Regioselective formylation of 1,3-disubstituted benzenes through in situ lithiation

Article abstract of DOI:10.1016/j.tetlet.2013.08.098

A facile method of regioselective formylation of disubstituted benzene via in situ deprotonation/metalation using n-BuLi/TMEDA/DIPA has been developed. Effect of different electron withdrawing and electron donating substituents in 1,3-interrelated aromatic system was studied; the metalation mostly occurred at the 2-position to afford the desired products in high yields.

Full text of DOI:10.1016/j.tetlet.2013.08.098

Accepted Manuscript
Regioselective formylation of 1, 3-disubstituted benzenes through in situ lith‐
iation
Le Wang, Yan Wang, Fangxu Guo, Yue Zheng, Pinaki S. Bhadury, Zhihua Sun
PII:
S0040-4039(13)01484-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.098
TETL 43461
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
28 June 2013
15 August 2013
24 August 2013
Please cite this article as: Wang, L., Wang, Y., Guo, F., Zheng, Y., Bhadury, P.S., Sun, Z., Regioselective formylation
of 1, 3-disubstituted benzenes through in situ lithiation, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.08.098
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through in situ Lithiation
∗
Le Wang, Yan Wang, Fangxu Guo, Yue Zheng , Pinaki S. Bhadury , Zhihua Sun
1-16a
1-16b
1-16c

1
Tetrahedron Letters
jo u rn al ho me p ag e : w ww .e lse vie r .c om
Regioselective formylation of 1, 3-disubstituted benzenes through in situ Lithiation
∗
Le Wang, Yan Wang, Fangxu Guo, Yue Zheng , Pinaki S. Bhadury , Zhihua Sun
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile method of regioselective formylation of disubstituted benzene via in situ
deprotonation/metalation using n-BuLi/TMEDA/DIPA has been developed. Effect of
different electron withdrawing and electron donating substituents in 1,3-interrelated
aromatic system was studied; the metalation mostly occurred at the 2-position to afford the
desired products in high yields.
Received in revised form
Accepted
Available online
Keywords:
2013 Elsevier Ltd. All rights reserved.
1
,3-disubstituted benzenes
Formylation
Regioselective Lithiation
∗
Corresponding author. Tel./fax: +86 2167791432.
E-mail: zhihuasun@sues.edu.cn or sungaris@gmail.com ( Z. Sun)

