Semmler-Wolff aromatisation: A concise route for the synthesis of 5-amino-quinazolines and 4-amino-indoles

Article abstract of DOI:10.1016/j.tetlet.2014.09.125

A simple and efficient methodology for the synthesis of 5-amino-quinazolines and 4-amino-indoles via Semmler-Wolff aromatisation reaction has been carried out. The oximation of keto intermediates followed by Semmler-Wolff aromatisation using acetic anhydride and a catalytic amount of sodium iodide in xylene provided the desired quinazolines and indoles.

Full text of DOI:10.1016/j.tetlet.2014.09.125

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Semmler–Wolff aromatisation: a concise route for the synthesis
of 5-amino-quinazolines and 4-amino-indoles
Sulur G. Manjunatha, Sreekanth Bachu, Vibha Gautam, Mohana Kumari, Sudhir Nambiar,
⇑
Sridharan Ramasubramanian, Ramachandra Puranik
Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Bellary Road, Bangalore, Karnataka 560024, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient methodology for the synthesis of 5-amino-quinazolines and 4-amino-indoles via
Semmler–Wolff aromatisation reaction has been carried out. The oximation of keto intermediates fol-
lowed by Semmler–Wolff aromatisation using acetic anhydride and a catalytic amount of sodium iodide
in xylene provided the desired quinazolines and indoles.
Received 5 August 2014
Revised 24 September 2014
Accepted 28 September 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
5-Acetamido-2-aryl-quinozoline
4-Acetamido N-alkyl/arylindole
Semmler–Wolff aromatisation
Acetic anhydride
Sodium iodide
The aromatisation of
a
,b-unsaturated cyclohexenyl ketoximes
recently reported the synthesis of a series of indazoles using this
approach (Scheme 1).10
into corresponding aromatic amines under acidic conditions was
first discovered by Semmler1 and further explored by Wolff.2 In
the acidic medium, the reaction competes with Beckmann rear-
rangement and ketooxime prefers to aromatise to yield desired
arylamine.3 The reaction has been well studied with various cyclic
and bicyclic oximes to generate corresponding carbocyclic and het-
erocyclic molecules.4 The advantage of this reaction is that it places
the amine functionality at a specific position of the aryl system in a
simple manner which otherwise is difficult to introduce or synthe-
sise by any other routes. One can visualise the application of
Semmler–Wolff aromatisation reaction for the synthesis of phar-
maceutically important heterocyclic compounds given in Figure 1
through appropriate oximes. The medicinal and biological value
of these compounds has stimulated an extensive research in the
area for their synthesis as they possess a wide spectrum of phar-
maceutical and biological properties including anti-inflammatory
(a, b),5 dengue virus inhibitor (c),6 antiphlogistics7 and antibacte-
rial (Fig. 1).8
This Letter describes yet another application of Semmler–Wolff
aromatisation to the synthesis of 5-amino-quinazolines and 4-
amino-indoles. (Scheme 2)
OH
N
NH2
F
CF3
OH
N
N
NH2
HN
N
(c)
F
(a)
N
Cl
During our search for a safe process for 4-acylaminoindole,9 we
applied Semmler–Wolff aromatisation reaction to its synthesis uti-
lising the strategy as described in Scheme 1. This led us to the
development of a safe manufacturing process for AZD1981.9
Employing the same strategy, we further visualised the application
of Semmler–Wolff aromatisation to the synthesis of indazole and
NHAc
F3C OH
S
NH
N
N
CO2H
AZD1981
N
(b)
⇑
Corresponding author.
Figure 1. Biologically and pharmacologically active amino substituted compounds.
http://dx.doi.org/10.1016/j.tetlet.2014.09.125
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S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx
NHAc
O
R1
R1
R1
O
R2
a) oximation
R2
R2
N
N
b) SW Aromatisation
O
N
R3
O
R3
O
Amino-Indole
NHAc
O
O
O
a) oximation
N
N
R
N
b) SW Aromatisation
N
R
O
Amino-Indazole
Scheme 1.
