Novel and highly regioselective Friedel-Crafts alkylation of 3,5-dimethoxyaniline using an aldehyde and triethylsilane as reducing agent

Article abstract of DOI:10.1055/s-2008-1078207

A novel and highly regioselective Friedef-Crafts alkylation, producing p-alkyl 3,5-dimethoxyanilines by the reaction of aldehydes with 3,5-dimethoxyaniline in the presence of trifluoroacetic acid and triethylsilane as reducing agent is reported. This procedure is lauded by its high regioselectivity, simplicity, and adaptability to aromatic, heteroaromatic, and aliphatic aldehydes. This reaction represents a useful way to prepare a variety of 4-substituted 3,5-dimethoxyanilines of potential pharmacological interest. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078207

LETTER
2429
Novel and Highly Regioselective Friedel–Crafts Alkylation of 3,5-Dimethoxy-
aniline Using an Aldehyde and Triethylsilane as Reducing Agent
N
ovel and
o
H
ighly Regi
h
oselective Fr
n
iedel–Crafts Alkyl
K
ation of 3,5-Dime
a
thoxyanilin
l
e
likat Augustine,*a,b Yanjerappa Arthoba Naik,b Ashis Baran Mandal,a Padma Alagarsamy,a Vani Akabotea
a
Syngene International Ltd., Biocon Park, Plot Nos. 2 and 3, Bommasandra IV Phase, Jigani Link Road, Bangalore – 560 100, India
Fax +91(80)28083150; E-mail: john.kallikat@syngeneintl.com
b
Department of Chemistry, Kuvempu University, Shankaraghatta Post, Shimoga – 577 451, India
Received 19 May 2008
thesis of para-methyl and para-ethyl 3,5-dimethoxya-
nilines have been reported by Barbara Roth and co-
workers via a multistep reaction,5 the lack of an efficient
method to prepare the other alkyl analogues prompted us
Abstract: A novel and highly regioselective Friedel–Crafts alkyl-
ation, producing p-alkyl 3,5-dimethoxyanilines by the reaction of
aldehydes with 3,5-dimethoxyaniline in the presence of trifluoro-
acetic acid and triethylsilane as reducing agent is reported. This pro-
cedure is lauded by its high regioselectivity, simplicity, and to develop a practical process for the synthesis of these
adaptability to aromatic, heteroaromatic, and aliphatic aldehydes.
This reaction represents a useful way to prepare a variety of 4-sub-
stituted 3,5-dimethoxyanilines of potential pharmacological inter-
in activated anilines.6 Similarly, Black and co-workers
est.
key intermediates. To our interest, Roth and Kok have
claimed that substitution para to the amino group occurs
have reported the formation of symmetrical para-substi-
Key words: Friedel–Crafts alkylation, regioselective, triethyl-
silane, activated aniline, nucleophilic
tuted product in aqueous solvent (Figure 2), while work-
ing with 3,5-dimethoxyaniline and ninhydrin.4
O
Activated anilines are synthetically versatile substrates in
MeO
HO
organic chemistry, as they possess multiple nucleophilic
sites. 3,5-Dimethoxyaniline is a classical example of acti-
vated anilines, where it is proven to be a versatile building
block for the construction of molecules that possess anti-
mitotic activity,1 protein kinase inhibitory activity,2 and as
key intermediate in the synthesis of selective estrogen re-
ceptor beta modulators.3 The reaction of 3,5-dimethoxy-
aniline and ninhydrin was reported to produce interesting
and synthetically useful products.4 Barbara Roth and co-
workers have reported the use of para-alkyl 3,5-
dimethoxyaniline for the construction of trimethoprim an-
alogues (Figure 1) which are found to possess antimicro-
bial activity.5
O
H2N
OMe
Figure 2
We envisioned that these observations could be exploited
to synthesize para-alkyl 3,5-dimethoxyanilines by react-
ing an aldehyde with 3,5-dimethoxyaniline under Friedel–
Crafts alkylation conditions. Herein we report on the first
high-yielding, highly regioselective, one-pot process for
rapid access to para-alkyl 3,5-dimethoxyanilines via the
sequence of a novel Friedel–Crafts alkylation reaction of
an aldehyde with 3,5-dimethoxyaniline induced by TFA
and triethylsilane as reducing agent.
