Regioselective ortho alkylation of nitro indole, carbazole, benzothiophene and benzofuran

Article abstract of DOI:10.1016/j.tetlet.2015.11.036

Substituted indoles, carbazoles, benzothiophenes and benzofurans are important motifs in the pharmaceutical industry. Herein we report a novel, regioselective method to introduce alkyl substituents into position ortho of nitro groups by the addition of a Grignard reagent followed by subsequent oxidation with DDQ.

Full text of DOI:10.1016/j.tetlet.2015.11.036

Tetrahedron Letters 56 (2015) 7165–7167
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective ortho alkylation of nitro indole, carbazole,
benzothiophene and benzofuran
⇑
Scott G. Lamont , Craig S. Donald, J. Lyman Feron, Sam D. Groombridge
AstraZeneca Pharmaceuticals, Building 310, Cambridge Science Park, 319 Milton Road, Cambridge, Cambridgeshire CB4 0WG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2015
Revised 14 October 2015
Accepted 11 November 2015
Available online 11 November 2015
Substituted indoles, carbazoles, benzothiophenes and benzofurans are important motifs in the pharma-
ceutical industry. Herein we report a novel, regioselective method to introduce alkyl substituents into
position ortho of nitro groups by the addition of a Grignard reagent followed by subsequent oxidation
with DDQ.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Carbazole
Indole
Benzofuran
Benzothiophene
Heterocycle
ortho alkylation
Heterocyclic motifs such as indoles, benzothiophenes and ben-
zofurans have long been of significant interest in the pharmaceuti-
cal industry. Drugs such as the PDE5 (phosphodiesterase type 5)
inhibitor Tadalafil1 and the SERM (selective oestrogen receptor
modulator) Raloxifene2 are representative examples which illus-
trate the importance of these heterocycles (Fig. 1).
OH
O
O
O
O
S
As part of a drug discovery programme3 we were interested in
synthesising carbazoles containing specific alkyl groups (e.g.,
methyl) 1a and 1b and as such we decided to approach this via
ortho-alkylation of the requisite nitrocarbazole. The ortho alkyla-
tion reaction is known in the literature,4–6 however during this
work unexpected regioselectivity was discovered when performing
the methylation step on 9-isopropyl-3-nitrocarbazole 1 (Scheme 1)
from which compound 1a was exclusively isolated (confirmed by
1H NMR and NOE studies). To the best of our knowledge there
are no examples of this observed regioselectivity in heterocyclic
systems. As it was believed to be a synthetically useful reaction
for organic chemists, we sought to determine the scope of such
selective alkylation reactions.
O
H
N
N
H
OH
N
N
O
Tadalafil
Raloxifene
Figure 1. Structures of Tadalafil and Raloxifene.
N
N
N
MeMgCl
DDQ
To rationalise the observed regioselectivity the likely transition
states resulting from Grignard addition at either the 2- or 4-posi-
tion (1d and 1c, respectively) were considered. It was postulated
that the observed selectivity arose due to the reaction progressing
via favourable structure 1c. Formation of 1d would be disfavoured
N+
N+
N+
O
O
O
-O
-O
-O
1
1a
1b
Not observed
Formed exclusively
Scheme 1. Initial observed selectivity in
a Grignard addition reaction with
carbazole 1. Reagents and conditions: (3.9 mmol), MeMgCl (5.9 mmol), THF
1
⇑
Corresponding author.
E-mail address: Scott.Lamont@astrazeneca.com (S.G. Lamont).
(40 mL), À15 °C, 1 h, then DDQ (6.69 mmol), À10 °C to RT, 16 h, 68%, 1a formed
exclusively.9
http://dx.doi.org/10.1016/j.tetlet.2015.11.036
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

