useful
synthetic method for the highly regioselective alkylation
of o- or p-methoxy-substituted aromatic carboxylic
acid derivatives by taking advantage of triethylcarbinyl
ester protection for carboxylic acid and of nucleophilic
aromatic substitution at the o- or p-methoxy position
using Grignard reagents. Further studies to apply this
method to the total synthesis of blepharismins and
stentorin are now in progress.
Although there have been reports of methods to carry
out this type of transformation using aryloxazolines6 or
2,6-dialkylphenyl arylcarboxylates7 to dictate the SNAr
reaction course, these methods have some disadvan-
tages in relation to the general applicability, simplicity,
convenience for handling or easiness for deprotection.
Therefore, there is still need to explore more efficient
and concise methodologies. We found that even t-butyl
ester 3a could react sufficiently with i-PrMgCl in Et2O
at the para-position to give the desired product 4a in
51% yield accompanied by significant amounts of by-
products 5 and 6 (Table 1, Run 1).8 The reaction was
quite sensitive to the solvent used, and in toluene at
−78°C the yield of 4a was increased to 77%, albeit the
reaction was fairly slow (Run 3). In our extensive
efforts to examine the reaction conditions, we found
that the use of more-hindered triethylcarbinyl ester 3b9
was reasonably convenient for facilitating the para-
methoxy substitution in view of its effectiveness and
ready accessibility. Thus, upon treatment of 3b with 3.8
equiv. of i-PrMgCl at 0°C for 7 h, 4b was obtained in
78% yield (Run 5).
Typical experimental procedure for the preparation of
4: To a solution of ester 3b (155 mg, 0.50 mmol) in
toluene (2 ml) at 0°C was added dropwise i-PrMgCl
(0.98 M in Et2O; 1.94 ml, 1.9 mmol) under Ar, and the
mixture was stirred for 7 h at 0°C. After quenching by
adding water, the mixture was extracted with AcOEt.
The extracts were washed with brine, dried (Na2SO4),
and concentrated. The crude product was purified by
preparative TLC (hexane/acetone=4:1) to give 4 (126
mg, 78%; Rf 0.63) as a pale yellow oil. Unreacted 3b (5
mg, 3%; Rf 0.41), tertiary alcohols 5 (17 mg, 12%; Rf
0.46) and 6 (9 mg, 6%; Rf 0.27) were isolated from the
later fractions.
Table 1. Reaction of 3 with i-PrMgCl under various conditions
Run
3
Equiv. of i-PrMgCl
Solvent
Conditions
Yield (%)a
3
4
5
6
1
2
3
4
5
3a
3a
3a
3b
3b
1.5
3.0
3.0
2.0
3.8
Et2O
0°C–rt, 11 h
−78°C, 4 days
−78°C, 5 days
0°C, 23 h
0
51
61
77
68
78
27
2
5
9
12
12
3
6
9
6
CH2Cl2
Toluene
Toluene
Toluene
26
11
8
0°C, 7 h
3
a Isolated yield.

T. Kojima et al. / Tetrahedron Letters 42 (2001) 1709–1712
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Table 2. Regioselective nucleophilic aromatic alkylation of aryl esters with Grignard reagentsa
a All reactions were performed in toluene as the solvent. b Isolated yield. c Unidentified complex by-products were formed. d 15% of 3,4,6-
(MeO)3C6H2C(n-Bu)2OH was also formed. e 16% of the free carboxylic acid (13, R=H) was also isolated. f 5% of the free carboxylic acid (15,
R=H) was also isolated.
References
Acknowledgements
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This work was supported in part by a Scientific
Research Grant from the Ministry of Education, Sci-
ence, Sports and Culture of Japan (No. 10480151), and
a Grant-in-Aid for Special Scientific Research from
Kochi University.

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T. Kojima et al. / Tetrahedron Letters 42 (2001) 1709–1712
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8. To suppress ester carbonyl alkylation, the use of Cu(I)
salts caused a significant decrease in reactivity of the
reagents.
9. All triethylcarbinyl esters were prepared in almost quanti-
tative yields by reacting acyl halides with 1.2 equiv. of a
lithium salt of triethylcarbinol in THF overnight at room
temperature. Deprotection of this functional group was
achieved quantitatively by exposure to
CF3COOH in CH2Cl2. The reaction was generally com-
pleted within 4 h at rt.
5 equiv. of
10. At present, we have no clear explanation for these differ-
ences in the reactivity of Grignard reagents.
11. It is well known that the naphthalene ring is highly
susceptible to nucleophilic aromatic alkylation by
organolithium or Grignard reagents. See, for example: (a)
Shindo, M.; Koga, K.; Asano, Y.; Tomioka, K. Tetra-
hedron 1999, 55, 4955–4968; (b) Kolotuchin, S. V.;
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5. (a) Kotsuki, H.; Ohishi, T.; Inoue, M. Synlett 1998,
255–256; (b) Kotsuki, H.; Ohishi, T.; Inoue, M.; Kojima,
T. Synthesis 1999, 603–606.
.
.