O
O
NR1R2
N
Various reports have been published for the synthesis of quina-
N
zolines and indoles which involves multiple synthetic steps.
Synthesis of quinazolines have been reported from N-phenyl
dimethyl propanamide,7 substituted benzyl amine11 and benzoni-
trile.12 However, very few methods are known for the synthesis of
5-aminoquinazolines. The current known method involves the of
3-substituted anthranilic acid with amidines and further to
5-aminoquinazolines as shown in Scheme 3.13–16 The major
drawback in this synthesis is the availability of appropriate 1,2,
3-trisubstituted nitro compounds and the safety issues involved
in handling.
N
a) oximation
O
N
b) SW Aromatisation
R
R
O
NR4R5
R1
R1
a) Alkylation/Arylation
b) oximation
R2
R2
N
N
H
R3
c) SW Aromatisation
Scheme 2.
In the present Semmler–Wolff strategy for the synthesis of
5-aminoquinazolines, the required ketointermediates (4) were
prepared by the reaction of enamide (2) with benzamidine
hydrochloride (3) using the reported procedure.17 Further 4 was
reacted with hydroxyl amine to get the corresponding oximes (5)
needed for exploring Semmler–Wolff aromatisation chemistry.
(Scheme 4). For example, 2-phenyl-7, 8-dihydro-6H-quinazolin-
5-one (4a) was obtained from 2-dimethylaminomethylene
R
R
O
NH2
R
COOH
N
N
NH2
N
H
N
NO2
Scheme 3. Synthesis of 5-aminoquinazoline.
O
NOH
c
O
O
b
NH3Cl
a
N
N
N
N
N
O
O
HN
R
R
5
2
1
4
R
3
Scheme 4. R@H, CH3, fluoro, OCH3, Br, NO2. Reaction conditions: (a) N,N-dimethylformamide dimethylisopropyl acetal, toluene, reflux; (b) IPA, water, aq HCl (catalytic),
65–70 °C, 16 h; (c) NH2OHÁHCl, NaOAc, water, IPA, 65–70 °C, 2 h.
Table 1
Derivatives of oximes
Entry
Substrate
Product
Reaction time (h)
Isolated/conversion yield (%)
O
NOH
N
N
N
N
1
2
84a
N
N
5a
4a
O
NOH
2
3
2
2
65a
N
N
5b
4b
O
NOH
N
N
80a
N
N
5c
4c
F
F
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S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 1 (continued)
Entry
Substrate
Product
Reaction time (h)
Isolated/conversion yield (%)
O
NOH
N
N
4
2
68a
N
N
OCH3
OCH3
4d
5d
NOH
O
N
N
N
N
5
6
2
2
70b
N
N
Br
4e
Br
5e
O
NOH
73b
N
N
NO2
NO2
4f
5f
a
Isolated yield.
Conversion yield.
b
cyclohexane-1,3-dione (2) on treating with benzamidine hydro-
chloride (3). Oximation of 4a with hydroxylamine resulted in
2-phenyl-7, 8-dihydro-6H-quinazolin-5-one oxime (5a).18a
Similar reaction conditions were applied to the synthesis of
keto intermediates (4a–f) to produce the desired corresponding
oximes (5a–f) in excellent yields. The oximation reactions were
clean and were completed in 2 h (Table 1). It was observed that
the introduction of the substituent on the phenyl ring did not make
any impact on the yields of the products.
O
NH
NOH
N
Ac2O, NaI, Xylene
100-120 o C
N
N
N
R
R
5
6
Scheme 5.
