Características de la Realidad Virtual

facile 1,4-addition reaction of morpholine to MAC occurred at 70ºC, indicated by a parent ion at m/z 173 in GC-MS analysis.

Figure 3.7: GC-MS spectrum for the reaction of 5a with MAC at 40, 50 and 70ºC show increasing yields for 4 (M+·

m/z 184) and the hydrolysed morpholine group was observed to react with the dienophile via 1,4-addition to give

the amine by-product (M+· m/z 173) observed as an earlier eluting component than 4 at tR = 12:06. A major by-

product is formed at high temperatures with a fragment ion of m/z 247. GC analysis conditions are listed in Section 6.10, Instrument 1.

Extraction of the D-A reaction mixtures with 0.5 M HCl facilitated the removal of aminated biproducts and the diastereoisomers of 4 were separated by column chromatography on silica gel (10:1 pentane:EtOAc). A pale yellow oil with TLC retention of Rf = 0.38 was isolated in >99% purity as

confirmed by GC-MS analysis. 1_{H NMR analysis of the pure isomer confirmed the presence of a methyl}

substituent H(9) at 1.70 and a methyl ester substituent H(10) at 3.72 as two large singlets, each with an integral area equivalent to three protons (Figure 3.8). 13_{C NMR analysis showed the expected C(5)}

ketone and C(8) ester carbonyl peaks at 210.3 and 172.2 respectively (Figure 3.8). The bridgehead proton H(4) adjacent to the electron withdrawing ether and carbonyl functionalities can be assigned to the broad downfield doublet (J = 6.6 Hz) at 4.37 with an integral region equal to one proton. The COSY NMR analysis indicates that the H(4) signal is correlated with two proton signals at 2.33 and 2.16, assigned as H(3A) and H(3B) resonances respectively. The H(3) peaks are confirmed by HMQC and

DEPT 135 analysis to be attached to the C(3) methylene carbon at 30.9 (Figure 3.9), thus confirming that the cycloaddition proceeded with para selective regiochemistry with respect to the ester and amine substituents. The downfield negatively oriented DEPT 135 NMR signal at 46.0 can be assigned to the C(6) methylene adjacent to the carbonyl group and HMQC data shows correlation to protons H(6A) and

H(6B) at 2.39 and 2.17, respectively. The H(6) protons show strong coupling to each other in COSY

analysis and appear as second order doublets almost overlapped with the diastereotopic signals from H(3). Coupling constants between H(6) methylene protons J6A, 6B = 17.8 Hz, J6B, 6A = 18.4 Hz were not

identical, indicating that H(6B) is split by an additional proton signal. The H(2) proton is assigned to the

signal at 2.88 in good agreement with Chemdraw predictions and COSY analysis indicated correlations to H(3A) and H(3B) in agreement with the proposed structure. 1H NMR analysis conducted using 300

MHz spectrometry did not sufficiently resolve the overlapping second order H(6) methylene signals and 500 MHz experiments were required to provide adequate resolution to measure 1H coupling constants for H(3A)/H(3B). The methylene protons on C(3) exhibit first order AX splitting (J3A, 3B = 13.4 Hz) and H(3A)

was observed to be a doublet of doublet of doublets (J3A, 3B = 13.4 Hz, J3A, 4 = 6.6 Hz, J3A, 2 = 11.4 Hz)

and the H(3B) signal appeared as a double doublet (J3B, 3A = 13.4 Hz, J3B, 2 = 5.4 Hz). The 1H coupling

constant between H(3B) and H(4) is ~0 Hz, and principles described by the Karplus equation suggest that

these protons are locked in almost orthogonal positions on the 7-oxanorbornane moiety [81]. The H(2) signal appears as a doublet of doublet of doublets (J2, 3A = 11.4 Hz, J2, 3B = 5.4 Hz, J2, 6B = 2.1 Hz) and

although no COSY correlation was apparent for the four-bond-w-coupling between H(2) and H(6B), 1H

homo-decoupling NMR experiments demonstrated the collapse of H(2) to form a doublet of doublets upon decoupling at the H(6B) frequency (Appendix 3.1). These observations indicate that the isolated

diastereomer is 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (4a) and is in the endo configuration whereby H(2) is coupled to H(6B) (J2, 6B = 2.1 Hz) and H(3A) has an equatorial

