Intramolecular-activation evidence for the unexpected Beckmannfragmentation of C(1)-substituted-7-bromonorbornane-2-ones

Antonio Garcıa Martınez,a,* Enrique Teso Vilar,b Amelia Garcıa Fraile,b

Santiago de la Moya Cereroa,* and Beatriz Lora Marotob

aDepartamento de Quımica Organica I, Facultad de Quımicas, Universidad Complutense de Madrid, 28040 Madrid, SpainbDepartamento de Quımica Organica y Biologıa, Facultad de Ciencias, UNED, Senda del Rey 9, 28040 Madrid, Spain

Received 28 May 2004; revised 22 July 2004; accepted 3 August 2004

In Memoriam to our friend Dr. del Amo Aguado, victim of the terrorist bombing in Madrid, March 11, 2004

Abstract—The competitive pathway timing for the previously described unexpected bromo-assisted Beckmann fragmentation of 7-anti-bromo-3,3-dimethyl-2-oxonorbornane-1-carboxamide has been investigated. It is concluded that this unusual process is activated by asynergic effect exerted by both the C(7)-anti-bromo and C(1)-aminocarbonyl groups. The effect consists in a specific intramolecularactivation of the bromo-assistance by the bridgehead aminocarbonyl group.q 2004 Elsevier Ltd. All rights reserved.

1. Introduction

In a previous publication, we described the unexpected insitu Beckmann fragmentation of enantiopure 7-anti-bromo-3,3-dimethyl-2-oxonorbornane-1-carboxamide 1 undersimple hydroxylamine treatment (Scheme 1).

The process resulted to be highly interesting, since itconstitutes the first example in which a C(1)-electronwith-drawing substituted 3,3-dimethylnorbornan-2-one exper-iments an in situ Beckmann fragmentation of the C(1)–C(2)norbornane bond (leading to the valuable enantiopuresynthetic intermediate 2),1 instead of the expected oximeformation and subsequent C(2)–C(3) Beckmann fragmenta-tion.2 This unexpected fragmentation was initially attributedto a single effect exerted by the bromo substituent located atthe C(7)-anti-norbornane position (bromo assistance).2

Going in this sense, we were interested in extending thissynthetically valuable fragmentative process to otherdifferently substituted 2-norbornanones. For this purpose,the establishment of the structural factors controlling theconsidered fragmentation was necessary, since other 2-bromonorbornanones (e.g., 7-anti-bromofenchone) do notexperiment such fragmentation in the same reaction

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2004.08.002

Keywords: Substituent effects; Cleavage reactions; Bicycles; Bridgehead

compounds.

* Corresponding authors. Tel.: C91-394-4236; fax: C91-394-4103;

e-mail: santmoya@quim.ucm.es

conditions in which 1 does (vide infra). For this purpose,we have revisited and investigated the fragmentation of 1 to2 (Scheme 1).

2. Results and discussion

Since during the considered reaction (Scheme 1), not onlyBeckmann fragmentation takes place, but also hydrolysis ofthe aminocarbonyl group (note the presence of the carboxylgroup in final product 2, Scheme 1), we were interested ininvestigating the mechanism of such reaction in order todetermine the timing of the individual processes (oximeformation, amide hydrolysis and Beckmann fragmentation).Thus, three possible reaction pathways (A, B and C) can beproposed on the base of three different timing possibilities.These reaction pathways are shown in Scheme 2.

Thus, the starting bromonorbornanone 1 can undergo twodifferent individual processes: (1) oxime formation, giving

Tetrahedron 60 (2004) 9447–9451

Scheme 1. Unexpected in situ Beckmann fragmentation of 1.

Scheme 2. Proposed reaction pathways.

