semmler–wolff aromatisation: a concise route for the synthesis of 5-amino-quinazolines and...

Tetrahedron Letters xxx (2014) xxx–xxx

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Tetrahedron Letters

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Semmler–Wolff aromatisation: a concise route for the synthesisof 5-amino-quinazolines and 4-amino-indoles

http://dx.doi.org/10.1016/j.tetlet.2014.09.1250040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author.

N NF

HN

OHF

OH

CF3

N

N

NH2

NH

N

N

SNHAc

CO2HNN

NH

OHF3C

(a)

(b)

(c)

AZD1981

Figure 1. Biologically and pharmacologically active amino substituted com

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

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

Article history:Received 5 August 2014Revised 24 September 2014Accepted 28 September 2014Available online xxxx

Keywords:5-Acetamido-2-aryl-quinozoline4-Acetamido N-alkyl/arylindoleSemmler–Wolff aromatisationAcetic anhydrideSodium iodide

a b s t r a c t

A simple and efficient methodology for the synthesis of 5-amino-quinazolines and 4-amino-indoles viaSemmler–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 iodidein xylene provided the desired quinazolines and indoles.

� 2014 Elsevier Ltd. All rights reserved.

2

Cl

The aromatisation of a,b-unsaturated cyclohexenyl ketoximesinto corresponding aromatic amines under acidic conditions wasfirst discovered by Semmler1 and further explored by Wolff.2 Inthe acidic medium, the reaction competes with Beckmann rear-rangement and ketooxime prefers to aromatise to yield desiredarylamine.3 The reaction has been well studied with various cyclicand bicyclic oximes to generate corresponding carbocyclic and het-erocyclic molecules.4 The advantage of this reaction is that it placesthe amine functionality at a specific position of the aryl system in asimple manner which otherwise is difficult to introduce or synthe-sise by any other routes. One can visualise the application ofSemmler–Wolff aromatisation reaction for the synthesis of phar-maceutically important heterocyclic compounds given in Figure 1through appropriate oximes. The medicinal and biological valueof these compounds has stimulated an extensive research in thearea 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

During our search for a safe process for 4-acylaminoindole,9 weapplied Semmler–Wolff aromatisation reaction to its synthesis uti-lising the strategy as described in Scheme 1. This led us to thedevelopment of a safe manufacturing process for AZD1981.9

Employing the same strategy, we further visualised the applicationof Semmler–Wolff aromatisation to the synthesis of indazole and

recently reported the synthesis of a series of indazoles using thisapproach (Scheme 1).10

This Letter describes yet another application of Semmler–Wolffaromatisation to the synthesis of 5-amino-quinazolines and 4-amino-indoles. (Scheme 2)

pounds.

http://dx.doi.org/10.1016/j.tetlet.2014.09.125


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R

NO2

RCOOH

NH2

R

NH

N

O NH2

N

N

Scheme 3. Synthesis of 5-aminoquinazoline.

O

O

O

O

N

O

R

NH3ClHN

ab

1 2

3

Scheme 4. R@H, CH3, fluoro, OCH3, Br, NO2. Reaction conditions: (a) N,N-dimethylform65–70 �C, 16 h; (c) NH2OH�HCl, NaOAc, water, IPA, 65–70 �C, 2 h.

Table 1Derivatives of oximes

Entry Substrate Product

1

O

N

N

4a

NOH

N

N

5a

2

O

N

N

4b

NOH

N

N

5b

3

O

N

N

F4c

NOH

N

N

F5c

O

O

O

O

O

O

R1

R2

O

N

O

O

N

NN

R3

R

R1

R2

NHAc

NR3

R1

R2

NHAc

NN

R

a) oximation

b) SW Aromatisation

a) oximation

b) SW Aromatisation

Amino-Indole

Amino-Indazole

Scheme 1.

O

O

O

N

N

R

NR1R2

N

N

R

O

NH

R1

R2

NR4R5

NR3

R1

R2

a) oximation

b) SW Aromatisation

b) oximation

c) SW Aromatisation

a) Alkylation/Arylation

Scheme 2.

2 S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx

Please cite this article in press as: Manjunatha, S. G.; et al. Tetrahedron

Various reports have been published for the synthesis of quina-zolines and indoles which involves multiple synthetic steps.Synthesis of quinazolines have been reported from N-phenyldimethyl propanamide,7 substituted benzyl amine11 and benzoni-trile.12 However, very few methods are known for the synthesis of5-aminoquinazolines. The current known method involves the of3-substituted anthranilic acid with amidines and further to5-aminoquinazolines as shown in Scheme 3.13–16 The majordrawback in this synthesis is the availability of appropriate 1,2,3-trisubstituted nitro compounds and the safety issues involvedin handling.