NH2
MeO
Our study began with reacting 3,5-dimethoxyaniline with
4-bromobenzaldehyde (1a). When a mixture of 3,5-
dimethoxyaniline (1 equiv) and 1a (1 equiv) in CH2Cl2
was treated with one equivalent of AlCl3 and one equiva-
lent of triethylsilane at 25 °C, the aldehyde was consumed
in five hours, to afford 2a in 16% yield in addition to re-
covered 3,5-dimethoxyaniline (Scheme 1).
N
N
NH2
R
OMe
Figure 1 Trimethoprim (R = OMe)
In our recent studies toward the synthesis of trimethoprim
analogues, we were interested to prepare various para-
alkyl 3,5-dimethoxyanilines as building blocks, which
could be further utilized for the construction of trimetho-
prim analogues. During our research, we realized that
there are few practical methods to introduce an alkyl-C4
substituent on 3,5-dimethoxyaniline. Although the syn-
OMe
CHO
OMe
Lewis acid
+
TES
CH2Cl2
H2N
OMe
Br
H2N
OMe
Br
1a
2a
Scheme 1
SYNLETT 2008, No. 16, pp 2429–2432
x
x
.x
x
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078207; Art ID: D16608ST
© Georg Thieme Verlag Stuttgart · New York

2430
J. K. Augustine et al.
LETTER
Screening a variety of Lewis acids (Table 1, entries 1–7) Table 2 Reaction of Aromatic Aldehydes with 3,5-Dimethoxy-
aniline
showed that InCl3, Sc(OTf)3, BF3·OEt2, AlMe3, TiCl4, and
Mg(ClO4)2 all led to similar yields of 2a, but interestingly,
Entry Substrate
Product
Yield
(%)a
when TFA (1 equiv) was employed instead of Lewis ac-
ids, the aldehyde was consumed in four hours to provide
2a in 57% isolated yield. Thus it was of interest to gain
further insight into the role of the trifluoroacetic acid.
NH2
Br
MeO
CHO
1
93
87
Br
Table 1 Screening of Lewis Acids for the Formation of 2a
OMe
1a
2a
Entry
Lewis acida
AlCl3 (1.0)
Time (h)
Yield of 2a (%)b
16 (63)
17 (70)
9 (82)
F
F
CHO
NH2
MeO
1
2
3
4
5
6
7
8
9
5
5
5
7
4
4
5
4
1
F
F
F
2
InCl3 (1.0)
F
OMe
Sc(OTf)3 (1.0)
BF3·OEt2 (1.0)
AlMe3 (1.0)
TiCl4 (1.0)
1b
2b
11 (78)
14 (70)
16 (66)
21 (70)
57 (24)
93
NH2
MeO
CHO
3
4
5
85
89
86
COOMe
COOMe
OMe
1c
2c
O2N
Mg(ClO4)2 (1.0)
TFA (1.0)
NH2
MeO
CHO
TFA (2.0)
O2N
OMe
OMe
a The amount of Lewis acid used is shown in parentheses.
1d
2d
MeO
b Yield in parentheses is that of recovered 3,5-dimethoxyaniline.
NH2
CHO
Cl
MeO
MeO
MeO
After some reaction optimization such as performing the
reaction in a mixture of dichloromethane and TFA (1:1)
and use of varying equivalents of TFA and triethylsilane,
we were able to conclude that use of TFA (2 equiv) and
triethylsilane (2 equiv) in CH2Cl2 at room temperature in-
deed was the ideal method to achieve optimum yield
(93%) in shorter duration (Table 2, entry 1).
Cl
OMe
1e
2e
NH2
MeO
CHO
6
91
OMe
1f
2f
NC
With the optimal reaction conditions in hand, we proceed-
ed to explore the scope and generality of this reaction.