A. Garcıa Martınez et al. / Tetrahedron 60 (2004) 9447–94519448

place to norbornanone oxime 3 and, (2) amide hydrolysis, togenerate bridgehead carboxylic acid 4. Of course, bothindividual processes could also occur competitively. Never-theless, we have discarded the amide-hydrolysis process bytwo simple experiments: (1) treatment of 1 with hydro-xylamine chlorhydrate in absence of base (acid medium)and, (2) treatment of 1 with pyridine (basic medium). Inboth cases, the reaction was carried out in refluxing aqueousethanol (Scheme 3).2

Scheme 3. Discarding hydrolysis as the first-occurring process.

Scheme 4. Detecting intermediates.

Figure 1. Proposed amide hydrolysis activation by the oxime function.

Oxime formation is not observed in any of theseexperiments (free hydroxylamine is not present in thereaction media), but the existence of an acid, or basic,medium could promote the amide hydrolysis (acid or basiccatalysis). However, as expected for a sterically hinderedamide,3 the hydrolysis of the bridgehead aminocarbonylgroup of 1 does not occur in the mild (acid or basic) reactionconditions (Scheme 3). Therefore, reaction pathway C,consisting of a first amide hydrolysis, subsequent oximeformation and final Beckmann fragmentation (1/4/6/2, see Scheme 2) can be discarded.

Once established that the first-occurring process is theoximination of 1 to 3, the formed oxime could undergo: (1)

a Beckmann fragmentation to 5, followed by amidehydrolysis to 2 (reaction pathway A) or; (2) an amidehydrolysis to 6 and subsequent Beckmann fragmentation to2 (reaction pathway B). Of course, once again, bothpossibilities could also occur competitively.

Trying to detect some reaction intermediate (3, 5 or 6), wequenched the reaction (1/2, Scheme 1) at a short time(Scheme 4). Thus, when 1 is treated with NH2OH$HCl/pyridine (mol equiv: 3:3) in refluxing aqueous ethanol foronly 6 h, a mixture of starting 1, final 2 and oximeintermediate 64 is obtained (1/2/6Z4:64:32).5

Detection of intermediate 6 indicates that pathway B (1/3/6/2) works. Nevertheless, it is not possible to discardthe competition of reaction pathway A (1/3/5/2).

Moreover, detection of 6, but not 5, seems to show thatamide-group hydrolysis of oxime 3 (3/6 in Scheme 2) ismore activated than the analogue amide hydrolysis ofstarting ketone 1 (1/4 in Scheme 2). This activation couldbe probably due to an intramolecular effect exerted by thehydroxyl group of the oxime function (Fig. 1).6

In the case of a possible competition between pathways Aand B, the last step in pathway A (5/2) must be faster thanthe last step in pathway B (6/2), since intermediate 6 is

A. Garcıa Martınez et al. / Tetrahedron 60 (2004) 9447–9451 9449

detected at short reaction times, whereas 5 is not (cf.Schemes 2 and 4). A way to test this possible competition iscomparing the reactions of C(1)-aminocarbonyl-substitutedbromonorbornan-2-one 1 and C(1)-carboxyl-substitutedbromonorbornan-2-one 43a with hydroxylamine in thesame reaction conditions (Scheme 5).

Scheme 5. Reaction of interemediate 4 with hidroxylamine.

Thus, after 12 h of reaction with NH2OH$HCl/pyridine(3:3) at refluxing aqueous ethanol, norbornanone 1 is totallyreacted to final 2 (Scheme 1), whereas 4 gives place to theformation of the corresponding oxime 6 (Scheme 4).4,5

Nevertheless, increasing the reaction time to 3 days allowsto detect a minor product 2 together with major 6 (6/2Z91:9).4,5

Consequently, reaction pathway A has to be the main one,since transformation of 4 to 2 under hydroxylaminetreatment (indefectible through intermediate 6, see Scheme2) is slower than transformation of 1 to 2 (either throughdetected intermediate 6 or through undetected intermediate5, cf. pathways B and A in Scheme 2).