In the present Semmler–Wolff strategy for the synthesis of5-aminoquinazolines, the required ketointermediates (4) wereprepared by the reaction of enamide (2) with benzamidinehydrochloride (3) using the reported procedure.17 Further 4 wasreacted 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

N

N

R

NOH

N

N

R

c

4 5

amide dimethylisopropyl acetal, toluene, reflux; (b) IPA, water, aq HCl (catalytic),

Reaction time (h) Isolated/conversion yield (%)

2 84a

2 65a

2 80a

Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.125


Table 2Synthesised quinazoline derivatives


1

NOH

N

N

5a

HN

N

N

O

6a

2

NOH

N

N

5b

HN

N

N

O

6b

3

NOH

N

N

F5c

HN

N

N

F

O

6c

4

NOH

N

N

OCH35d

HN

N

N

OCH

O

6d

Table 1 (continued)

Entry Substrate Product Reaction time (h) Isolated/conversion yield (%)

4

O

N

N

OCH34d

NOH

N

N

OCH3

5d

2 68a

5

O

N

N

Br4e

NOH

N

N

Br5e

2 70b

6

O

N

N

NO24f

NOH

N

N

NO25f

2 73b

a Isolated yield.b Conversion yield.

NOH

N

N

R

NH

N

N

R

Ac2O, NaI, Xylene

100-120 o C

O

5 6

Scheme 5.

S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx 3


cyclohexane-1,3-dione (2) on treating with benzamidine hydro-chloride (3). Oximation of 4a with hydroxylamine resulted in2-phenyl-7, 8-dihydro-6H-quinazolin-5-one oxime (5a).18a

Similar reaction conditions were applied to the synthesis ofketo intermediates (4a–f) to produce the desired correspondingoximes (5a–f) in excellent yields. The oximation reactions wereclean and were completed in 2 h (Table 1). It was observed thatthe introduction of the substituent on the phenyl ring did not makeany impact on the yields of the products.

Reaction time (h) Isolated/conversion yield (%)

1.5 80a

0.5 82a

1.5 80a

3

2 80a

(continued on next page)



Table 2 (continued)

Entry Substrate Product Reaction time (h) Isolated/conversion yield (%)

5

NOH

N

N

Br5e

HN

N

N

Br

O

6e

2 78b

6

NOH

N

N

NO25f

HN

N

N

NO2

O

6f

2 75b

a Isolated yield.b Conversion yield.

NOH

NR

NH2OH.HCl, NaOAc

H2O, IPA, 60-70oC

O

NR

8 9

O

NH

7

CsCO3

DMF50oC

RX

Scheme 6. X = halogen; R = propyl, 4-nitrophenyl, 4-methylbenzyl.

N

NR

NOH

NR

O O

Ac2O, NaI

Xylene, 100-120oC

9 10

Scheme 7. R = propyl, 4-nitrophenyl, 4-methylbenzyl.


The reaction conditions for Semmler–Wolff aromatisation usingacetic anhydride and sodium acetate in the presence of inorganiciodide in xylene at higher temperature (100–120 �C), as reportedin our previous finding,9 provided good yields. The aromatisationof synthesised oximes (5a–f) to corresponding quinazoline deriva-tives under similar reaction conditions was then explored. It wasinferred that oximes (5a–f) too aromatised to 5-amino-quinazo-lines (6a–f) in a similar manner to produce good yields(Scheme 5).18b The reactions were clean and were completed inaround 2 h. Prolonged heating of oximes (5a–f) in acetic anhydridedid not have any impact on the yield of the product. Presence ofsubstitutions on the aryl group like methyl, fluoro, bromo, nitro

Table 3Series of synthesised indole oximes


1

O

N

8a

NOH

N

9a

2

O

N

8b

NO2

9b

N

NO2

NOH

3

O

N

8c

NOH

N

9c


and methoxy substituents did not affect the reaction course andresulted in aminoquinazolines (6a–f) in good yields (Table 2).

Subsequently to our development of manufacturing process for4- aminoindole derivative (AZD1981) via Semmler–Wolff aromati-sation, we further explored the application of this chemistry tosynthesise various other N-substituted indoles in order tounderstand the generality of the reaction and the effect of aryland alkyl substitution on the nitrogen atom during the course ofthe reaction.