1
Introduction
optimized the reaction conditions for regioselective formylation
taking 1-fluoro-3-(trifluromethyl)benzene (Scheme 1) as the
1
Benzene was first discovered over a century ago by Kekule.
Since then, the generation, structure, and reactivity of benzene
and related aromatics have been studied in both industrial and
model compound. The course of formation of the target product
1
such as type of base employed for lithiation, molar equivalent of
the reacting components and formylating agent DMF, reaction
time and temperature were studied in THF to obtain the best
selectivity and yield of 1b.
19
b was followed by F NMR spectroscopy. Different parameters
2
academic laboratory. Regiocontrolled introduction of different
groups into benzene and benzene-like substrates bearing multiple
active sites that can lead to structural fragments of modem drugs
3
and pesticides has gained enormous significance.
It is evident from the data presented in Table 1 that under
similar reaction conditions (entries 1-6), n-BuLi and lithium
diisopropylamide (LDA) afforded much higher yield compared
to other bases e.g. lithium bis(trimethylsilyl) amide (LiHMDS)
and lithium 2,2,6,6-tetramethyl piperidide (LTMP). The
selectivity of the product 1b in relation to other regioisomers was
however slightly superior with n-BuLi.
A number of studies dealing with lithiations of 1,2- and 1,4-
4
disubstututed arenes have been conducted. However, literature
furnishes much less information regarding lithiations of 1,3-
interrelated systems, which offer selection of either of the three
5
possible ortho substitutions (C-2, C-4, and C-6). (Fig.1)
Because of harsh conditions and possibility of formation of
mixtures of positional isomers, these reactions are hard to control
in synthetic protocol. Herein, we performed a few of systematic
regioselective formylation of 1,3-disubstituted benzene bearing
different electron withdrawing or donating groups via in situ
deprotonation/metalation using n-BuLi/TMEDA/DIPA.
Having identified n-BuLi as the most suitable base for
formylation of 1a, we tried to enhance the selectivity for the
formation of regioisomer 1b in the presence of ligands
7
N,N,N′,N′-tetramethyl-1,2-ethylenediamine(TMEDA) and diiso-
8
propylamine (DIPA) . The results are depicted in entries 7-9 of
Table 1. While TMEDA in conjunction with n-BuLi helped to
improve the selectivity of the product significantly, the use of
5
% DIPA with TMEDA (1 eq.) further increased the isomeric
purity of the product (entry 9). The selectivity or yield could not
be improved significantly by altering the molar eq. of the base
and reaction time while a lower temperature was desirable for
obtaining optimal results. (entries 9-14).
Fig.1 The structure of 1,3-interrelated system
Results &Discussion
9
Under optimal conditions , the regioselective formylation of
disubstituted benzene was conduced with 1 eq. of substrate, 1.1
Since fluorine is a known ortho-directing group in aromatic
metalation and exhibits excellent physical, chemical and
6
biological properties , 1,3-disubstituted fluorinated benzene is
o
eq. each of n-BuLi and TMEDA, and 5 mol% of DIPA at -78 C
for 1.5 h..(Table 2.) For fluorinated products, the progress of the
widely studied for regioselective substitution through ortho-
lithiation . Of these various electrophilic reagents such as N,N-
1
9
reaction and regiomeric distributions were studied by F NMR
spectroscopy while non-fluorinated products were analyzed by
GC/MS.
2
dimethyl formamide (DMF), D O or carbon dioxide which are
employed for aromatic electrophilic substitution, DMF appears
to be the most convenient electrophile. At the outset, we
1
Scheme 1. Regioselective formylation of 1-fluoro-3-(trifluromethyl) benzene
a
1b
a
Table 1. Optimization of reaction conditions via Scheme 1
b
n (mole)
c
d
Yield (%)
o
T( C)
Isomer selectivity
%)
Entry
Base
t(h)
(
1
2
3
4
5
6
7
8
9
LDA
1.1
-78
-78
0
1.5
1.5
1.5
1.5
3.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1
65
nd
nd
nd
nd
71
90
78
97
69
e
e
e
e
LiHMDS
1.1
<10%
<20%
<10%
<20%
75
LiHMDS
2.2
LTMP
1.1
-78
-78
-78
-78
-78
-78
0
LTMP
4.4
n-BuLi
1.1
n-BuLi/TMEDA
n-BuLi/ DIPA
n-BuLi/TMEDA/DIPA
n-BuLi/TMEDA/DIPA
n-BuLi/TMEDA/DIPA
n-BuLi/TMEDA/DIPA
n-BuLi/TMEDA/DIPA
n-BuLi/TMEDA/DIPA
1.1/1.1
1.1/1.1
1.1/1.1/5%
1.1/1.1/5%
1.1/1.1/5%
1.5/1.1/5%
1.1/1.1/5%
1.1/1.1/5%
85
77
90
e
10
11
12
13
4
<30%
70
nd
-50
-78
-78
-78
81
70
79
90
85
87
1
2.5
83
a
General procedure. To a stirred solution of base (n equiv) in anhydrous THF was added dropwise under argon substrate 1-fluoro-3-(trifluromethyl) benzene (3
mmol) dissolved in dry THF (10 mL) at the temperature mentioned. After adding DMF (4.5 mmol, 1.5 equiv), the reaction mixture was worked up in the usual
b
manner (see the supporting information). w.r.t. the starting material. The isomeric ratio of m-1-fluoro-3-(trifluromethyl)benzaldehyde was determined by
c
19
F
d
e
NMR. overall crude yield Not determined.

