Tetrahedron Letters 53 (2012) 2417–2419

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Tetrahedron Letters

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Tandem Michael addition–Fries rearrangement of sorbylanilides:a convenient one pot synthesis of novel benzo[b]azocin-6-ones

Amit Anand a, Pardeep Singh a, Vishu Mehra a, Amandeep a, Vipan Kumar a,⇑, Mohinder P. Mahajan a,b

a Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, Indiab Apeejay Stya Research Foundation, Gurgaon, India

a r t i c l e i n f o a b s t r a c t

Article history:Received 1 October 2011Revised 27 February 2012Accepted 1 March 2012Available online 7 March 2012

Keywords:Michael addition–Fries rearrangementSorbylanilidesBenzo[b]azocin-6-onesTriflic acid

0040-4039/$ - see front matter � 2012 Elsevier Ltd. Ahttp://dx.doi.org/10.1016/j.tetlet.2012.03.002

⇑ Corresponding author.E-mail address: vipan_org@yahoo.com (V. Kumar)

The Letter pertains to an unprecedented tandem Michael addition–Fries rearrangement of sorbyl anilidesresulting in a convenient one pot synthesis of novel benzo[b]azocin-6-ones. The reaction is thought toproceed via a d-lactam intermediate, earlier considered un-reactive for Fries rearrangement. The pro-posed mechanism was further supported by examining the reactions of a,b-unsaturated anilides. Theirinability to undergo any transformation under similar reaction conditions, especially the Fries–Michaelrearrangement, indirectly validated the mechanism.

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Fries rearrangement, a 100 year old odyssey, is one of the mostsignificant synthetic strategies for the preparation of versatile acyl-ated scaffolds of biological and medicinal interest.1,2 The utility ofvariety of catalysts such as polyphosphoric acid,3 methanesulfonicacid/POCl3,4 montmorillonite clays,5 hafnium trifluoromethanesul-fonate,6 scandium trifluoromethanesulfonate,7 zirconium tetra-chloride8, and titanium tetrachloride9 in the said conversion hasbeen adequately demonstrated. However, Fries rearrangement ofanilides remains and is one of the areas of contemporary interest.Taddei and co-workers have recently disclosed the utility of photo-Fries rearrangement of anilides in the regio-controlled synthesis of1,4-benzodiazepin-2-ones.10 The methodology was further ex-tended to the synthesis of 2,4-disubstituted quinazolines, benzo-quinazolines, and enantiomerically pure quinazolies.11 Abedi andKaboudin have reported the thermal adaptation of Fries rearrange-ment of anilides in the presence of methanesulphonic acid/P2O5.12

Interestingly, such reaction in case of N-phenylcinnamide, an a,b-unsaturated amide, led to intramolecular cyclization withoutundergoing the desired Fries rearrangement. As an interesting var-iant, Anderson et al. have explored the triflic acid mediated Friesrearrangement of N-aryl-2-azetidinones, a cyclic anilide, leadingto the exclusive formation of o-acylated ring expanded products,2,3-dihydro-4(1H)-quinolones.13 The ring expansion in this case,was attributed solely to the inherent ring strain in b-lactams asc-lactam failed to undergo the rearrangement under the reactionconditions.

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.

The lack of substantial evidence concerning the Fries rearrange-ment in a,b-unsaturated anilides and in continuation of ourpursuits in the synthetic transformations sorbyl based precur-sors,14 it was thought worthwhile to explore the Fries rearrange-ment of sorbyl anilides. Interestingly, the treatment of 1,prepared by reported procedure15 with trifluoromethanesulphonicacid (1.0 equiv) led to the exclusive formation of novel benzo[b]azocin-6-one derivatives 2 in good yields (80–90%) probably viaan in situ Fries rearrangement of the initially formed d-lactam,an intramolecular Michael product (Scheme 1).

The structure 2 was assigned to the products on the basis ofspectral studies and analytical evidences.16

Interestingly, the use of other lewis acid catalysts viz. alumin-ium(III) chloride, zinc(II) chloride, titanium(IV) chloride, and meth-ane sulfonic acid did not result in any transformation of 1 underthe similar as well as stringent reaction conditions.

