Electron Impact Fragmentation Patterns of3,3-Dimethyl-1,2-norbornane Derivatives

Antonio Garcıa Martı nez1*, Enrique Teso Vilar 2*, Amelia Garcıa Fraile2,Santiago de la Moya Cerero1 and Paloma Martınez Ruiz1

1Departamento de Quı´mica Organica I, Facultad de Ciencias Quı´micas, Universidad Complutense de Madrid (UCM), CiudadUniversitaria s/n. E-28040 Madrid, Spain2Departamento de Quı´mica Organica y Biologıa, Facultad de Ciencias, Universidad Nacional de Educacio´n a Distancia(UNED), Senda del Rey s/n, E-28040 Madrid, Spain

The electron impact mass spectra of several 3,3-dimethyl-1,2-norbornanediols, diamines, amino alcoholsand related derivatives have been studied and their fragmentation pathways discussed. Differentfragmentation patterns were observed, depending not only on the nature of the substituents, but also ontheir relative positions on the norbornane framework. In general, the dominant peaks in the spectra of thesecompounds originate from initial C1–C2 bond cleavage (a-cleavage) with charge retention on theheteroatom (oxygen or nitrogen) attached at the bridgehead position, followed by hydride shift and loss ofthe C2–C3 fragment by homolytic cleavage of the C3–C4 bond. This fragmentation pathway leads to ahighly stabilized cyclopentenylimmonium or cyclopentenyloxonium ion, which constitutes the base peak inthe spectra in most of the studied compounds. Copyright# 1999 John Wiley & Sons, Ltd.

Received 26 April 1999; Revised 19 May 1999; Accepted 20 May 1999

Enantiomerically pure vicinal diols, diamines, aminoalcohols and related derivatives are an important class ofcompounds in pharmaceutical chemistry due to their notablebiological activities.1 Furthermore, these compounds canact as chiral bidentate ligands and have found broadapplication in stereoselective synthesis.2 In this sense,enantiomerically pureb-amino alcohols have particularrelevance as chiral catalysts in enantioselective additionreactions.3 The most interesting of these chiral ligands aremolecules with a bicyclic framework, mainly camphor andother norbornane-based derivatives,4 such as the well-known 3-exo-dimethylaminoisoborneol (DAIB).3c

For all these reasons, the development of new syntheticroutes to this class of compounds is of great interest.However, the preparation of 1,2-disubstituted norbornaneshas serious limitations derived from the inertness of therigid bridgehead derivatives towards substitution reactions.Due to the lack of general procedures for the synthesis ofbicyclic structures of this kind, no systematic studies of theirmass spectra have been reported to date.

In the last years, we have described facile and convenientprocedures for the enantiospecific synthesis of 3,3- and 7,7-dimethyl-substituted 1,2-norbornane derivatives (diols,diamines, amino alcohols and other related compounds)starting from commercially available (ÿ)-fenchone and(�)-camphor.5 Now, we report here on the behaviour underelectron impact (EI) of a wide group of 3,3-dimethyl-substituted norbornane compounds with either amino orhydroxy groups (or their corresponding acyl or benzylderivatives) in both C1 and C2 positions (Fig. 1) in order todetermine their fragmentation pathways. The conclusionsderived from this study, in combination with other results

previously reported for norbornyl derivatives,6–11 canconstitute a helpful tool to elucidate the mass spectralpatterns of substrates of this kind.

EXPERIMENTAL

The 3,3-dimethyl-1,2-norbornane derivatives1–4and7–11(Fig. 1) were prepared from (�)-camphor by reaction withtriflic anhydride and subsequent transformations, accordingto procedures previously described by us (1,5a 2–4,5b

7–115c). Dimethylamino alcohols5 and 18 were easilyobtained from the corresponding primary precursors3 and2by a standard procedure.12 Ethyl- and diethylamino alcohols17and6 were prepared by alkylation of2 and4 respectivelywith ethyl iodide and potassium carbonate in refluxingethanol. Benzoyl derivatives14 and 15 were synthesizedfrom the corresponding amino alcohols4 and2 by reactionwith benzoyl chloride, using pyridine as buffer andmethylene chloride as solvent. Benzylamino alcohols13and16 were obtained from the benzoyl derivatives14 and15 by reduction with lithium and aluminium hydride indiethyl ether. Finally, diol12 was prepared following thesame procedure used for1,5a starting from the correspond-ing 7-pentyl-1-norbornyl triflate.5b IR, 1H- and 13C-NMRspectra were taken for each compound, and confirmed theexpected structures.