Table 2
Synthesised quinazoline derivatives
Entry
Substrate
Product
Reaction time (h)
Isolated/conversion yield (%)
NOH
O
N
N
N
HN
N
1
1.5
80a
N
N
N
N
5a
6a
NOH
O
O
HN
HN
N
2
3
0.5
1.5
82a
5b
N
6b
NOH
80a
N
5c
F
N
6c
F
NOH
O
N
HN
80a
N
N
4
2
5d
OCH3
N
6d
OCH3
(continued on next page)
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S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2 (continued)
Entry
Substrate
Product
Reaction time (h)
Isolated/conversion yield (%)
NOH
O
N
N
HN
N
5
6
N
N
2
2
78b
5e
Br
N
6e
Br
NOH
O
HN
75b
N
5f
NO2
N
6f
NO2
a
Isolated yield.
Conversion yield.
b
and methoxy substituents did not affect the reaction course and
resulted in aminoquinazolines (6a–f) in good yields (Table 2).
Subsequently to our development of manufacturing process for
4- aminoindole derivative (AZD1981) via Semmler–Wolff aromati-
sation, we further explored the application of this chemistry to
synthesise various other N-substituted indoles in order to
understand the generality of the reaction and the effect of aryl
and alkyl substitution on the nitrogen atom during the course of
the reaction.
NOH
O
O
RX
CsCO3
NH2OH.HCl, NaOAc
H2O, IPA, 60-70oC
N
R
N
R
N
H
50oC
DMF
9
7
8
Scheme 6. X = halogen; R = propyl, 4-nitrophenyl, 4-methylbenzyl.
N-alkyl/aryl-6,7-dihydro-5H-indol-4-one oximes (9a–c) were
synthesised from commercially available 1,5,6,7-tetrahydroin-
dole-4-one (7) via N-alkylation/arylation. This protocol proved
The reaction conditions for Semmler–Wolff aromatisation using
acetic anhydride and sodium acetate in the presence of inorganic
iodide in xylene at higher temperature (100–120 °C), as reported
in our previous finding,9 provided good yields. The aromatisation
of synthesised oximes (5a–f) to corresponding quinazoline deriva-
tives under similar reaction conditions was then explored. It was
inferred that oximes (5a–f) too aromatised to 5-amino-quinazo-
O
O
NOH
N
Ac2O, NaI
Xylene,
N
R
o
100-120 C
N
R
lines (6a–f) in
a similar manner to produce good yields
(Scheme 5).18b The reactions were clean and were completed in
around 2 h. Prolonged heating of oximes (5a–f) in acetic anhydride
did not have any impact on the yield of the product. Presence of
substitutions on the aryl group like methyl, fluoro, bromo, nitro
10
9
Scheme 7. R = propyl, 4-nitrophenyl, 4-methylbenzyl.
Table 3
Series of synthesised indole oximes
Entry
Substrate
Product
Reaction time (h)
Conversion yield (%)
O
NOH
1
18
92
89
N
N
9a
8a
O
NOH
N
N
N
2
3
18
18
8b
9b
NO2
NO2
O
NOH
82
N
9c
8c
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S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
Table 4
Series of synthesised indole-4-amides
Entry
Substrate
Product
Reaction time (h)
Conversion yield (%)
NOH
O
O
N
N
1
18
50
9a
N
10a
NOH
N
O
O
N
2
18
57
N
9b NO2
10b
NO2
NOH
O
O
N
N
3
18
68
N
9c
10c
superior over the previous one9 as a series of analogues could be
synthesised by the reaction of indole-4-one (7) with various alkyl
or aryl groups. Refluxing the synthesised ketone (8a–c)18c with
hydroxyl amine in the presence of sodium acetate and isopropyl
alcohol as the solvent resulted in desired oximes (9a–c) in excel-
lent yields18d (Scheme 6). (Table 3)
Oximes (9a–c)) were then subjected to previously optimised
Semmler–Wolff’s aromatisation conditions. Unlike the quinazo-
lines, mono and diacylated products were observed at the initial
stage of the reaction which on prolonged heating resulted in a sin-
gle N,N-diacylated product (10a–c) along with the other side impu-
rities (Scheme 7). Substitution on the nitrogen in 9a–c did not
affect the course of the reaction and proceeded similarly to yield
desired indoles (10a–c) after column purification (Table 4).18e
As per the previous reports, compounds 6(a–f) and 10(a–c) can
be converted to the corresponding amines by treating with aque-
ous NaOH solution.10
3. (a) Nunn, A. J.; Rowell, F. J. J. Chem. Soc. Perkin Trans. 1 1973, 2697–2703; (b)
Bardakosla, V.; Sucrow, W. Chem. Ber. 1976, 109, 1898–1910.