1
As may be observed from the data presented in Table 2 that
in general (entries 3,4,7 and 9-12) formylation of 1,3-
disubstituted benzenes afforded the desired product with very
high crude yields and very good regioselectivities. With the
exception of 3-nitro fluorobenzene and 3-methyl fluorobenzene
using directed metalation groups such as F, Cl,
3 3
CF ,OCH ,OMOM and some excellent results were obtained
with some selected substrates. Interpretation of regioselectivities
at the the 2 or 4-position for 1,3-disubstituted systems must take
into account coordination, steric and inductive effects as well as
formation of the ortho-lithiated species. The directed ortho
(
entries 2 and 5), both electron donating and electron
2
withdrawing groups such as fluoro, chloro, trifluoromethyl,
methoxy and methoxymethyl exert an activating effect for in situ
lithiation and subsequent formylation (entries 3-12). In most
cases very high ortho-selectivity of 1,3-disubstituted benzene at
the position flanked by two substituents was observed (entries3-
metalation (DOM) reaction mechanism was preliminary
proposed (Fig.2 ), and the further research is in progress.
4,6,9-12).The relatively bulky CF group not only imposes steric
3
restrictions to the incoming electrophile adjacent to it but also
reveals a powerful π-polarization at the ortho, meta and para
Fig.2 The proposed mechanism of 1,3-interrelated system
1
0
positions. Therefore, metalation of 3-substituted trifluoromethyl
benzene occurs preferentially at the methoxy or methoxymethyl
neighboring position (entries13-15). At the same time,
fluorobenzene also was studied as a control (entry 16) which
mainly afforded formylated product at the 2-position.
In summary, A facile method of regioselective formylation of
disubstituted benzene via in situ deprotonation/metalation using
n-BuLi/TMEDA/DIPA was reported. Different combinations of
directed metalation groups for 1,3-interrelated system have been
discussed and most of them showed metalation at the 2-position.
Studies on functionalization of in situ generated lithiated
benzene to generate more useful products are currently
underway.
Given the normal electrophilic substitution rules, the preparation
of regio-controlled 2/4-formylated 1,3-disubstituted benzene can
become a challenge. Regioselective formylation was achieved
1-16a
1-16b
1-16c
a
Table 2 Regioselective formylation of 1,3-disubstituted substrate under optimal conditions
b
b
Yield
Regioisomer distribution
b or c (%) Others
Yield
Regioisomer distribution
b or c (%) Others
Entry Substrate
Entry Substrate
(%)
(%)
Cl
1
2
3
4
5
9
8
5
97 (1b)
3
85
90(9b)
10
1
CF3
c
10
11
nd
c
0
nd
99(10b)
99(11b)
99(12b)
75(13c)
94(14c)
70(15c)
9
4
9
9
0
1
9
9
9 (3b)
4(4b)
1
91
90
60
86
12
1
1
6
CF3
c
13
nd
c
25
6
<
5(5b)
nd
CF3
6
7
8
88(6b)
14
15
16
9
9
3
0
1
5
2
2
0
20
9
5(7b)
66
64
d
-
d
-
88(8b)
12
a
b
0
Under optimal conditions, the reaction was conduced with 1 eq of substrate, 1.1 eq each of n-BuLi and TMEDA, and 5 mol% of DIPA at -78 C for 1.5 h.
c
Overall crude yield. Not determined. The isomeric ratio of o-fluorobenzaldehyde was 72% .
d
Chemicals Ltd. and Shanghai Municipal Science and
Technology Commission (No.12430501300). We all thank the
financial supports from the Special Scientific Foundation for
Outstanding Young Teachers in Shanghai Higher Education
Institutions(shgcjs023), Start-up Funding of Shanghai University
Acknowledgments
Financial support of this work was provided by Shanghai Saijia

2
Pharmaceutical and Medicinal Chemistry; Imperial College
Press: London, 2012.
of Engineering Science,Innovation Program of University Students
in Shanghai University of Engineering Science (cx1104035).
7
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C.;Roger, A. R.; Jennifer, L. R. ; Collum, D. B. J. Am. Chem. Soc.
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9
.
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1
.
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General synthetic method: To a flame dried 100 mL flask was
added 1,3-disustituted benzene (3.0 mmol), TMEDA (1.1 equiv.,
;
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3
.3 mmol), DIPA (5% equiv., 0.16 mmol) and THF (10.0 mL).
o
The solution was cooled to – 78 C for 10 min and then n-BuLi
1.1 equiv., 3.3mmol) was added dropwise. Thee mixture was
(
2
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.
.
Victor, S. Chem. Rev. 1990, 90, 879-933
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was added and the mixture was further stirred for another half an
o
hour at -78 C. The mixture was allowed to warm up to room
2
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mL×3). The combined organic layers were dried over anhydrous
MgSO , filtered, and concentrated in vacuo. The regioselectivity
4
Cl-
,
H
2
2
4
5
6
.
.
.
4
(
1
9
of the crude product was ascertained by F NMR (for fluorinated
products) or by GC/MS (for non-fluorinated ones) and then
subjected to flash chromatography to obtain the desired products
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2