On the other hand, since intermediate 5 is not detected, theslow steps (limiting steps) of the overall process 1 to 2 mustbe the Beckmann-fragmentation steps (3/5 for pathway A,and 6/2 for pathway B). Additionally, since Beckmannfragmentation 3/5 takes place faster (easily) than theBeckmann fragmentation 6/2, the differential C(1)-group(aminocarbonyl for 3 and carboxyl for 4) has to play someimportant role in activating such fragmentation.

In order to explain these experimental facts, we havepostulated a specific intramolecular activation of the bromoassistance for the fragmentation. This intramolecularactivation would be exerted by the C(1)-group, due to itsnucleophile (bromophile) character (Fig. 2). Thus, theactivating effect should be stronger for the C(1)-aminocar-bonyl group than for the C(1)-carboxyl one, which wouldexplain the higher facility for Beckmann fragmentationexhibited by 3, when compared with 6.7

Additionally, the postulated intramolecular electronicactivation of the bromo-assistance for the Beckmann

Figure 2. Intramolecular bromophile-reaction activation.

fragmentation of 3 (see Fig. 2) would also explain theunexpected fast hydrolysis of the amide intermediategenerated after the fragmentation8 since such intermediatewould not be the primary amide 5, but the highly reactive(undetected) N-bromo-substituted amide Br-5 (Scheme 6).

We have tested the existence of this possible synergic effectby submitting to hydroxylamine treatment an analogous7-anti-bromonorbornan-2-one bearing a C(1)-group withoutthe possibility of exerting such activating effect. The chosennorbornanone was 7-anti-bromo-1,3,3-trimethylnorbornan-2-one (7-anti-bromofenchone) 7,9 due to its syntheticavailability (Fig. 2). As expected, when 7 was submittedto hydroxylamine treatment in the same reaction conditionsin which 1 and 4were reacted,2 corresponding 2-norbornaneoxime 8 was detected as the only reaction product (Scheme7).5,10 This fact also discards a controlling intermolecularbromophile-reaction activation.7

Finally, a referee has proposed a possible participation offree ammonia (coming from the activated amide hydrolysisof 3 to 6, see Scheme 2 and Fig. 1) as the possibleresponsible of the bromo-activation instead of the bridge-head amide group. This intermolecular activation would bemore effective than the analogue free-pyridine or free-hydroxylamine activation, due to the stronger base characterof ammonia (cf. pKa 9.2 for ammonium and pKa 5.2 forhydroxylammonium or pyridinium). In order to test thispossibility, we have try to activate the fragmentation ofoxime 6, treating such oxime with ethanolamine (pKa 9.5 forethanolamonium) in the standard reaction conditions.Nevertheless, such activation was not observed, being theoxime recovered unaltered.

3. Summary

The competitive reaction pathways for the unexpected insitu Beckmann fragmentation of 7-anti-bromo-3,3-dimethyl-2-oxonorbornane-1-carboxamide have beeninvestigated. It is concluded that the main reaction pathwayconsists probably in a first oxime-formation process,subsequent Beckmann fragmentation and final amidehydrolysis. This pathway seems to be competitive with asecondary one, in which the amide hydrolysis of oximeintermediate 3 occurs before Beckmann fragmentation.Furthermore, the differential behavior exhibited by thenorbornanones 1, 4 and 7 in their reactions with hydro-xylamine, has allowed to conclude that the Beckmannfragmentation process is probably promoted by a synergic

Scheme 7. Reaction of 7 with hydroxylamine.

Scheme 6. Effect of the synergic activation on the amide-hydrolysis rate.

A. Garcıa Martınez et al. / Tetrahedron 60 (2004) 9447–94519450

effect, consisting in a specific intramolecular electronicactivation of the bromo-assistance exerted by the amino-carbonyl group. When such electronic activation isinexistent (e.g., in 7-anti-bromonorbornan-2-one 7), in situBeckmann fragmentation does not take place after hydro-xylamine treatment. Further investigation on the applicationof the postulated synergic effect, as synthetic tool promotingthe Beckmann fragmentation of 7-halonorbornanones, is inprogress.