Hz. Confirmation of the connectivity of the bicyclic ether was established from the strong correlation between C(1) at 86.0 and C(4) at 81.4 in heteronuclear multiple bond correlation (HMBC) analysis (Appendix 3.2) and 1_{H homo-decoupling experiments conducted at 200 MHz are shown in Appendix 3.1}

and confirm the structure proposed for 4a.

Figure 3.8: 500 MHz 1_{H and COSY NMR analysis of endo 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-}

carboxylic acid methyl ester (4a). The 300 MHz 1_{H NMR for the overlapping H(3}

Figure 3.9: 500 MHz HMQC spectrum of 4a, 125 MHz 13_{C and DEPT 135 NMR analysis is also shown with}

structural assignments. 13_{C NMR data for 4a is also included in Appendix 3.2.}

The exo diastereomer of 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (4b) was produced in low concentration during the reaction of 5a in hexane and was not isolated from the product mixtures in suitable purity for characterization. Further D-A reactions between 5a and MAC were conducted in DCM to successfully yield a mixture of 4 and 25 as indicated by GC-MS (Figure 3.10), and no change of diastereomeric ratio was observed over time suggesting that the cycloaddition is under kinetic control. Reactions performed at 25ºC (Figure 3.10) and 45ºC gave identical product mixtures and in both cases a large GC peak with a molecular ion corresponding to the enamine intermediate 25 (m/z 253) was observed at tR= 14:18 min.

Figure 3.10: GC-MS analysis of the crude D-A reaction of 5a with MAC in DCM at 25ºC indicates clean

conversion to the cycloadduct 25 with significant in situ hydrolysis to 4 due to atmospheric moisture. Hydrolysis in 0.5 M HCl gave 4a and 4b in a 4:1 ratio.

During D-A reactions of 5a in DCM, decomposition accompanied reaction times longer than 12 h. The enamine 25 was labile to hydrolysis from traces of moisture and crude mixtures typically contained both 4 and 25. Attempts to isolate 25 were unsuccessful and a retro D-A reaction to reform 5a occurred during distillation and column chromatography on silica gel. Hydrolysis of the crude material in 0.5 M HCl and extraction with DCM provided an isolated 93% combined yield of 4 in an endo:exo ratio of 4:1 as determined by GC integral regions (Figure 3.10). Cycloadditions conducted at sub-ambient temperatures were also successful and as expected returned a mixture of unreacted 5a and 4 due to decreases in reaction rates at lower temperatures (Appendix 3.3). Reactions conducted in DCM progressed with the formation of much less by-product than reactions in hexane and purification by column chromatography on silica gel (10:1 pentane:EtOAc) provided 4b in 19% yield (TLC, Rf= 0.12)

as a pure white crystalline solid with similar GC-MS fragmentation to the endo isomer (Appendix 3.4). 300 MHz 1_{H NMR experiments on 4b (Figure 3.11) showed a doublet for H(4) at 4.47 and the}

COSY spectrum indicates correlation to H(3A) (J4, 3A = 6.4 Hz) but not H(3B), suggesting a similar 90º

dihedral angle for H(3A) and H(4) as observed in 4a. The H(2) proton at 2.80 appears as a double

and four-bond-w-coupling to the H(6) AB quartet at 2.25 is not observed, as expected for the exo configuration. The H(3) methylene signals demonstrate AX coupling (J3A, 3B = 13.4 Hz) and H(3A) (

2.52) shows COSY correlations to H(2), H(4) and H(3B), appearing in 1H NMR data as an apparent

doublet of triplets. H(3B) ( 1.94) appears as a double doublet with the expected coupling to H(3A) (J =

