Synthesis of 3,6-dimethoxybenzene-1,2-diamine and of 4,7-dimethoxy-2- methyl-1H-benzimidazole

Article abstract of DOI:10.1055/s-0028-1088049

Hydrogenation of a mixture of ortho- and para-dinitro derivatives of 1,4-dimethoxybenzene in ethyl acetate under palladium catalysis, allows 3,6-dimethoxybenzene-1,2-diamine to be isolated as the sole product; this diamine is then converted into 4,7-dimet

Full text of DOI:10.1055/s-0028-1088049

PRACTICAL SYNTHETIC PROCEDURES
1753
Synthesis of 3,6-Dimethoxybenzene-1,2-diamine and of 4,7-Dimethoxy-2-
methyl-1H-benzimidazole
3
T
, 6-Dimethoxyb
a
enzene-1,2
t
-diami
i
ne and
a
4,7-Dimeth
n
oxy-2-methy
a
l-1
H
-benzimida
z
B
ole esset, Christophe Morin*
Département de Chimie Moléculaire (CNRS, UMR-5250, ICMG FR-2607), Université Joseph Fourier,
01 Rue de la Chimie, B. P. 53, 38041 Grenoble Cedex 9, France
3
Fax +33(4)76635983 ; E-mail: Christophe.Morin@ujf-grenoble.fr
Received 11 December 2008; revised 19 February 2009
PSP
No158
Abstract: Hydrogenation of a mixture of ortho- and para-dinitro derivatives of 1,4-dimethoxybenzene in ethyl acetate under palladium
catalysis, allows 3,6-dimethoxybenzene-1,2-diamine to be isolated as the sole product; this diamine is then converted into 4,7-dimethoxy-
2
-methyl-1H-benzimidazole, a building block for the preparation of imidazobenzo(hydro)quinones.
Key words: benzimidazoles, diamines, heterocycles, hydroquinones, reduction
OMe
OMe
OMe
OMe
OMe
1
) HNO3
) H2
H2N
H2N
N
2
AcOH
96%
>70% overall
74%
N
H
OMe
1
2
Scheme 1
3
,6-Dimethoxybenzene-1,2-diamine (1) is a synthon that dressed as this could be of some help in establishing a re-
has been used for the construction of aromatics, heterocy- liable and high-yielding synthesis of 1. An efficient
1
,2
3–5
cles, and quinones of both physical and biological
preparation of benzimidazole 2, which is a building block
4
relevance; 1 is obtained after nitration/reduction of 1,4- in the synthesis of imidazobenzoquinones, from 1 is also
dimethoxybenzene (hydroquinone dimethyl ether) presented.
(
Scheme 1 and Scheme 2). Since the first mention of this
Nitration of 1,4-dimethoxybenzene has been performed
using various methods and conditions to yield a mixture
of ortho- 3 and para-isomers 4 (Scheme 3), the proportion
of which depends on the experimental conditions
6
,7
procedure, a dozen alternatives have been reported
Table 1 and Table 2), which suggest that some difficul-
(
ties exist in its preparation. A close look at the described
procedures led us to identify several points to be ad-
(
Table 1). The isolation of 3 in its pure state has been ef-
OMe
OMe
OMe
O
NC
NC
N
N
N
N
H2N
H2N
N
Ref. 1
Ref. 5
S
R
N
OMe
O
1
Ref. 2
Ref. 4
Ref. 3
R
R
O
O
OMe
O
O
N
N
N
N
OMe
OMe
O
O
R1
R1
R3
N
N
N
R
R
R2
R2
OMe
N
Scheme 2 3,6-Dimethoxybenzene-1,2-diamine as a synthon
SYNTHESIS 2009, No. 10, pp 1753–1756
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0028-1088049; Art ID: T21708SS
Georg Thieme Verlag Stuttgart · New York
©

1
754
T. Besset, C. Morin
PRACTICAL SYNTHETIC PROCEDURES
3
a,6,7
fected by crystallization from ethyl acetate
or from With regard to the reduction step to diamine 1, several
2
,4a
acetic acid, but, in our hands, using either solvent and methods have been proposed (Table 2). Due to the ease of
starting with batches of different compositions, the en- work-up,10 catalytic hydrogenation appears to be the
richment of 3 did not proceed beyond 90%.8,9 A chro- method of choice and it has been performed under pres-
matographic purification has also been proposed, but this sure in the presence of various catalysts (Table 2). As at
necessitates large quantities of adsorbent (1 kg of silica atmospheric pressure, hydrogenation with palladium as
gel for the purification of an 8 g mixture of 3/4).4p
catalyst has led to 5 and as it could be further reduced at
atmospheric pressure,3h ‘one-pot’ conditions for full re-
duction to 1 were sought. Although the reduction of 3/4 at
atmospheric pressure was slow (2–3 days), it could be
driven to completion.11 During our search for optimal
conditions, it was serendipitously discovered that, when
the reduction was carried out in ethyl acetate, pure 1 could
OMe
OMe
OMe
O2N
O2N
O2N
HNO3
+
NO2
OMe
OMe
OMe
3
4
be isolated after mere filtration of the reaction mixture on
Celite, followed by evaporation of the solvent.1
2,13
This
71%
74 %
H2
H2
avoids the indirect procedures that have been used for the
isolation of 13
c,g,4a
and sets up a high-yielding trouble-free
OMe
OMe
OMe
preparation (83% from a 9:1 mixture of dinitro isomers;
H2N
H2N
N
96% based on 3).