4. (a) Auerand, L.; Hewjts, R. J. Org. Chem. 1962, 27, 3982–3985; (b) Martin, L. L.;
Scott, S. J.; Agnew, M. N.; Setescak, L. L. J. Org. Chem. 1986, 51, 3697–3700; (c)
Tamura, Y.; Nishikawa, O.; Shimizu, T.; Akita, M.; Akita, Y. Chem. Ind. (London,
U.K.) 1975, 922; (d) Koh, Y. K.; Bang, K. H.; Kim, H. S. J. Heterocycl. Chem. 2001,
38, 89–92.
5. Baeurle, S.; Berger, M.; Jaroch, S.; Krolikiewicz, K.; Nguyen, D.; Rehwinkel, H.;
Schaecke, H.; Schmees, N.; Skuballa, W. EP1786823 (A1), 2007.
6. Chao, B.; Tong, X.-K.; Tang, W.; Li, D.-W.; He, P.-L.; Garcia, J.-M.; Zeng, L.-M.;
Gao, A.-H.; Yang, L.; Li, J.; Nan, F.-J.; Jacobs, M.; Altmeyer, R.; Zuo, J.-P.; Hu, Y.-H.
J. Med. Chem. 2012, 55, 3135–3143.
7. Rehwinkel, H.; Baeurle, S.; Berger, M.; Schmees, N.; Schaecke, H.; Krolikiewicz,
K.; Mengel, A.; Nguyen, D.; Jaroch, S.; Skuballa, W. EP1670778 (A1), 2006.
8. Harris, N. V.; Smith, C.; Bowden, K. J. Med. Chem. 1990, 33, 434–444.
9. Sulur, M.; Sharma, P.; Ramakrishnan, R.; Naidu, R.; Merifield, E.; Gill, D. M.;
Clarke, A. M.; Thomson, C.; Butters, M.; Bachu, S.; Benison, C. H.; Dokka, N.;
Fong, E. R.; Hose, D. R. J.; Howell, G. P.; Mobberley, S. E.; Morton, S. C.; Mullen,
A. K.; Rapai, J.; Tejas, B. Org. Process Res. Dev. 2012, 16, 1746–1753.
10. Manjunatha, S. G.; Bachu, S.; Krishna, V. K.; Murugan, A.; Ramasubramanian, S.;
Ramachandra, P.; Nambiar, S. Tetrahedron Lett. 2014, 55, 3348–3350.
11. Barbara, B.; Colin, L.; Luigi, S.; Valeria, Z.; Antonio, V.; Halina, S.; Enrica, G.;
Manuela, B.; Mark, B.S.; Andrea, B; WO2004/046124 A1.
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28, 1387–1393.
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2779.
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WO2011/42529A1.
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In our present study, the synthesis of a series of 5-amino-qui-
nazoline and 4-amino-indole derivatives employing Semmler–
Wolff aromatisation under mild conditions has been explored. This
synthetic methodology provides us the opportunity to place the
amino group in its respective position in a very simple manner
avoiding harsh conditions and multiple steps.
Acknowledgments
16. Naff, M. B.; Christensen, B. E. J. Am. Chem. Soc. 1951, 73, 1372–1373.
17. Tonikikh, N. N.; Strakov, A. Ya.; Petrova, M. V. Chem. Heterocycl. Compd. 2000,
36, 174–177.
The authors are thankful to the management of AstraZeneca for
their support. We thank the Analytical Department for their sup-
port and discussions during the course of work.