4. Experimental

4.1. General

All starting materials and reagents were obtained from well-known commercial suppliers and were used without furtherpurification. Anhydrous solvents were properly dried understandard conditions. Flash chromatography was performedover silica gel (150 mesh). 1H and 13C NMR were recordedon 200-MHz and 300-MHz spectrometers. Chemical shifts(d) for 1H and 13C NMR were recorded in ppm downfieldrelative to the internal standard tetramethylsilane (TMS),and coupling constants (J) are in Hz. IR spectra wererecorded on a FT spectrometer. Mass spectra were recordedon a 60 eV mass spectrometer. For gas–liquid chromato-graphy (GLC), a chromatograph equipped with capillarysilicon-gum column (TRB-1) was used. HRMS wererecorded in a mass VG Autospec spectrometer, using theFAB technique.

4.1.1. Synthesis of 7-anti-bromo-3,3-dimethyl-2-oxonor-bornane-1-carboxamide 1. Norbornane-1-carboxamide 1was prepared from 3-endo-bromocamphor, as previouslydescribed by us.2a Pale yellow solid. Mp 156–158 8C.

[a]D20ZK68.1 (1.04, CHCl3). HRMS: 180.1031 (calculated

for C10H14NO2, 180.1025).1H NMR (CDCl3, 200 MHz), d:

6.75 (br s, 1H), 6.42 (br s, 1H), 4.72 (s, 1H), 2.45–2.26 (m, 3H),2.01 (m, 1H), 1.69 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H) ppm. 13CNMR (CDCl3, 50 MHz), d: 212.6 (CO), 169.6 (CONH2), 68.6(C), 55.0 (CH), 52.3 (CH), 49.8 (C), 25.9 (CH2), 25.8 (Me),22.6 (CH2), 22.3 (Me) ppm. FTIR (CCl4), n: 3331, 1755,1668 cmK1. MS, m/z: 180 (MC%KBr, 3), 28 (100).

4.1.2. Synthesis of 7-anti-bromo-3,3-dimethyl-2-oxonor-bornane-1-carboxylic acid 4. Norbornane-1-carboxylicacid 4 was prepared from 3-endo-bromocamphor, aspreviously described by us.3a White solid. Mp 145–146 8C(decomposes). [a]D

20ZK58.6 (3.21, CHCl3). HRMS:181.0864 (calculated for C10H13O3, 181.0865).

1H NMR(CDCl3, 200 MHz), d: 10.62 (br s, 1H), 4.73 (s, 1H), 2.48–2.22 (m, 3H), 1.98–1.67 (m, 2H), 1.19 (s, 6H) ppm. 13CNMR (CDCl3, 50 MHz), d: 210.2 (CO), 173.0 (CO2H), 69.6(C), 54.1 (CH), 52.6 (CH), 50.0 (C), 24.6 (CH2), 23.3 (Me),22.3 (Me), 22.2 (CH2) ppm. FTIR (CCl4), n: 2986 (broad),1749, 1701 cmK1. MS, m/z: 181 (MC%K Br, 11), 41 (100).

4.1.3. Synthesis of 7-anti-bromo-1,3,3-trimethylnorbor-nan-2-one (7-anti-bromofenchone) 7. Norbornanone 7was prepared from fenchone, as previously described byus.9 White solid. Mp 45–46 8C. [a]D

20ZC163.1 (2.23,CHCl3).

1H NMR (CDCl3, 300 MHz), d: 4.27 (d, JZ1.1 Hz, 1H), 2.34 (d, JZ3.8 Hz, 1H), 2.22 (m, 1H), 1.90–1.75 (m, 2H), 1.37 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H), 1.10(s, 3H) ppm. 13C NMR (CDCl3, 50 MHz), d: 217.1 (CO),61.3 (CH), 58.8 (C), 52.7 (CH), 49.1 (C), 29.4 (CH2), 23.1(Me), 22.9 (CH2), 22.5 (Me), 12.7 (Me) ppm. FTIR (CCl4),n: 1747 cmK1. MS, m/z: 151 (MC%KBr, 2), 81 (100).