AcOH
H2
N
H
∆
Table 2 Reduction of Dinitro Derivatives 3/4
H2N
O2N
OMe
2
OMe
1
OMe
5
Entry Substrate Conditions
Yield Ref.
%)
(
Scheme 3 Preparation of 1 and 2
4
a
1
2
3
4
5
3
3
3
3
H , PtO , EtOH
40
2
2
Table 1 Nitration of 1,4-Dimethoxybenzene
4c
H , Raney Ni, EtOH, 50 °C
60
2
Sn (14.5 equiv), concd HCl, 100 °C
Sn (5.8 equiv), 12 M HCl, 100 °C
Sn, 12 M HCl, reflux
56b
98a
98
16d
4p
Entry Conditions
Ratio Yield Ref.
/4 (%)
3
4p
1
2
3
4
5
6
7
8
9
0
1
70% HNO , Ac O, 0 °C
45:55 95
3
2
4j
3 + 4
(40:60)
concd HNO , AcOH, r.t. then 70–80 °C –a
80
80
3a
3c
3
concd HNO , AcOH, r.t. then 90 °C
–a
6
3 + 4
SnCl (9.1 equiv),
78b
4h
3
2
(
89:11) concd HCl, 90–100 °C
16d
NO , O , CH Cl , –10 °C
54:46 81
2
3
2
2
7
8
9
3 + 4c
3
H (2–3 bar), Raney Ni, MeOH
12b
55b
12
3a
4f
3c
2
–a
–a
76
70
16c
4f
NO BF , DME, –50 °C
2
4
NH NH ·x H O, Raney Ni
2
2
2
concd HNO , Ac O, 0 °C
3
2
3 + 4c
Na S O (10 equiv),
2 2 4
THF–MeOH (1:1), reflux
b
16b
4h
2
concd HNO , 0–5 °C, 24 °C, then reflux 88:12 91.6
3
concd HNO , 0 °C, r.t., then 90 °C
89:11b 89
3 + 4c
62b
3c
2
3
10
11
H (3.45 bar), PtO , EtOH
2
2
62% HNO , 0 °C, r.t., then 100 °C
–a
–a
90c
35d
3
3
H (5 bar), 10% Pd/C, EtOAc
99
2
16e
1
1
concd HNO , AcOH, r.t., 80 °C
3 + 4c
b
16a
3
12
H (Parr apparatus), 10% Pd/C, AcOH 94
2
16f
a
Ag0.51K0.42Na0.07NO ·K Fe(CN)
45:55 35
3
3
6
Mixture of two isomers (no ratio indicated), isolated as hydrochlo-
rides.
The crude product was used as such in the next step (yield is given
(
4 equiv), 160 °C
b
a
b
c
d
Not available.
Ratio from H NMR and/or VPC.
Yield of 3.
for two steps).
Ratio not available.
1
c
Yield of 4.
With 1 in hand, we looked for its conversion into 2, a key
building block for the preparation of imidazobenzoqui-
An indirect way to 1 consists of the selective reduction of
4
3
h
nones. The synthesis of 2 is based on the general method
3
into 5, a compound that is easily purified, which is fol-
of Phillips,14 which refers to the condensation of ortho-
lowed by another reduction; however, this procedure adds
an extra step. All of the above results explain why most of
the syntheses presented in Scheme 2 were carried out
starting with a mixture of dinitro isomers 3/4.
benzenediamines with carboxylic acids. Thus, reaction of
a,j,n
1
with acetic acid gives 2,4 but our attempts to repro-
duce the described literature procedure led to impure 2
and only in fair yield.15 During attempts to improve its
Synthesis 2009, No. 10, 1753–1756 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
4,7-Dimethoxy-2-methyl-1H-benzimidazole
1755
preparation, we found that performing the reaction under Anal. Calcd for C10
H N O
12 2 2
1.97; H, 6.42, N, 14.78.