HN

OH5

H8

H7

H4aH3

H2

H1CH3

H4b

2b

H6

The compound 2b, for example, characterized as (Z)-2-methyl-

1,2-dihydrobenzo[b]azocin-6(5H)-one, was analyzed for C13H15NOand showed a molecular ion peak at m/z 187 (M+) in its massspectrum. The salient features of its 1H NMR spectrum include adoublet at d 1.73(J = 4.8 Hz) corresponding to azocinone ring methylprotons, doublet of an AB quartet at d 2.61(J = 6.3 Hz, 7.8 Hz,

HN

O

CH3R

R

HN

O

CH312

Product Rreaction time

(hrs) % yield

CF3SO3HDCE, rt

a p-CH3 7.2 87b H 7.2 81c p-Cl 7.5 90d p-OCH3 7.0 82e o-CH3 7.7 81f m-OCH3 6.2 84g p-NO2 9.3 52h 3,4-CH3 7.3 69

NR

H3C

O

Scheme 1. Triflic acid mediated synthesis of benzo[b]azocin-6-ones.

2418 A. Anand et al. / Tetrahedron Letters 53 (2012) 2417–2419

16.2 Hz) due to methylene protons, a quartert at d 3.63(J = 4.8 Hz)corresponding to methine proton and an unresolved multiplet at d5.48 corresponding to two olefinic protons. The structure assignedwas further authenticated unambiguously using 2-D NMR spectro-scopic techniques.16

The plausible mechanism for the formation of benzo[b]azocin-6-one 2 is depicted in Scheme 2 and may follow either Path Ainvolving an initial [6-endo-trig] Michael addition to form 6-methyl-1-aryl-3,6-dihydro-1H-pyridin-2-one 3 which undergoesFries rearrangement to yield the desired product 2. Alternatively,the sorbyl anilides may follow Path B involving an initial Fries rear-rangement to form substituted 1-(2-amino-aryl)-hexa-2,4-dien-1-one 4 which upon intramolecular [8-endo-trig] Michael additionresults in 2. However, 4 may prefer a more favored [6-endo-trig]process favoring the formation of 5 over a [8-endo-trig] processto form 6. The formation of 5 may also be preferred due to thehigher stability of six-membered ring over an alternative mediumsized eight-membered ring. Hence, the Path B may be discountedin favor of Tandem Michael addition–Fries rearrangement Path Afor the formation of 2.

In order to further support the proposed mechanism, we haveexamined the reactions of a,b-unsaturated anilides 7 under similarreaction conditions. It was felt that in this case, the tandem Friesrearrangement–Michael addition would be facilitated over

HN

OR

1

R

HN

O

CH3

HN

OH

CH3R

NR

OH

H3C

NR

O

H3C

RN

O

CH3

H

Path-A

FriMichael-Fries rearrangment

3

[6-endo-trig]

2

Scheme 2. Proposed mechanistic pa

Michael–Fries as the latter would involve the initial formation ofstrained b-lactam ring 9, while no such energy constrains will bepresent in the former case (Scheme 3). However, the inability of7 to undergo any transformation indirectly supports the Michaeladdition–Fries rearrangement for the formation of 2 in case ofsorbyl anilides.

Recent revelations by Abedi and Kaboudin on the attemptedFries rearrangement of N-phenylcinnamide showed the isolationof quinoline-2(1H)-one as the major product via intramolecularcyclization.12 However such an intramolecular cyclization in caseof sorbyl anilides may be ruled out because:

(a) Sorbyl anilides 1 did not undergo any transformation underthe intramolecular cyclization reaction conditions viz. P2O5/CH3SO3H reported by Abedi and Kaboudin.

(b) The intramolecular cyclization of sorbyl anilide 1 wouldprefer the favored [6-endo-trig] process to yield more stable6-membered product over the [8-endo-trig] process to formrelatively less stable eight-membered product. These obser-vations also provide circuitous evidences in favor of theMichael-Fries mechanism leading to the formation ofbenzo[b]azocin-6-ones in the reactions of sorbylanilides 1with trifluoromethanesulphonic acid.

CH3HN

OH

CH3R

NHR

O

CH3H

NH2R

O

CH3

R

HN

HO

CH3

Path-B

es-Michael rearrangement

4

[6-endo-trig][8-endo-trig]

HN

R

O

CH3

56

thways for the formation of 2.