7166
S. G. Lamont et al. / Tetrahedron Letters 56 (2015) 7165–7167
This hypothesis was further supported by observations made
with the corresponding benzothiophene 2 and benzothiophene
dioxide 3. In the case of fully aromatic benzothiophene, complete
regioselectivity was observed to exclusively give methyl com-
pound 2a. However, with benzothiophene dioxide a 2:1 mixture
of 3a and 3b was obtained (Scheme 3). Because in the case of 3
the central ring is not aromatic, it was rationalised that the relative
energy barriers of the transition states leading to 3a and 3b were
similar, therefore giving rise to a mixture of products.
These observations prompted us to investigate the synthetic
utility of this regioselective reaction with additional heterocy-
cles (Table 1). In the case of indoles with no substitution on
nitrogen, it was necessary to use tosyl protected derivatives to
avoid deprotonation by the Grignard reagent (Table 1). It should
be noted that the yields of these reactions are as yet
unoptimised.
N
N
MeMgCl
H
MgCl
1
1c
N+
N+
O
O
-O
-O
O
O
Cl
Cl
CN
CN
MeMgCl
OH
O
Cl
Cl
CN
CN
N
N
H
MgCl
1d
1a
N+
Mg
Cl
N+
O
O
-O
-O
Following our initial observations with carbazole 1, analogous
carbazoles 4 and 5 were investigated, and were noted to proceed
with similar selectivity to give methyl analogues 4a and 5a. A
similar outcome was observed when nitroindoles were used as
substrates. In the cases of 5-nitro indole 7 and 6-nitro indole 6,
the reaction proceeded with the expected selectivity, however
when 4-nitro indole 10 and 7-nitro indole 11 were employed,
an inseparable mixture of isomers was obtained. This was due
to competing alkylation occurring at the para position. Because
this competing reaction does not break the aromaticity of the
heterocyclic ring it is therefore still energetically favourable (see
Scheme 4).
Additionally, we were interested to see if this methodology
could be extended to other heterocyclic systems. In the case of
benzofuran 8 and benzothiophene 9, the reaction proceeded with
the expected selectivity to give the corresponding ortho methyl
compounds 8a and 9a.
disfavoured due to aromaticity
being broken in the pyrrole ring
Scheme 2. Proposed reaction pathway and unfavourable reaction intermediate.
S
S
1) MeMgCl
2) DDQ
N+
N+
O
2
3
O
O
48%
2a
3a
-O
-O
O
O
S
O
O
O
O
S
S
1) MeMgCl
2) DDQ
+
N+
N+
N+
O
O
-O
-O
3b
-O
34%
Other Grignard reagents could also be employed in this reac-
tion. When carbazole 1 was treated with ethyl magnesium chloride
ethyl substituted carbazole 1e was the only product isolated.
When the same carbazole was treated with isopropyl magnesium
chloride, the analogous isopropyl carbazole 1f was formed exclu-
sively. Unfortunately, when carbazole 1 was treated with phenyl
magnesium chloride the corresponding phenyl carbazole 1g was
not observed, presumably due to the lower nucleophilicity of the
phenyl Grignard reagent.
In summary, we have described a highly regioselective method-
ology for the alkylation of a variety of nitro containing aromatic
heterocycles. Given the highly versatile nature of the nitro func-
tional group we believe this methodology to be of synthetic value
and allows the expedient synthesis of a wide variety of non-com-
Scheme 3. Grignard additions to benzothiophene and benzothiophene dioxide.
Reagents and conditions: 2 or 3 (3.9 mmol), MeMgCl (5.9 mmol), THF (40 mL),
À15 °C, 1 h, then DDQ (6.69 mmol), À10 °C to RT, 16 h. 2a, 48% and 3a and 3b, 34%.
as this would require breaking the aromaticity of the carbazole
pyrrole ring. It was believed that the energy barrier to disrupting
the aromaticity was significant enough to give rise to the observed
selectivity. The reaction is completed by the addition of DDQ (4,5-
dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile) which
furnishes the desired product. It is well known in the literature that
DDQ can be used to oxidise semi-saturated rings to aromatic sys-
tems.7,8 The proposed mechanism involves hydride transfer to
the quinone oxygen followed by transfer of magnesium to the phe-
nolate ion (Scheme 2).
Table 1
Substrate
Product
Yielda (%)
Substrate
Product
Yielda (%)
S
S
N
N
NO2
NO2
68
39
NO2
NO2
NO
2
9
9a
1
1a
4a
Tos
N
Tos
N
Tos
N
N
N
55
74
NO2
NO2
NO2
NO2
4
10
10a:10b(1:1 mixture)