4.2. Reaction of 7-anti-bromonorbornan-2-ones withhydroxylamine. General procedure

For comparison, 7-anti-bromonorbornan-2-ones 1, 4 and 7were reacted with hydroxylamine (NH2OH$HCl/pyridine)following the same standard conditions described pre-viously for 1 (refluxing aqueous ethanol for 12 h).2a

4.2.1. Reaction of 4 with hydroxylamine: 7-anti-bromo-2-hydroxyimino-3,3-dimethylnorbornane-1-carboxylic

A. Garcıa Martınez et al. / Tetrahedron 60 (2004) 9447–9451 9451

acid 6. Detected in the reaction-extract mixture as a coupleof stereoisomers.4,5 Yield 90%. An analytical sample of theenriched major isomer of oxime 6 was obtained afterpurification by elution chromatography (silica gel andCH2Cl2/ether 8:2). 1H NMR (CDCl3, 200 MHz), d: 9.89(br s, 1H), 4.39 (s, 1H), 2.40 (m, 1H), 2.28–2.10 (m, 2H),1.88 (m, 1H), 1.70 (m, 1H), 1.28 (s, 3H), 1.24 (s, 3H) ppm.13C NMR (CDCl3, 50 MHz), d: 174.6 (CO2H), 164.3(CNOH), 61.5 (C), 57.7 (CH), 53.9 (CH), 43.8 (C), 26.6(Me), 25.2 (CH2), 25.0 (Me), 22.4 (CH2) ppm. FTIR (CCl4),n: 3103 (broad), 1716 cmK1.

4.2.2. Reaction of 7 with hydroxylamine: 7-anti-bromo-1,3,3-trimethylnorbornan-2-one oxime (7-anti-bromo-fenchone oxime) 8.Detected in the reaction-extract mixtureas a single stereoisomer (probably the anti one), as it occursin the oximination of other related 3,3-dimethylsubstituytednorbornan-2-ones.11 Purification was realized by elutionchromatography (silica gel and CH2Cl2). Yield: 88%. Whitesolid. Mp 133–135 8C. [a]D

20ZK34.0 (1.80, CHCl3).1H

NMR (CDCl3, 300 MHz), d: 8.71 (s, 1H), 4.13 (s, 1H),2.13–2.02 (m, 2H), 1.89–1.74 (m, 2H), 1.45 (m, 1H), 1.41(s, 3H), 1.35 (s, 3H), 1.89 (s, 3H) ppm. 13C NMR (CDCl3,50 MHz), d: 168.9 (CNOH), 61.7 (CH), 54.9 (CH), 54.9 (C),43.7 (C), 31.3 (CH2), 23.0 (CH2), 22.8 (Me), 22.7 (Me), 14.7(Me) ppm.

Acknowledgements

We would like to thank the Ministerio de Educacion,Ciencia y Tecnologıa of Spain (BQU2001-1347-C02-02)and UNED (research project 2001V/PROYT/18) for thefinancial support of this work. B. L. M. wishes to thank theMinisterio de Educacion, Cultura y Deporte for a post-graduate grant.

References and notes

1. Enantiopure cyclopentene nitriles and cyclopentene car-

boxylic acids are important intermediates in the preparation

of valuable natural products with biological activities. Some

interesting example are: (a) Trost, B. M.; Chan, M. T. J. Am.

Chem. Soc. 1983, 105, 2315 and references cited therein.

(b) Garcıa Martınez, A.; Teso Vilar, E.; Garcıa Fraile, A.; de la

Moya Cerero, S.; Maichle, L. R.; Subramanian, L. R.