: C, 62.25; H, 6.29; N, 14.58. Found: C,
6
argon with freshly prepared 1 and using degassed acetic
acid were decisive: this led to a reliable procedure, 2 being
isolated in 96% yield.
Acknowledgment
Thus the preparations of 1 and 2 are now made simple and
high yielding (74% and 71% overall yields, respectively,
from 1,4-dimethoxybenzene), which thus improves previ-
ous procedures.
T.B. is grateful to the French ‘Ministère de l’Education Nationale,
de la Recherche et de la Technologie’ for a doctoral fellowship.
References
(
1) Nishida, J.; Naraso, M. S.; Fujiwara, E.; Tada, H.; Tomura,
M.; Yamashita, Y. Org. Lett. 2004, 6, 2007.
2) Hammershoej, P.; Reenberg, T. K.; Pittelkow, M.; Nielsen,
Pd/C was purchased from Acros (palladium on activated carbon un-
reduced 10%; specific area: 800 m /g; particle size distribution:
2
(
9
0% < 90 mm). Reactions were monitored by TLC using Al-backed
C. B.; Hammerich, O.; Christensen, J. B. Eur. J. Org. Chem.
silica gel plates (Merck, Kieselgel 60 PF ); TLC spots were visu-
2
54
2006, 2786.
alized under UV light and after spraying with 5% phosphomolybdic
acid–EtOH followed by heating. NMR spectra were recorded on a
(
3) (a) King, F. E.; Clark, N. G.; Davis, P. M. H. J. Chem. Soc.
1949, 3012. (b) Mitra, G. K.; Pathak, B. C. J. Indian Chem.
Soc. 1978, 55, 422. (c) Shaikh, I. A.; Johnson, F.; Grollman,
A. P. J. Med. Chem. 1986, 29, 1329. (d) Bock, H.;
Dickmann, P.; Herrmann, H.-F. Z. Naturforsch., B: Chem.
Sci. 1991, 46, 326. (e) Ahmad, A. R.; Mehta, L. K.; Parrick,
J. J. Chem. Soc., Perkin Trans. 1 1996, 2443. (f) Bu, X.-H.;
Liu, H.; Du, M.; Wong, K. M.-C.; Yam, V. W.-W.;
Shionoya, M. Inorg. Chem. 2001, 40, 4143. (g) Lion, C.;
Baudry, R.; Hedayatullah, M.; da Conceicao, L.; Genard, S.;
Maignan, J. J. Heterocycl. Chem. 2002, 39, 125. (h) Morin,
C.; Besset, T.; Moutet, J.-C.; Fayolle, M.; Brückner, M.;
Limosin, D.; Becker, K.; Davioud-Charvet, E. Org. Biomol.
Chem. 2008, 6, 2731.
1
Bruker Avance 300.12 spectrometer operating at 300.12 MHz ( H)
1
3
1
and 75.47 MHz ( C); internal standards (d[ H] CHCl = 7.26;
3
1
3
d[ C] CDCl = 77.0). Elemental analyses were performed by the
3
Service de Micro-Analyses, Département de Chimie Moléculaire,
Grenoble.
1
,4-Dimethoxy-2,3-dinitrobenzene (3) and 1,4-Dimethoxy-2,5-
dinitrobenzene (4)
The nitration of 1,4-dimethoxybenzene was carried out according to
ref. 2; crystallization (AcOH) afforded a mixture of 3 and 4 in 91:9
ratio.
ortho-Isomer 3
1
(4) (a) Weinberger, L.; Day, A. R. J. Org. Chem. 1959, 24,
H NMR (300 MHz, CDCl ): d = 3.92 (s, 6 H, OCH ), 7.21 (s, 2 H,
3
3
1451. (b) Taffs, K. H.; Posser, L. V.; Wigton, F. B.; Joullié,
H2, H3).