The 60 eV EI mass spectra were recorded using a QP5000 spectrometer coupled to a GC-17 capillary gaschromatograph (Shimadzu).

RESULTS AND DISCUSSION

According to the nature of the substituents attached to boththe C1 and C2 positions, two main fragmentation patternsare observed. Thus, title compounds1–18(Fig. 1) have beenarranged into two different series as shown in Tables 1 and2. The most significant peaks in the mass spectra of the

*Correspondence to: A. Garcı´a Martınez and E. Teso Vilar,Departamento de Quı´mica Organica y Biologıa, Facultad de Ciencias,Universidad Nacional de Educacio´n a Distancia (UNED), Senda delRey s/n, E-28040 madrid, Spain.E-mail: enriteso@sr.uned.es

CCC 0951–4198/99/141472–05 $17.50 Copyright# 1999 John Wiley & Sons, Ltd.

RAPID COMMUNICATIONS IN MASS SPECTROMETRYRapid Commun. Mass Spectrom.13, 1472–1476 (1999)

compounds are listed depending on their compositions orthe nature of the lost fragments (radicals or neutralmolecules).

The main fragmentation pathway of the compoundsincluded in series 1 (compounds1–15 in Fig. 1) starts withC1–C2 bond cleavage directed by the heteroatomicsubstituent attached to the bridgehead position, regardlessof its nature and substitution (Scheme 1). Thus, thefragmentations of these compounds can be best explainedif the charge is located almost totally on the bridgeheadheteroatomic substituent. Subsequent hydride shift from C7and homolytic C3–C4 bond cleavage leads to the highlystabilized cyclopentenylonium ion20, which constitutes thebase peak in the mass spectra of compounds1–9, 12and13,and the second peak in the mass spectra of compounds10,11 and14 (Table 1).

On the other hand, the base peak21 (C5H8N�, m/z82) in

the spectra of bisamides10and11 (see Table 1) arises fromthe parent cyclopentenylonium ion20 [m/z124 (50%) andm/z138 (52%), respectively] by loss of the correspondingketene (Scheme 2).

This fragmentation route is also supported by thespectrum of 7-anti-pentyl-3,3-dimethylnorbornano-1,2-endo-diol (12), which shows a peak atm/z 97 (32%, seeTable 1) as the result of a loss of an olefinic neutral

molecule from the parent cyclopentenylonium ion20 (m/z153, base peak) (Scheme 3).

The presence of aromatic substituents linked to thenitrogen or oxygen atom (13–15) introduces some easilypredictable variations in the mass spectra (Table 1). Thus,for N,O-dibenzoyl-N-ethyl-3,3-dimethyl-1-amino-2-endo-norbornanol (14) the main fragmentation route is directedby the benzoyl group, leading to the very stable benzoyl ion(C6H5CO�, m/z 105) as the base peak of the spectrum.However, the corresponding cyclopentenyl ion20 (m/z214)is also of great intensity (65%), emphasizing the importanceof the general fragmentation route of these compounds.Analogously, N-benzyl-N-ethyl-3,3-dimethyl-1-amino-2-endo-norbornanol (13) shows an intense peak atm/z 91[C7H7

� (tropylium ion, 89%)], together with the corre-sponding cyclopentenyl ion20 [m/z200 (100%)], becauseof the competitive tropylium-ion cleavage (Table 1).

The fragmentation pathway of compound15 is domi-nated by the aromatic substituents. In this case, the acylium-ion cleavage almost totally overrides the fragmentation ofthe C1–C2 bond, leading to benzoyl ion (m/z105) as thebase peak of the spectrum and C6H5

� [m/z77 (38%)] as thesecond fragment (see Table 1).

Compounds bearing either a mono- or disubstitutedamino group at the C2 position and a hydroxy group at C1

Figure 1. 3,3-Dimethyl-1-1,2-norbonane derivatives studied.

Copyright# 1999 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom.13, 1472–1476 (1999)

EI OF 3,3-DIMETHYL-1,2-NORBORNANE DERIVATIVES 1473

Table 1. EI mass spectra of 1,2-norbornane derivatives of series 1 [m/z (%B)]

CompoundMain cation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

M�.155 (2) 183 (1) 211 (2) 237 (2) 391 (1)

20 83 (100) 83 (100) 82 (100) 110 (100) 110 (100) 138 (100) 82 (100) 110 (100) 110 (100) 124 (50) 138 (52) 153 (100) 200 (100) 214 (65)21 82 (6) 82 (3) 82 (6) 82 (6) 82 (29) 82 (100) 82 (100) 211 (1)25 30 (84)C7H7

