Electron ionization mass spectra of naphthoxazine, naphthpyrrolo-oxazinone and naphthoxazinobenzoxazine derivatives

Some naphthoxazinobenzoxazines ( 1a , 1b , 2a − 2d , 3a , 3b ), naphthoxazines ( 4a , 4b , 5 , 6a , 6b ) and naphthpyrrolo-oxazinones ( 7 , 8a , 8b ) were studied using mass spectrometry to find out regioisomeric effects and the effects of substituents. As expected the spectra of regioisomeric pairs 1a − 3a vs 1b − 3b were very different. For example the relative abundances of molecular ions were higher for 1a − 3a and the [M − OH] + ions were observed only for them. Compounds derived from (1-α -aminobenzyl)-2-naphthol were usually characterized by abundant m/z 231 ions and 1-aminomethyl-2-naphthol derivatives by m/z 156 ions. Ions related or similar to their complementary ions were also observed. Many of the studied compounds exhibited fairly abundant ions [M − C 17 H 11 O 2 ] + ( 1a , 2a , 3a : [M − 247] + ), [M − C 17 H 12 O] +• ( 2b − 2d : [M − 232] +• ) or ion [M − C 11 H 8 O] +• ( 1b , 5 , 6a , 7 : [M − 156] + ). The results may be useful when making regiochemical conclusions.


Introduction
3][4] They and their analogues commonly contain stereogenic centers and therefore regioselective and diastereoselective syntheses using Betti base synthons is gaining popularity.For example the ligands corresponding to the structure of N,N-dialkyl Betti base are becoming important in asymmetric syntheses catalyzed by metallic ions. 5,61-α-Aminobenzyl)-2-naphthol and its derivatives can be transformed to naphthoxazinobenzoxazine derivatives via ring-closure reactions. 3,4Ring-closure reactions can be also used to synthesize naphthoxazinones and naphthoxazinoisoindolones from 1-aminomethyl-2-naphthol. 3 These syntheses are usually highly diastereoselective. 3,4o continue our studies on the electron ionization mass spectrometry (EI MS) of condensed isomeric heterocycles, 7,8 especially molecules containing 1,3-oxazine moiety, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] a group of naphthoxazine, naphthpyrrolo-oxazinone and naphthoxazino-benzoxazine derivatives were studied.The EI spectra of 16 compounds 1a, 1b, 2a−d, 3a, 3b, 4a, 4b, 5, 6a, 6b, 7, 8a, 8b, (the formulas are given in Chart 1 and the names 3,4 in Table 1) were studied.Compounds consisted of three pairs of regioisomers (1a/b, 2a/b and 3a/b), the mass spectra of which were compared with each other.The other ten compounds were studied to clarify the effects of different substituents.The conformational analysis using NMR spectroscopy, molecular modelling and geometry optimization of selected compounds 2b, 2c, 8b and also 1a, 1b, 3a were reported earlier. 3,44][25] The ring-openings related to tautomerism require a hydrogen-transfer.However in some ring-openings also a zwitterion can be formed.This does not require any hydrogen-transfer, for example photochromic compounds have been designed based on photoinduced ring opening of 1,3-oxazine ring. 26,27Ring opening has not been reported for the sixteen compounds studied now.The ring-chain tautomerism requiring transfer of hydrogen from nitrogen to oxygen is not possible for the studied molecules with tertiary nitrogen.However mass spectrometric processes involving ring opening have been reported also for 1,3-oxazine compounds with tertiary nitrogen. 16or 1,3-oxazines the most significant EI MS fragmentations can usually be interpreted based on the charge localisation on the nitrogen. 10,15,16,20,28However the charge can also be localized on aromatic rings or oxygen, such is the case with octahydro-1,3-benzoxazines. 20lso the EI MS fragmentations of imino-compounds 6a and 6b can be compared with Nunsubstituted 4,5-cyclohexane-annelated 1,3-oxazines. 29perimental Section General Procedures.The electron ionization (EI) mass spectra were recorded on a VG ZABSpec mass spectrometer (VG Analytical, Division of Fisons, Manchester, UK), that was equipped with Opus V3.3X program package (Fisons Instruments, Manchester, UK).The ionization energy was 70 eV and source temperature 160 °C.Direct insertion probe was used.Perfluorokerosine (PFK) was used for calibration of the mass scale.
The fragmentation pathways were confirmed by B/E-linked scans for metastable ions.Also B 2 /E-linked scans were used to clarify these pathways.The low resolution, B/E and B 2 /E spectra were measured using resolution of 3000.The accurate masses were determined by voltage scanning or by peak matching (10% valley definition) using 6000-10000 resolution for small m/z values and over 10000 for the larger ones.