Various easily accessible aromatic aldehydes (1b–i) were
reacted with 3,5-dimethoxyaniline under the standard
conditions to obtain corresponding para-alkyl 3,5-di-
methoxyanilines in good yields (Table 2). In most cases,
the products obtained did not require further purification
and were obtained as solids. As depicted in Table 2, alde-
hydes bearing multiple functional groups did not differ in
reactivity and provided the corresponding para-substitut-
ed 3,5-dimethoxyanilines in excellent yield. In general, all
aromatic aldehydes behaved well in the reaction but
mixed results were obtained with heteroaromatic alde-
hydes (Table 3, 1j–p). While nitrogen heterocycles such
as pyridine (Table 3, entries 1–3), quinoline (Table 3,
entry 6), imidazole, and thiazole behaved well in the reac-
tion, to our surprise, thiophene (Table 3, entry 7) decom-
posed completely within minutes of addition of
triethylsilane to provide a tarry substance. This could be
attributed to the reduction of thiophene system to thiolane
under the above reaction conditions.7
NH2
MeO
CHO
CHO
7
8
94
88
NC
OMe
OMe
1g
2g
F
NH2
MeO
NC
NC
F
1h
2h
F
F
F
MeO
F
F
F
F
NH2
F
F
9
90
F
F
CHO
F
OMe
1i
2i
a Isolated yields.
formed very well on all the substrates we tried. While
yield of products were excellent with purely aliphatic al-
dehydes, aliphatic aldehyde with an aromatic tail
(Table 4, entry 7) gave only moderate yield.
We next examined the application of this protocol to ali-
phatic aldehydes (Table 4, entries 1–7). The reaction per-
Synlett 2008, No. 16, 2429–2432 © Thieme Stuttgart · New York

LETTER
Novel and Highly Regioselective Friedel–Crafts Alkylation of 3,5-Dimethoxyaniline
2431
Table 3 Reaction of Heteroaromatic Aldehydes with 3,5-
Dimethoxyaniline
Table 4 Reactions of Aliphatic Aldehydes with 3,5-Dimethoxy-
aniline
Entry Substrate
Product
Yield (%)a
85
Entry Substrate
Product
Yield
(%)a
NH2
MeO
CHO
N
NH2
MeO
1
N
MeCHO
1q
1
89
89
88
90
93
94
81
OMe
1j
OMe
2j
2q
NH2
Cl
MeO
N
CHO
NH2
MeO
2
86
90
88
87
i-PrCHO
1r
2
Cl
N
OMe
1k
OMe
2k
2r
NH2
MeO
MeO
N
CHO
NH2
NH2
NH2
NH2
MeO
3
4
5
i-BuCHO
1s
N
3
OMe
OMe
OMe
1l
OMe
OMe
OMe
OMe
2l
2s
2t
NH2
MeO
HN
HN
CHO
N
4
5
6
7
N
CHO
1m
1t
2m
NH2
MeO
MeO
MeO
S
S
CHO
CHO
N
N
CHO
1n
1o
1u
2n
2o
2u
CHO
N
NH2
MeO
S
6
7
91
0b
S
N
OMe
1v
2v
NH2
NH2
MeO
MeO
CHO
Br
S
Br
S
CHO
OMe
OMe
1p
1w
2w
2p
a Isolated yields.
a Isolated yields.
b No product was isolated. Reaction mass turned into black tar within
minutes of addition of triethylsilane.
hours, affords para-substituted 3,5-dimethoxyanilines in
good yields, and the chemistry is highly regioselective.
Preferential electrophilic substitution at C4 is probably re-
lated to the formation of anilinium salt of the amino group
with trifluoroacetic acid, resulting in a steric impediment
to attack at C2.
Further, we examined if we could extend this methodolo-
gy to other activated anilines. Thus, 3,5-dimethylaniline,
3,5-dichloroaniline, and 3-methoxyaniline were reacted
with 4-bromobenzaldehyde under the standard reaction
conditions. In all these cases, we found only the N-alkyla-
To conclude, we have unveiled a novel and highly regio-
selective, Friedel–Crafts alkylation of 3,5-dimethoxy-
aniline, using an aldehyde and triethylsilane as reducing
agent.8 The method is convergent and avoids the synthesis
of complicated precursors giving a high level of complex-
ity in single step. This novel finding provides an interest-
ing insight into chemistry of electron-rich anilines and
represents a very useful way to prepare para-alkyl 3,5-
dimethoxyanilines of potential pharmacological interest.
tion
product.