� 91 (89)[M ÿ NH3]

� 138 (21) 137 (5)PhC�O� 105 (100) 105 (100)[M ÿ PhC�O]� 286 (1) 258 (13)C6H5

� 77 (32) 77 (38)[M ÿ 15]� 140 (2) 168 (2) 168 (2) 196 (29)[20 ÿ C2H4]

� 110 (5) 110 (3) 172 (4) 186 (6)

Other peaks 55 (16) 123 (32) 55 (3) 55 (6) 55 (10) 56 (5) 165 (6) 152 (2) 43 (27) 181 (2) 97 (32) 176 (17)C4H7

� [138ÿ 15]� C4H7� C4H7

� C4H7� C4H8

�.[M ÿC2H5]

� [M ÿ NHCOH]� CH3C�O� [M ÿ EtC�O]� [153ÿ C4H8]� (26)

72 (70) 154 (1) 122 (6)(26) [M ÿC2H5]

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(16–18) are listed in Table 2. The proposed fragmentationpathway for this second series is characterized bya-cleavage of the C1–C2 bond with charge retention at thenitrogen atom, which is more able to localize the positive

charge than oxygen. Subsequent hydride shift and C2–C3bond cleavage in intermediate24 give rise to thecorresponding methyleneimmonium ion25, as shown inScheme 4. This behaviour agrees with previously reportedresults for 1,2-cyclohexane amino alcohols, which undergoanalogous C1–C2 bond cleavage with methyleneimmoniumion formation.8

The fragmentation pathway is strongly dependent on thenature of the nitrogen substituents. Thus, amino alcohols16–18, in which the C2 substituents are ethylamino anddimethylamino groups, respectively, undergo preferentiallythis fragmentation type with formation of25, which appearsas the base peak in the spectra of17 and 18, and as thesecond fragment [m/z120 (37%)] in the spectrum of16 (seeTable 2). Unlike this behaviour, amino alcohol2, in whichthe C2 substituent is a primary amino group (Fig. 1), followspreferentially the fragmentation route corresponding toseries 1 (see Table 1). Therefore, either mono or dialkylsubstitution on the C2 amino group plays an important rolein focusing the charge location almost totally on thenitrogen atom.

Table 2. EI mass spectra for 1,2-norbornane derivatives of series 2[m/z (% B)]

CompoundMain cation 16 17 18

M�. 245 (1) 183 (3) 183 (4)20 83 (14) 83 (13)25 120 (37) 58 (100) 58 (100)C7H7

� 91 (100)[M ÿ 15]� 168 (2) 168 (2)Other peaks 138 (4) 138 (1)

[M ÿ NHEt]� [M ÿ Me2N]�

123 (8) 100 (7)[138ÿ 15]� (26)100 (12)

(26)84 (12)72 (17)44 (25)

Scheme 1.

Scheme 2.

Scheme 4.

Scheme 3.

Copyright# 1999 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom.13, 1472–1476 (1999)

EI OF 3,3-DIMETHYL-1,2-NORBORNANE DERIVATIVES 1475

The aziridinium ion26 (m/z100), resulting from24 byC3–C4 homolyticb-cleavage (Scheme 4), is also present inthe mass spectra of both17and18 (12 and 7%, respectively,see Table 2)

When the C2 substituent is a benzylamino group(compound 16), the benzylic C–N bond cleavage ispredominant over C1–C2 cleavage, and tropylium ion (m/z91) is the base peak of the spectrum. Thus, like in series 1,the presence of aromatic groups also modifies substantiallythe fragmentation route in compounds of series 2.

Cyclopentenyloxonium ion20, resulting from chargelocation on the oxygen atom (see Scheme 1), is also presentin the fragmentation pattern of compounds16 and 17,although with weak intensity (14 and 13%, respectively)due to a preferential localization of the charge at thenitrogen atom. The charge is totally localized on thenitrogen atom when the amino group is dialkyl-substituted.Consequently, ion20 (m/z 83) is absent from the massspectrum of compound18 (Table 2).

It is noteworthy that 3,3-dimethyl-2-endo-amino-1-nor-bornanol (2), which belongs to series 1, shows intense peaksfor both25 [m/z30 (84%)] and26 [m/z72 (70%)] (Table 1),resulting from the fragmentation pathway proposed forseries 2 and shown in Scheme 4. This means that, in thiscase, the competitive initial C1–C2a-cleavage with respectto the nitrogen atom also becomes important. Therefore, theelectron impact behaviour of this compound is intermediatebetween the two fragmentation routes proposed for series 1and 2.