Results and Discussion
General fragmentation pathways are described in Scheme 1. Common fragment ions and their relative abundances (RA) are listed in Tables 2 and 3 and other fragments in Table 4 and 5

Table 2. Main electron induced fragmentations and their relative abundances m/z(%RA).
Abundances are corrected for 13 C isotopes, 1b, 4a, 6a and 8a have been renormalised.Abundances are rounded to the nearest half percent.(Continued in table 3)  (20), 76 (9), 75 (10), 74 (11), 69(4), 64 (7), 63 (13), 62(6), 52 (9)  The ion [M − OH] + was most abundant for 2a (RA 67.5%) and 8a (RA 57.5%).It was also formed by compounds 1a, 3a, 7, and 8b.It is questionable which oxygen is lost with the hydroxyl.OH-loss requires hydrogen migration after ionization and ring-opening, possible mechanisms involving distonic ions shown in Scheme 3. The OH-loss from 3a having a carbonyl group cannot proceed via the first route in Scheme 3; based on steric reasons the carbonyl oxygen may abstract hydrogen from the position bearing the phenyl substituent.Solving the exact mechanism would require complicated deuterium labeling.For 2a the B/E scans of the [M − OH] + ion gave no significant signals, so this ion is unusually stable, the positive charge being probably stabilized by the aromatic groups.For 1a the ion [M − OH] + may fragment further by loss of C 2 H 3 N forming the ion m/z 231, and B 2 /E scan revealed also the C 3 H 4 N • loss.If the ion at m/z 231 from 1a has the structure described in Scheme 2, then the oxygen that is attached to the phenyl group is the one lost with OH and not the oxygen attached to the naphthyl group.Also For 7 and 8b (and perhaps also for 8a) it is probable that the hydroxyl group is formed from the carbonyl group by hydrogen migration.In this case the naphthyl oxygen is not lost as hydroxyl.Scheme 3. Possible ring openings of 2a and the consequent OH-loss.
Weak CO loss was observed only for 7 and 8a.[M − CONH] +• ion was abundant for 4a (RA 94%) and was also present for 3a and 4b.An abundant [M − Ph] + ion (RA 44%) was exhibited by 6b, and traces by 4b and 8b.The phenyl substituent is axial in 2b−d, 4 and hence they are expected to fragment similarly but different from 2a in which the phenyl group is equatorial. 4his may at least partly explain why 2a gives an abundant C 7 H The methyl-(2c: R = Me) and ethyl-substituted (2d: R = Et) gave very similar spectra.In addition to the common ions mentioned before, both have nearly identical spectra below m/z 120.The greatest differences are as follows: the ion m/z 147 (C 9 H 9 NO +• ) was obtained only for 2c and the ion m/z 161 (C 10 H 11 NO +• ) for 2d.Furthermore the ion m/z 132 (C 8 H 6 NO + ) was most abundant for 2d.When the molecular ions loose C 17 H 12 O, the ions C 10 H 11 NO +• (2d, m/z 161), C 9 H 9 NO +• (2c, m/z 147) and C 8 H 7 NO +• (2b, m/z 133) are formed.Similar fragment ions have been observed for substituted 1,3-benzoxazino[4,3-b][1,3]1,3-benzoxazines 16 , where the bond between C-7 and O is cleaved first, resulting to ring-opening of the oxazine ring.
For 2c and 2d the ion , but this is very weak for 6b.For 6b [M − Ph] + can be observed, but 6a exhibits relatively abundant [M − H] + ion -so it is probable that the Ph−C rather than the Ph−N bond is cleaved.Both 6a and 6b gave also weak [M − NHPh] + ions (RA < 10%). In

Comparison of regioisomeric pairs 1a−3a vs 1b−3b
The cyclization of the aminonaphtols used to synthesize these compounds are affected by different chemical stabilities of the unsubstituted or phenyl-substituted aminonaphthols. 3Since 1a−3a were synthesized from derivatives of (1-α-aminobenzyl)-2-naphthol and 1b−3b from derivatives of 1-aminomethyl-2-naphthol, 4 the mass spectra of these regioisomeric pairs were expected to be very different.For 1a−3a M ), m/z 105 (C 7 H 5 O + ) and m/z 132 (C 8 H 6 NO + ), but these ions were missing from the spectra of 2b and 3b, respectively.