M. M. J. Org. Chem. 1961, 26, 462. (c) Zakhs, E. R.; Efros,
L. R. Zh. Org. Khim. 1966, 2, 1095. (d) Grinev, A. N.;
Zotova, S. A. A.; Bogdanova, N. S.; Nikolaeva, I. S.;
Pershin, G. N. Khim.-Farm. Zh. 1974, 8, 5; Chem. Abstr.
para-Isomer 4
1
H NMR (300 MHz, CDCl ): d = 3.97 (s, 6 H, OCH ), 7.56 (s, 2 H,
3
3
H2, H5).
,6-Dimethoxybenzene-1,2-diamine (1)
1974, 81, 25605. (e) Shaikh, I. A.; Johnson, F.; Grollman, A.
P. J. Med. Chem. 1986, 29, 329. (f) Narayan, S.; Kumar, V.;
Pujari, H. K. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 1986, 25, 267. (g) Antonini, I.; Claudi, F.; Cristalli,
G.; Franchetti, P.; Grifantini, M.; Martelli, S. J. Med. Chem.
1988, 31, 260. (h) Flader, C.; Liu, J.; Borch, R. F. J. Med.
Chem. 2000, 43, 3157. (i) Garuti, L.; Roberti, M.; Pession,
A.; Leoncini, E.; Hrelia, S. Bioorg. Med. Chem. Lett. 2001,
3
The above mixture of 3 and 4 (4 g, 17.5 mmol) in EtOAc (80 mL)
was stirred under a H atmosphere (balloon) in the presence of 10%
2
Pd/C (0.4 g) until the soln became colorless (2–3 d), at which stage
1
TLC analysis or H NMR showed the absence of intermediate 5
1
[
R = 0.71, CH Cl , orange spot; H NMR (300 MHz, CDCl ):
f
2
2
3
d = 3.82 (2 s, 6 H, CH ), 5.35 (br s, 2 H, NH ), 6.16 (d, J = 8.9 Hz,
3
2
11, 3147. (j) Alvarez, F.; Gherardi, A.; Nebois, P.; Sarciron,
1
H, H4), 6.74 (d, J = 8.9 Hz, 1 H, H5)]. After filtration over a short
M.-E.; Petavy, A.-F.; Walchofer, N. Bioorg. Med. Chem.
Lett. 2002, 12, 977. (k) Ryu, C.-K.; Song, E.-H.; Shim, J.-
Y.; You, H.-J.; Choi, K. U.; Choi, I. H. K.; Lee, E. Y.; Chae,
J. Bioorg. Med. Chem. Lett. 2003, 13, 17. (l) Hong, S.-Y.;
Chung, K.-H.; You, H.-J.; Choi, I. H.; Chae, M. J.; Han, S.
Y.; Jung, O.-J.; Kang, S.-O.; Ryu, C.-K. Bioorg. Med. Chem.
Lett. 2004, 14, 3563. (m) Garuti, L.; Roberti, M.; Pizzirani,
D.; Pession, A.; Leoncini, E.; Cenici, V.; Hrelia, S. Farmaco
pad of Celite and rinsing with a small amount of EtOAc (10 mL),
the volatiles were removed under reduced pressure to afford 1 as the
sole product (2.44 g, 83%, 96% based on 3); 1 was flushed with ar-
gon and used immediately in the next step; mp 73–74 °C.1
0
1
H NMR (300 MHz, CDCl ): d = 3.50 (br s, NH ), 3.81 (s, 6 H,
3
2
OCH ), 6.31 (s, 2 H, H4, H5).
3
1
3
C NMR (100 MHz, CDCl ): d = 55.9, 100.6, 124.6, 143.1.
3
2004, 59, 663. (n) O’Shaughnessy, J.; Aldabbagh, F.
4
,7-Dimethoxy-2-methyl-1H-benzimidazole (2)
Synthesis 2005, 1069. (o) Lavergne, O.; Fernandes, A.-C.;
Brehu, L.; Sidhu, A.; Brezak, M.-C.; Prevost, G.;
Argon was bubbled with stirring for 30 min through distilled AcOH
(
80 mL); this was then added to freshly prepared 1 (2.44 g, 12.7
Ducommun, B.; Contour-Galcera, M.-O. Bioorg. Med.
Chem. Lett. 2006, 16, 171. (p) Taleb, A.; Alvarez, F.;
Nebois, P.; Walschofer, N. Heterocycl. Commun. 2006, 12,
111. (q) Chung, K.-W.; Hong, S.-Y.; You, H.-J.; Park, R.-E.;
Ryu, C.-K. Bioorg. Med. Chem. 2006, 14, 5795. (r) Ryu,
C.-K.; Lee, R.-Y.; Lee, S.-Y.; Chung, H.-J.; Lee, S. K.;
Chung, K.-H. Bioorg. Med. Chem. Lett. 2008, 18, 2948.
mmol) and the soln was stirred under argon at 110 °C for 15 h; after
removal of AcOH acid under reduced pressure, co-evaporation with
toluene was performed twice; the residue was then washed with
Et O to afford pure 2 (2.52 g, 96%); mp 210 °C (dec) (EtOH) (Lit.