In summary, the study of the EI fragmentation patterns ina large number of 3,3-dimethyl-1,2-norbornanediols, di-amines, amino alcohols and related derivatives, haspermitted determination of the factors (nature and relativepositions of the substituents) controlling two alternativefragmentation pathways. Thus, the patterns of compoundsassigned to series 1 are in general very simple, as can beobserved in Table 1. Molecular ion peaks have either verylow intensity or are absent, and the spectra are clearlydominated by the corresponding cyclopentenylonium-ionpeaks, while the other few peaks are of quite low intensity.Compounds of series 2 also show a very simple fragmenta-

tion pattern, but are now dominated by the correspondingmethyleneimmonium ions (see Table 2).

REFERENCES

1. (a) M. Rouhi,Chem. Eng. News1996, 6; (b) N. Farrel,TransitionMetal Complexes as Drugs and Chemotherapeutic Agents, Chap.3. Structure-Activity Relationships of Platinum-Amine Com-plexes, pp. 67–94, inCatalysis by Metal Complexes, R. Ugo andB. R. James, (Eds) Vol. 11, Kluwer Academic Publishers,Dordrecht (1989).

2. (a) R. Noyori,Asymmetric Catalysis in Organic Synthesis,Wiley,New York, (1994); (b) Y. L. Bennani and S. Hanessian,Chem.Rev.97, 3161 (1997); (c) V. Dimitrov, K. Kostova and M. Hesse,Tetrahedron: Asymmetry5, 1891 (1994); (d) V. Dimitrov, M.Genov, S. Simova and A. Linden,J. Organomet. Chem.525,213(1996).

3. (a) H.-U. Blaser,Chem. Rev.92, 935 (1992); (b) K. Soai and S.Niwa, Chem. Rev.92, 833 (1992); (c) R. Noyori and M. Kitamura,Angew. Chem. Int. Ed. Engl.30, 49 (1991); (d) M. Kitamura, M.Yamakawa, H. Oka and R. Noyori,Chem. Eur. J.2, 1173 (1996).

4. (a) M. Genov, K. Kostova and V. Dimitrov,Tetrahedron:Asymmetry8, 1869 (1997); (b) W. Oppolzer and R. N. Radinov,Tetrahedron Lett.32, 5777 (1991); (c) W. Oppolzer,Tetrahedron43, 1969 (1987).

5. (a) A. Garcı´a Martınez, E. Teso Vilar, A. Garcı´a Fraile, S. de laMoya Cerero and L. R. Subramamian,Tetrahedron: Asymmetry5,1373 (1994); (b) A. Garcı´a Martınez, E. Teso Vilar, A. Garcı´aFraile, S. de la Moya Cerero, P. Martı´nez Ruiz and L. R.Subramanian,Tetrahedron: Asymmetry7, 1257 (1996); (c) A.Garcıa Martınez, E. Teso Vilar, A. Garcı´a Fraile, S. de la MoyaCerero and P. Martı´nez Ruiz,Tetrahedron: Asymmetry9, 1737(1998); (d) A. Garcı´a Martınez, E. Teso Vilar, A. Garcı´a Fraile, S.de la Moya Cerero, P. Martı´nez Ruiz and P. P. Garcı´a Alvarez,Tetrahedron: Asymmetry8, 849 (1997); (e) P. Martı´nez Ruiz“Sintesis y Aplicaciones de Derivados 1,2-Norbornı´licos Quir-ales.” Ph.D. Thesis, Universidad Complutense de Madrid, Madrid(1997).

6. T. Partanen, P. J. Ma¨lkonen and P. Vainiotalo,J. Chem. Soc.Perkin Trans.2 777 (1990).

7. T. Partanen, P. Vainiotalo, G. Sta`ger, G. Berna´th and K. Pihlaja,Org. Mass Spectrom.29, 126 (1994).

8. A. Daniel and A. A. Pavia,Org. Mass Spectrom.5, 1257 (1971).9. H.-F. Grutzmacher,Suomen Kemistil. A46, 50 (1973).

10. B. Kralj, V. Kramer, M. Trokman and J. Mansel,Croat. Chem.Acta.49, 727 (1977).

11. T. Partanen, P. Vainiotalo, G. Sta`jer, G. Berna´th, G. Gondos and K.Pihlaja,Rapid Commun. Mass Spectrom7, 1121 (1993).

12. B. L. Sondengam, J. H. He´mo, G. Charles,Tetrahedron Lett.3,261(1973).

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1476 EI OF 3,3-DIMETHYL-1,2-NORBORNANE DERIVATIVES