Tetrahedron: Asymmetry 1994, 5, 949. (c) Garcıa Martınez,

A.; Teso Vilar, E.; Garcıa Fraile, A.; de la Moya Cerero, S.;

Martınez Ruiz, P.; Subramanian, L. R. Tetrahedron: Asym-

metry 1996, 7, 2177. (d) Garcıa Martınez, A.; Teso Vilar, A.;

Garcıa Fraile, A.; de la Moya Cerero, S.; de Oro Osuna, S.;

Lora Maroto, B. Tetrahedron Lett. 2001, 42, 7795 and

references cited therein.

2. (a) Garcıa Martınez, A.; Teso Vilar, E.; Garcıa Fraile, A.; de la

Moya Cerero, S.; Lora Maroto, B. Eur. J. Org. Chem. 2002,

781 and supporting references therein. On the importance of

the stero- and regiocontrol in the alkenyl-function formation at

Bekmann fragmentations, see a related silicon-directed

Beckmann fragmentation in (b) Nishiyama, H.; Sakuta, K.;

Osaka, N.; Arai, H.; Matsumoto, M.; Itho, K. Tetrahedron

1988, 44, 2413 and references therein.

3. On the hydrolysis conditions of related bridgehead carboxylic-

acid derivatives, see: (a) Garcıa Martınez, A.; Teso Vilar, E.;

Garcıa Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B.

Tetrahedron: Asymmetry 2002, 13, 1837. (b) Garcıa Martınez,

A.; Teso Vilar, E.; Garcıa Fraile, A.; de la Moya Cerero, S.;

Gonzalez-Fleitas de Diego, J. M.; Subramanian, L. R.

Tetrahedron: Asymmetry 1994, 5, 1599. On the dependence

of the rate of amide hydrolysis on the substitution near the

amide group see: (c) Cason, J.; Gataldo, C.; Glusker, D.;

Allinger, J.; Ash, L. B. J. Org. Chem. 1953, 18, 1129. (d) de

Roo, M.; Bruylants, A. Bull. Soc. Chim. Belg. 1954, 63, 140.

4. Intermediate oxime 6 was detected by NMR of corresponding

reaction extracts as a couple of stereoisomers (E/Z) in near 3:1

ratio.

5. Determined by 1H NMR analysis of the reaction extract

mixture.

6. On a related intramolecular amide-hydrolysis activation

produced by the hydroxyl group of a carboxyl function see,

for example: (a) Kirby, A. J.; Lancaster, P. W. J. Chem. Soc.,

Perkin Trans. 2 1972, 1206. (b) Kluger, R.; Lam, C. H. J. Am.

Chem. Soc. 1978, 100, 2191.

7. At this point, a controlling activation via an intermolecular

‘X-philic’ reaction Zefirov, N. S.; Makhon’kov, D. I. Chem.

Rev. 1982, 82, 615, involving attack at bromo by pyridine or

free hydroxylamine can be discarded, since such activation

should play a similar role in both intermediated 6 and 3.

8. It is well known the low reactivity of a,b-unsaturated amides

towards hydrolysis for example see: Robinson, B. A.; Tester,

J. W. Int. J. Chem. Kinet. 1990, 22, 431.

9. Garcıa Martınez, A.; Teso Vilar, E.; Garcıa Fraile, A.; de la

Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry

2003, 14, 1607.

10. This experiment also demonstrates that the Beckmann

fragmentation of the studied C(1)-substituted 7-anti-bromo-

norbornan-2-one oximes probably takes place synchronously,

since a stepped process (through an a-substituted cyclopentyl-carbocation intermediate) would be more favored for a methyl

a-group (electron-donor group), than for an aminocarbonyl, or

carboxyl, a-group (electron-acceptor group).

11. Garcıa Martınez, A.; Teso Vilar, E.; Garcıa Fraile, A.; de la

Moya Cerero, S.; Dıaz Oliva, C.; Subramanian, L. R.; Maichle,

C. Tetrahedron: Asymmetry 1994, 5, 949 and references cited

therein.