2
4
a
2
24–226 °C).
1
H NMR (300 MHz, CDCl ): d = 2.62 (s, 3 H, 2-CH ), 3.91 (s, 6 H,
3
3
(s) For closely related analogues see: Newsome, J. F.;
OCH ), 6.54 (s, 2 H, H4, H5), 6.70 (br s, NH).
3
Colucci, M. A.; Hassani, M.; Beal, H. W.; Moody, C. J. Org.
Biomol. Chem. 2007, 5, 3665.
1
3
C NMR (75 MHz, CDCl ): d = 14.6, 55.9, 102.4, 129.9, 142.6,
3
1
49.4.
Synthesis 2009, No. 10, 1753–1756 © Thieme Stuttgart · New York

1
756
T. Besset, C. Morin
PRACTICAL SYNTHETIC PROCEDURES
(
5) (a) Warren, J. D.; Lee, V. J.; Angier, R. B. J. Heterocycl.
Chem. 1979, 16, 1617. (b) Dzieduszycka, M.; Stefanska, B.;
Martelli, S.; Bontemps-Gracz, M.; Borowski, E. Eur. J. Med.
Chem. 1994, 29, 561.
(12) Hydrogenation of a 6:4 mixture of 3 and 4 was performed
under the same protocol and, here also, only diamine 1 is
isolated (51% yield; 85% based on 3).
(13) When the Celite pad was thoroughly washed with MeOH,
2,5-dimethoxybenzene-1,4-diamine was obtained together
with minor unidentified material. The 2,5-dimethoxy-
benzene-1,4-diamine was identified spectroscopically, see:
Miller, S. E.; Lukas, A. S.; Marsh, E.; Bushard, P.;
Wasielewski, M. R. J. Am. Chem. Soc. 2000, 122, 7802.
(14) Phillips, M. A. J. Chem. Soc. 1928, 2393.
(
(
(
6) Nietski, R.; Regberg, F. Ber. Dtsch. Chem. Ges. 1890, 23,
1
212.
7) Kawai, S.; Kosaka, J.; Hatano, M. Proc. Jpn. Acad. 1954, 30,
74.
7
8) Ref. 7 reads that this is a co-crystallization process and that,
provided there are no ‘small aggregates’, the separation of
‘
rhombic plates’ from ‘long columns’ can be effected by
(15) Impure 2 could not be freed from byproducts by
crystallization or by chromatography, which furthermore led
to severe losses of material.
hand.
(
9) The ratio of isomers is determined by relative integration in
1
H NMR spectra, for data see experimental.
(16) (a) Gum, W. F. Jr.; Joullié, M. M. J. Org. Chem. 1967, 32,
53. (b) Fisher, G. H.; Moreno, H. R.; Oatis, J. E. Jr.; Schultz,
H. P. J. Med. Chem. 1975, 18, 746. (c) Dwyer, C. L.;
Holzapfel, C. W. Tetrahedron 1998, 54, 7843. (d) Nose,
M.; Suzuki, H. Synthesis 2000, 1539. (e) Wu, J.; Fang, F.;
Lu, W.-Y.; Hou, J.-L.; Li, C.; Wu, Z.-Q.; Jiang, X.-K.; Li,
Z.-T.; Yu, Y.-H. J. Org. Chem. 2007, 72, 2897. (f) Mascal,
M.; Yin, L.; Edwards, R.; Jarosh, M. J. Org. Chem. 2008, 73,
6148.
(
10) The mp recorded for this material is in the range of literature
4
e
2
4a
values (68–70 °C, 75 °C, 85–87 °C ). Note that this
material is labile: darkening with time of this electron-rich
diamine has been noted previously and we found
experimentally that even after minimal exposure to air, 1
became unreactive.
(
11) A H -filled balloon is used, monitoring of the reaction can be
2
performed by TLC or NMR (for data see experimental) but,
most simply, it can be done by visual inspection as the
mixture becomes colorless when reaction is complete.
Synthesis 2009, No. 10, 1753–1756 © Thieme Stuttgart · New York