13.4 Hz) and H(2) (J = 8.7 Hz). Although 13_{C NMR spectrum of 4b was similar to 4a, HMQC analysis}

(Appendix 3.4) revealed that the C(2) carbon in 4b is present at 49.4 and appears at lower frequency than the C(6) methylene carbon at 50.5, whereas these signals are in the reverse order in 4a (C(2) 51.1, C(6) 46.0, Figure 3.9). The structure of 4b was also consistent with HMBC data (Figure 3.11) and the ether bridge was confirmed by strong correlation of the methine bridge doublet H(4) to C(1) and C(2). Signals from H(3) correlate to C(2) and the C(5) carbonyl shifts and H(3A) correlates to C(4)

whereas H(3B) correlates to C(1). The H(6) AB quartet signal correlates to the expected C(9), C(2), C(1)

and C(5) carbon shifts.

A simple procedure for the separation of 4b from a mixture of diastereomers of 4 was realised upon the addition of Et2O to D-A hydrolysis mixtures, after which the exo diastereomer 4b crystallised in

high purity whereas the endo diastereomer 4a is completely soluble. Recrystallization of 4b in Et2O

allowed for the preparation of suitable material for X-ray crystal structure analysis and crystal data determined conclusively the identity of 4b as the exo product (Figure 3.12). The X-ray crystal CIF file and a summary of bond distances for C-C bonds is included in Appendix 3.5, and comparison with figures quoted by Allen et al. [82] indicate that distances are close to the expected values.

Figure 3.12: ORTEP drawing of exo-methyl 1-methyl-5-oxo-7-oxa-bicyclo[2.2.1]heptane-2-carboxylate 4b. Crystal

Data. C9H12O4, MW = 184.19, T = 293(2) K, = 0.71073 Å, triclinic, space group P-1, a = 7.2235(10), b =

8.1158(11), c = 8.3058(12) Å, = 75.273(2)o_{, = 74.540(3)}o_{, = 86.114(2)}o_{, V = 453.89(11) Å}3_{, Z = 2, D}

c= 1.348

Mg/m3_{,µ(Mo K ) = 0.106 mm}-1_{, F(000) = 196, crystal size 0.50 x 0.15 x 0.10 mm}3_{, 2428 reflections measured,}

1583 independent reflections (Rint = 0.0587); the final wR(F2) was 0.1414 (all data) and final R was 0.0529 for 1311

unique data [I > 2 (I)]. Goodness of fit on F2_{= 1.029. Crystallographic data for the structure reported has been}

deposited with the Cambridge Crystallographic Data Centre as deposition No. 288600.

The diene 5a was not reactive with MAC in Et2O or dioxane however reactions performed with

heating in the aromatic solvents benzene and toluene led to the exclusive formation of a by-product at tR

= 16:17 min featuring a predominant m/z 247 fragment in GC-MS analysis (Appendix 3.6). This compound was observed to have an identical mass spectrum to the major product formed in hexane at 70ºC (Figure 3.7) and product mixtures obtained from toluene at 111ºC provided suitably pure material

for NMR analysis (Appendix 3.6). 1H and 13C NMR analysis features signals for the 7- oxabicyclo[2.2.1]heptane moiety indicating that the D-A cycloaddition was successful. However the absence of a ketone or enamine signals in 13_{C NMR analysis suggests that the side reaction has occurred}

at the C(5) carbon. 1_{H NMR integral regions indicate the presence of two morpholine moieties in}

different chemical environments and 13C NMR aromatic signals characteristic of a 2,3,5-trisubstituted furan point toward the nucleophilic addition product involving the C(2’) position of 5a with 25 to provide 26 (Scheme 3.24). Similar structures have been reported by Bridson [73] during the D-A reaction of N-3’-furylbenzamide (Section 3.2.1) and tentative NMR assignments for 26 are included in Appendix 3.6 based on previously assigned structures and Chemdraw predictions.

O O O N O O N O O N O O O 5a 25 a) 3.0 equiv. MAC 5a 26 5 5 _2' O N O 2' a) Toluene, 111ºC, 8 h.