Similarly,
N,N-dimethyl-(3,5-di-
methoxy)aniline did not react with 4-bromobenzaldehyde
under the same reaction conditions. We now wish to re-
port that such transformation is general in scope among
the reactions we examined for 3,5-dimethoxyaniline, but
could be limited to highly electron-rich anilines. In gener-
al, the reaction of aromatic or aliphatic aldehydes (1
equiv) and 3,5-dimethoxyaniline (1 equiv) in dichlo-
romethane containing trifluoroacetic acid (2 equiv) and
triethylsilane (2 equiv), at room temperature for 1–2
Synlett 2008, No. 16, 2429–2432 © Thieme Stuttgart · New York

2432
J. K. Augustine et al.
LETTER
(6) Roth, H. J.; Kok, W. Arch. Pharm. 1975, 308, 301.
(7) Kursanov, D. N.; Parnes, Z. N.; Bolestova, G. I.; Belenkii,
L. I. Tetrahedron 1975, 31, 311.
Acknowledgment
The authors gratefully acknowledge Dr. Goutam Das, COO, Syn-
gene International Ltd. for his invaluable support.
(8) Representative Procedure for the Synthesis of 2a
To a mixture of 4-bromobenzaldehyde (10 g, 0.054 mol) and
3,5-dimethoxyaniline (8.26 g, 0.054 mol) in CH2Cl2 (60 mL)
was added TFA (12.30 g, 0.108 mol), and the mixture was
stirred at r.t. for 10 min. To this was added TES (12.5 g,
0.108 mol) in drops over a period of 10 min, and the reaction
was stirred at r.t. for additional 2 h. The completion of
reaction was confirmed by TLC (2% MeOH in CH2Cl2). The
solvent was removed under vacuum and the residue was
diluted with H2O (50 mL) and washed with hexane (2 × 50
mL). The aqueous phase was basified with sat. aq solution of
NaHCO3 and extracted with CH2Cl2 (2 × 100 mL). The
combined organic phase was washed with H2O (1 × 100
mL), brine (1 × 50 mL), and dried over Na2SO4. The solvent
was removed under vacuum to afford 16 g (93%) of 4-(4-
bromobenzyl)-3,5-dimethoxyaniline(2a) as an off-white
solid; mp 167.9–169.0 °C. 1H NMR (400 MHz, DMSO-d6):
d = 7.36–7.34 (d, 2 H, J = 8 Hz), 7.04–7.02 (d, 2 H, J = 8
Hz), 5.89 (s, 2 H), 5.24 (br s, 2 H), 3.65 (s, 2 H), 3.63 (s, 6
H). 13C NMR (100 MHz, DMSO-d6): d = 158.6, 148.8,
142.3, 131.1, 130.7, 118.4, 104.0, 91.0, 55.6, 27.6. MS (ESI-
APCI): m/z found for C15H16BrNO2: 324 [M + 2])+. Anal.
Calcd (%) for C15H16BrNO2: C, 55.92; H, 5.01, N, 4.35.
Found: C, 55.99; H, 5.05, N, 4.28.
References and Notes
(1) (a) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.; Lawson,
M. A.; Dumontet, C.; Boumendjel, A. J. Med. Chem. 2004,
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Collignon, F.; Decaestecker, C.; Frydman, A.; Guillaumet,
G.; Kiss, R. J. Med. Chem. 2002, 45, 2543. (c) Tabarrini,
O.; Cecchetti, V.; Fravolini, A.; Nocentini, G.; Barzi, A.;
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2136.
(2) Traxler, P.; Green, J.; Mett, H.; Sequin, U.; Furet, P. J. Med.
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(3) Gungor, T.; Chen, Y.; Golla, R.; Ma, Z.; Corte, J. R.;
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(4) (a) Black, D. S. C.; Bowyer, M. C.; Condie, G. C.; Craig,
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(5) Roth, B.; Aig, E.; Rauckmann, B. S.; Strelitz, J. Z.; Phillips,
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Synlett 2008, No. 16, 2429–2432 © Thieme Stuttgart · New York