Conclusions
Some of the fragmentations such as OH-loss require ring-opening with hydrogen migration.In 7, 8a and 8b the carbonyl group oxygen participates in the loss of a hydroxyl group.Compounds derived from (1-α-aminobenzyl)-2-naphthol were usually characterized by strong or medium strong ions at m/z 231 and 1-aminomethyl-2-naphthol derivatives by ions at m/z 156.
The fragmentations depend on the regiochemistry and geometry of the compounds studied.

1 Scheme 2 . 7 +.
Scheme 1 based on the geometry4 the phenyl oxygen is more likely to be lost as hydroxyl.[M − OH] + from 7 fragments further by loss of C 3 H 5 N (C 13 H 9 O + , m/z 181), C 5 H 5 N (C 11 H 9 O + , m/z 157) or C 11 H 7 (C 5 H 7 O + , m/z 97) and that from 8b by loss of C 8 H 5 N (C 17 H 11 O + , m/z 231).

Table 1 .
The names of the compounds
7 + ion, but 2b−d not.In contrast to 2a for which the base peak is that of the molecular ion, compounds 2b−d all exhibit M +• ions of low abundance and the ions C 17 H 11 O + (m/z 231) form their base peaks instead.Common ions of similar abundance for 2b−d

, 2a−d, 3a, 3b, 4b, 6b and 8b also
addition to the ion m/z 231, C 17 H 11 O + or ion m/z 156, C 11 H 8 O +• compounds 1ashow ions related or similar to their complementary ion.The ion [M − C 17 H 11 O 2 ] + was abundant for 1a−3a.The resulting ions were C 2 H 4 N + (1a), C 8 H 8 N + (2a) and C 8 H 6 NO + (3a).The ions corresponding to [M − 232] +• , i.e.C 8 H 7 NO +• (2b), C 9 H 9 NO +• (2c) and C 10 H 11 NO +• (2d), were moderately abundant.Also 6b exhibited a weak [M − 232] +• , i.e. that found for N-unsubstituted 4,5-cyclopentane-fused 1,3-oxazines 29 where C 7 H 5 NO • but no C 7 H 5 N 2 • loss was observed.This may be caused by different annelation positions.Another difference is the ion [M − C 6 H 6 N] + (6a, 6b) which is missing from Nunsubstituted 4,5-annelated 1,3-oxazines, exhibiting the ions C 6 H 7 N +• and C 6 H 6 N + instead. 29 NO +• , m/z 133, was more abundant than for 1,2a and the former also gave more abundant ions between m/z values 50 and 78 than the latter.In the case of 1,2b C 8 H 7 NO +• may be formed by a mechanism similar to that suggested for 1,3-benzoxazino-1,3-benzoxazines. 161a gave an abundant ion C 17 H 11 O + at m/z 231 which was missing from 1b.For 2b, 3a and 3b m/z 231 was the base peak, but for 2a its RA was only 27%.For 1b the ion C 10 H 8 +• m/z 128 was the base peak, but very weak for 1a.Compound 2a gave ions at m/z 91 (C These conformations possibly cause favored loss of C 2 H 4 N • from the molecular ion of 1a leading to the product ion C 17 H 11 O 2 + , probably because in the CH 2 groups the hydrogens are sterically less favored in 1a as compared to 1b.Also the loss of C 8 H 8 N • from 2a (i.e.C 6 H 5 CHNCH 2 • ) corresponds to loss of C 2 H 4 N • from 1a, in both cases the product ion is C 17 H 11 O 2 + .The ion C 2 H 4 N + is observed also for 1a and C 8 H 8 N + for 2a.The formation of the C 7 H 5 O + ion is easier to explain for 3a, due to the tertiary α-hydrogen vicinal to phenyl group which can migrate to the carbonyl oxygen.Also the boat conformation of benzo-fused oxazine ring in 3a makes the loss of C 8 H 6 NO • , i.e. the formation of the [M − C 6 H 5 CHNCO] + ion, C 17 H 11 O 2 +, possible.
The formation of fragment ions [M − C 17 H 11 O 2 ] + , [M − C 17 H 12 O] +• and [M − C 11 H 8 O] +• occurred logically from the structures studied.However, these three ions were nearly missing from the spectra of derivatives 3b, 4a, 4b, 6b, 8a, 8b with carbonyl or imino substituents; they favoured the ions C 17 H 11 O + or C 11 H 8 O + instead.