S. G. Lamont et al. / Tetrahedron Letters 56 (2015) 7165–7167
7167
Table 1 (continued)
Substrate
Product
Yielda (%)
Substrate
NO2
Product
Yielda (%)
Tos
N
Tos
N
NO2
Tos
NO2
Tos
N
Tos
N
N
NO2
69
33
65
NO2
11
5
5a
11a:11b(1:1 mixture)
Tos
N
Tos
N
NO2
NO2
N
N
33
71
NO2
NO2
NO2
NO2
6
6a
1
1
1e
Tos
N
Tos
N
N
N
N
NO2
NO2
55
NO2
7
7a
1f
O
O
N
NO2
NO2
NO2
8
48
0
8a
1
1g
References and notes
O-
O-
Cl
O-
O
O
O
N+
Mg
H
N+
N+
Tos
N
Tos
N
Tos
N
MeMgCl
1. (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348–
1349; (b) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.-C.;
Coste, H.; Linget, J. M.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. J. Med. Chem.
2003, 46, 4533–4542.
2. Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A. R.;
Falcone, J. F.; Clemens, J. A. J. Med. Chem. 1984, 27, 1057–1066.
3. Block, M. H.; Boyer, S.; Brailsford, W.; Brittain, D. R.; Carroll, D.; Chapman, S.;
Clarke, D. S.; Donald, C. S.; Foote, K. M.; Godfrey, L.; Ladner, A.; Marsham, P. R.;
Masters, D. J.; Mee, C. D.; O’Donovan, M. R.; Pease, J. E.; Pickup, A. G.; Rayner, J.
W.; Roberts, A.; Schofield, P.; Suleman, A.; Turnbull, A. V. J. Med. Chem. 2002, 45,
3509–3523.
4. Bartoli, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1985, 26, 115–118.
5. Bentley, S. J.; Milner, D. J. J. Organomet. Chem. 1993, 447, 1–3.
6. Makosza, M.; Surowiec, M. J. Organomet. Chem. 2001, 624, 167–171.
7. Walker, H. Chem. Rev. 1967, 67, 153–195.
DDQ
ortho
11a
11
MeMgCl para
O-
O
O-
O
Cl
Mg
N+
N+
Tos
N
Tos
N
DDQ
H
11b
8. Fu, P.; Harvey, R. Chem. Rev. 1978, 78, 317–361.
Scheme 4. ortho/para alkylations observed with 7-nitroindole 11.
9. Representative procedure for the Grignard alkylation reaction. Preparation of 9-
isopropyl-4-methyl-3-nitro-9H-carbazole (1a). Methylmagnesium chloride
(1.97 mL, 5.90 mmol) was added dropwise to a stirred solution of 9-isopropyl-
3-nitro-9H-carbazole (1 g, 3.93 mmol) in THF (40 mL) at À15 °C. The resulting
solution was stirred at À15 °C for 1 h. DDQ (1.518 g, 6.69 mmol) was then added
keeping the temperature below À10 °C and then the reaction mixture was
allowed to warm temperature and stirred for 16 h. Dichloromethane (100 mL)
was then added and the mixture washed with water (100 mL). The organic layer
was passed through a phase separating cartridge and concentrated in vacuo to
mercial or highly expensive substituted heterocycles from readily
available starting materials.
Acknowledgement
give
a brown solid. The crude product was purified by flash silica
We would like to thank Howard Beeley, Paul Davey, Peter Bar-
ton and David Whittaker for analytical support.
chromatography, gradient 0–30% dichloromethane in heptane. Pure fractions
were evaporated to dryness to afford 9-isopropyl-4-methyl-3-nitro-9H-
carbazole (0.722 g, 68%) as a yellow solid.; 1H NMR (400 MHz, DMSO) 1.65 (d,
J = 7.0 Hz, 6H), 3.02 (s, 3H), 5.24 (p, J = 7.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.49–
7.64 (m, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 9.1 Hz,
1H), 8.34 (d, J = 8.0 Hz, 1H). 13C NMR (176 MHz, DMSO, 30 °C) 16.49, 20.17,
46.50, 108.24, 111.24, 120.06, 121.29, 122.13, 123.04, 123.10, 126.26, 129.64,
140.07, 140.62, 141.81. HRMS (ESI): MH+, found 269.12836, C16H16O2N2
requires 269.12845.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.11.
036.