HN

O

Fries rearragement

Fries rearragement

Michael addition

Michael addition

Fries-Michael rearrangement

Michael-Fries rearrangement

7

8

9

10

RR1

NH2R

R1

O

NR O

R1

R = H, -p-CH3, -p-OCH3, m-OCH3R1 = H, CH3, C6H5

R

HN

O

R1

[4-endo trig]

[6-endo trig]

Scheme 3. Reaction of triflic acid with a,b-unsaturated anilides.

A. Anand et al. / Tetrahedron Letters 53 (2012) 2417–2419 2419

In conclusion, the present Letter explicates an easy access to arange of novel benzoazocin-6-ones which constitute an importantframework in several alkaloids. Alkaloids such as manzamine-A,keramamine-A with some dibenzoazocines have been reported toexhibit hypotensive properties.17 The approach assumes signifi-cance as it entails an unprecedented tandem Michael addition–Fries rearrangement of sorbyl anilides via a d-lactam intermediate,earlier considered un-reactive even under drastic reaction condi-tions.13 Further studies on this methodology and its potentialapplications to explore its potential for the synthesis of novel het-erocyclics are under progress.

Acknowledgments

The financial support from CSIR, New Delhi under Scheme No.01(2407)/10/EMR-II (V.K.) is gratefully acknowledged.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2012.03.002.

References and notes

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3. Shargi, H.; Eshghi, E. Bull. Chem. Soc. Jpn. 1993, 66, 135.4. Kaboudin, B. Tetrahedron 1999, 55, 12865.5. Venkatachalapathy, C.; Pitchumani, K. Tetrahedron 1997, 53, 17171.6. Kobayashi, S.; Moriwaki, M.; Hachiya, I. Tetrahedron Lett. 1996, 37, 2053.7. Kobayashi, S.; Moriwaki, M.; Hachiya, I. J. Chem. Soc., Chem. Commun. 1995,

1527.8. Horrowven, D. C.; Dainty, R. R. Tetrahedron Lett. 1996, 37, 7659.9. Martin, R.; Demerseman, P. Synthesis 1989, 25.

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(b) Anand, A.; Bhargava, G.; Hundal, M. S.; Mahajan, M. P. Heterocycles 2007, 73,689; (c) Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett. 2007, 48,2365; (d) Bhargava, G.; Mohan, C.; Mahajan, M. P. Tetrahedron 2008, 64, 3017;(e) Bhargava, G.; Anand, A.; Mahajan, M. P.; Saito, T.; Sakai, K.; Medhi, C.Tetrahedron 2008, 64, 6801; (f) Anand, A.; Bhargava, G.; Singh, P.; Mahajan, M.P. Heterocycles 2009, 77, 547; (g) Anand, A.; Bhargava, G.; Kumar, V.; Mahajan,M. P. Tetrahedron Lett. 2010, 51, 2312; (h) Raj, R.; Mehra, V.; Singh, P.; Kumar,V.; Mahajan, M. P.; Handa, S.; Slaughter, L. M. Eur. J. Org. Chem. 2011, 2697–2704; (i) Singh, P.; Bhargava, G.; Kumar, V.; Mahajan, M. P. Tetrahedron Lett.2010, 51, 4272.

15. Narasimhan, B.; Judge, V.; Narang, R.; Ohlan, R.; Ohlan, S. Bioorg. Med. Chem.Lett. 2007, 17, 5836.

16. For Detailed 1H NMR, 13C, DEPT, HSQC and HMBC, see Supplementary data.17. (a) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am. Chem. Soc. 1986, 108,

6404; (b) Ichiba, T.; Sakai, R.; Kohmoto, S.; Saucy, G.; Higa, T. Tetrahedron Lett.1988, 29, 3083; (c) Nakamura, H.; Deng, S.; Kobayaski, J.; Ohizumi, Y.;Tomokate, Y.; Matsuzaki, T.; Hirata, Y. Tetrahedron Lett. 1987, 28, 621; (d)Casadio, S.; Pala, G.; Crescenzi, E.; Marazzi-uberti, E.; Coppi, G.; Turba, C. J. Med.Chem. 1968, 11, 97.