N-alkyl/aryl-6,7-dihydro-5H-indol-4-one oximes (9a–c) weresynthesised from commercially available 1,5,6,7-tetrahydroin-dole-4-one (7) via N-alkylation/arylation. This protocol proved

Reaction time (h) Conversion yield (%)

18 92

18 89

18 82



Table 4Series of synthesised indole-4-amides

Entry Substrate Product Reaction time (h) Conversion yield (%)

1

NOH

N

9a

N

N

O O

10a

18 50

2

NOH

N

9b NO2

N

N

OO

10b NO2

18 57

3

NOH

N

9c

N

N

OO

10c

18 68

S. G. Manjunatha et al. / Tetrahedron Letters xxx (2014) xxx–xxx 5

superior over the previous one9 as a series of analogues could besynthesised by the reaction of indole-4-one (7) with various alkylor aryl groups. Refluxing the synthesised ketone (8a–c)18c withhydroxyl amine in the presence of sodium acetate and isopropylalcohol 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 optimisedSemmler–Wolff’s aromatisation conditions. Unlike the quinazo-lines, mono and diacylated products were observed at the initialstage 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 notaffect the course of the reaction and proceeded similarly to yielddesired indoles (10a–c) after column purification (Table 4).18e

As per the previous reports, compounds 6(a–f) and 10(a–c) canbe converted to the corresponding amines by treating with aque-ous NaOH solution.10

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. Thissynthetic methodology provides us the opportunity to place theamino group in its respective position in a very simple manneravoiding harsh conditions and multiple steps.

Acknowledgments

The authors are thankful to the management of AstraZeneca fortheir support. We thank the Analytical Department for their sup-port and discussions during the course of work.

Supplementary data

Supplementary data (spectral data for all the newly synthesisedcompounds) associated with this article can be found, in the onlineversion, 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.


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.

12. Ishikawa, F.; Saegusa, J.; Inamura, K.; Sakuma, K.; Ashida, S. J. Med. Chem. 1985,28, 1387–1393.

13. Warrener, R. N.; Russel, R. A.; Marcuccio, S. M. Aust. J. Chem. 1980, 33, 2777–2779.

14. Woodcraft, J.; Jones, C.; Gaeta, A.; Trigg, W.; Jones, P.; Plant, S.; Jackson, A.WO2011/42529A1.

15. Wu, F.; Buettner; Frank, H.; Chen, R.; Hickey, E.; Jakes, S.; Kaplita, P.; Kashem,M. A.; Kerr, S.; Kugler, S.; Paw, Z.; Prokopowicz, A.; Shih, C.-K.; Snow, R.; Young,E.; Cywin, C. L. Bioorg. Med. Chem. Lett. 2010, 20, 3235–3239.

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, 174–177.18. 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. Theresultant mixture was warmed to 65–70 �C and stirred for 1 h. The reactionwas completed as indicated by TLC. The reaction mixture was then quenchedwith 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 �Cand stirred for 1 h, by which time the reaction was completed as indicated byTLC. The reaction mixture was cooled to 60 �C and water (5.0 ml) was added tothe reaction mass. Then the reaction mixture was cooled to rt. The solid wasfiltered and the product was then purified by IPA slurry to obtain as a light



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yellow solid (6a). (c) Synthesis of 1-propyl-6,7-dihydro-5H-indol-4-one (8a): To astirred solution of 1,5,6,7-tetrahydroindole-4-one (7) (1 g, 6.51 mmol) andalkyl 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 asindicated by TLC. The reaction mixture was quenched with water andextracted with ethyl acetate and dried over anhydrous Na2SO4. The filtratewas concentrated under reduced pressure and solid obtained was dried in ovenat 50 �C. (d) Synthesis of 1-propyl-6,7-dihydro-5H-indol-4-one oxime (9a): to astirred 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 addedhydroxylamine 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 thereaction was completed as indicated by TLC. The reaction mixture wasquenched with water (10 ml) and stirred for additional 15 min, extracted with


ethyl acetate and dried over anhydrous Na2SO4. The filtrate was concentratedunder reduced pressure and solid obtained was dried in oven at 50 �C. Theproducts 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 stirredsolution 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. Theresultant mixture was heated to 100–120 �C and stirred for overnight, bywhich time the reaction was completed as indicated by TLC. The mixture wascooled to 20–25 �C and concentrated under vacuum. The residue was extractedwith dichloromethane. The organic layer was washed with water, dried overanhydrous Na2SO4 and concentrated under reduced pressure. Columnpurification of the isolated product resulted in pure 10a.



semmler–wolff aromatisation: a concise route for the synthesis of 5-amino-quinazolines and...

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