18. Representative procedures: (a) Synthesis of 2-phenyl-7, 8-dihydro-6H-
quinazolin-5-one oxime (5a): To a stirred solution of 2-phenyl-7,8-dihydro-
6H-quinazolin-5-one (4) (0.6 g, 2.68 mmol) in isopropanol (6.0 ml) and water
(0.6 ml) mixture, were added hydroxylamine hydrochloride (0.20 g,
2.94 mmol) and sodium acetate (0.24 g, 8.48 mmol) at 20–25 °C. The
resultant mixture was warmed to 65–70 °C and stirred for 1 h. The reaction
was completed as indicated by TLC. The reaction mixture was then quenched
with water (22.5 ml) and stirred for additional 2 h. The precipitated product
(5a) was then filtered and dried in oven at 50 °C. (b) Synthesis of N-(2-
phenylquinazolin-5-yl) acetamide (6a): To a stirred solution of 2-phenyl-7,8-
dihydro-6H-quinazolin-5-one oxime (5) (0.5 g, 2.09 mmol) in acetic anhydride
(1.5 ml) and xylene (5.0 ml) mixture was added sodium iodide (0.16 g,
1.04 mmol) at 20–25 °C. The resultant mixture was heated to 110–120 °C
and stirred for 1 h, by which time the reaction was completed as indicated by
TLC. The reaction mixture was cooled to 60 °C and water (5.0 ml) was added to
the reaction mass. Then the reaction mixture was cooled to rt. The solid was
filtered and the product was then purified by IPA slurry to obtain as a light
Supplementary data
Supplementary data (spectral data for all the newly synthesised
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.125.
References and notes
1. Semmler, F. W. Ber. Dtsch. Chem. Ges. 1892, 25, 3352–3354.
2. Wolff, L. Justus Liebigs Ann. Chem. 1902, 322, 351.
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S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx
yellow solid (6a). (c) Synthesis of 1-propyl-6,7-dihydro-5H-indol-4-one (8a): To a
ethyl acetate and dried over anhydrous Na2SO4. The filtrate was concentrated
under reduced pressure and solid obtained was dried in oven at 50 °C. The
products were confirmed by LCMS and subsequently taken to the next step. (e)
Synthesis of N-acetyl-N-(1-propyl-1H-indol-4-yl) acetamide (10a): To a stirred
solution of 1-substituted-6,7-dihydro-5H-indol-4-one oxime (9a) (1 g,
6.66 mmol) in acetic anhydride (1.88 ml, 19.97 mmol) and xylene (10 ml)
mixture was added sodium iodide (0.49 g, 3.33 mmol) at 20–25 °C. The
resultant mixture was heated to 100–120 °C and stirred for overnight, by
which time the reaction was completed as indicated by TLC. The mixture was
cooled to 20–25 °C and concentrated under vacuum. The residue was extracted
with dichloromethane. The organic layer was washed with water, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. Column
purification of the isolated product resulted in pure 10a.
stirred solution of 1,5,6,7-tetrahydroindole-4-one (7) (1 g, 6.51 mmol) and
alkyl or aryl halide in DMF (10 ml) was added cesium carbonate (4.42 g,
13.02 mmol) at 30 °C for 2 h by which time the reaction was completed as
indicated by TLC. The reaction mixture was quenched with water and
extracted with ethyl acetate and dried over anhydrous Na2SO4. The filtrate
was concentrated under reduced pressure and solid obtained was dried in oven
at 50 °C. (d) Synthesis of 1-propyl-6,7-dihydro-5H-indol-4-one oxime (9a): to a
stirred solution of 1-substituted-6,7-dihydro-5H-indol-4-one (8a) (1 g,
7.39 mmol) in isopropanol (10 ml) and water (10 ml) mixture, were added
hydroxylamine hydrochloride (0.56 g, 8.129 mmol) and sodium acetate
(0.72 g, 8.87 mmol) at 20–25 °C and stirred overnight, by which time the
reaction was completed as indicated by TLC. The reaction mixture was
quenched with water (10 ml) and stirred for additional 15 min, extracted with
Please cite this article in press as: Manjunatha, S. G.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.125