karl hughes final year project.pdf

7/28/2019 Karl Hughes Final Year Project.pdf

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KARL HUGHES CHEM 356, MAY 2012

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The simplest of these, 5, will be prepared in this experiment.

5

Thiophenes, like all aromatic molecules can undergo Friedel-Crafts acylation or alkylation

using a Lewis acid catalyst (Scheme 1).

Scheme 1


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However, this fails when 2-aminothiophenes are used10because of deactivation of the

catalyst by the amine and, therefore, other methods are required. Accordingly, several

methods of synthesising 2,3,5-trisubstituted thiophenes have been developed.

Scheme 2 depicts two such methods, the Vilsmeier-Haack reaction11of8 with POCl3 and that

of8 with Lawesson Reagent or P2S512. These both have disadvantages: Lawesson Reagent

and P2S5 are both expensive and the Vilsmeier-Haack reaction uses explosive POCl3.

Moreover, the latter may also give low yields of the intermediate hypochlorite 1113.

Scheme 2

None of these is desirable, especially when carrying out a large-scale synthesis, such as that

of a pharmaceutical. Thus, if this class of products is to be a viable alternative to traditional

NSAIDs, another method is needed.

Liebscher and Rolfs have developed a method13, 14which is similar to the above route but

uses a Willgerodt-Kindler reaction for the first step (Scheme 3) to produce thioamide 16. The

Kindler modification of the Willgerodt reaction uses elemental sulfur, a cheap alternative to

the other methods. A versatile reaction, it proceeds with aromatic, alicyclic and aliphatic

substrates15 and is therefore also a useful method for preparing analogues to be tested for

biological activity. This will be followed by the reaction of HC(OEt)3 and morpholine to

form thioacrylamide 17. Finally, an SN2 of 17 with the -bromoketone 18 and subsequent

cyclisation with Et3N yields the title compound 5.


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Scheme 3


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Results and discussion

Phenylthioacetic acid morpholide, 16

Acetophenone, morpholine and elemental sulfur were refluxed with catalytic TsOH for 3 h.Equimolar amounts of acetophenone and sulfur were used, with morpholine in excess as both

reagent and solvent. The reaction was quenched by pouring the reaction mixture into MeOH

followed by cooling and recrystallisation from MeOH and water (initial 1:1 ratio). The near-

colourless 16 was obtained in 44% yield; however, it should be noted that although

increasing the amount of sulfur to 2 equivalents does increase the yield of16, it also results in

a difficult-to-remove impurity, 1914.

Mechanism of the Willgerodt-Kindler reaction

There is some disagreement about the mechanism and many attempts to elucidate it have

been recorded16. Brown16 suggests that, given the wide range of substrates with which and

conditions under which the reaction proceeds, there may be several different mechanisms.

Nevertheless, those suggestions made by King and McMillan17(Scheme 4a) and DeTar and

Carmack18(Scheme 4b) seem to be the most widely accepted.

Scheme 4a


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These differ predominantly in whether the amine adds before or after addition of sulfur.

However, they both involve a so-called migrating group. In the first mechanism, it is the

sulfur which migrates (after either reduction to the alcohol and then elimination to form the

olefin, to which sulfur can add, or direct displacement of oxygen to yield the thioketone

followed by elimination of H2S); in the second, the amine migrates after first adding onto the

carbonyl and eliminating watervia the imine and then tautomerising to the enamine and the

intermediate in this case is an acetylene. Both of these mechanisms at some point require the

formation of a primary cation; while this is obviously unfavourable, the subsequent steps are

essentially irreversible and so would drive the reaction to completion.

Scheme 4b

It has been reported19that, in base, the polysulfide anion is present and from this, Kanbara19

suggested that the initial steps were simultaneous condensation of the amine and ketone, and

attack by the amine on the S8 ring. In acidic media, the thiol could be present which would

react in the same way; this alternative mechanism is shown here (Scheme 5).


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Scheme 5

Characterisation of 16

16 was characterised by elemental analysis, IR, and 1H spectroscopy (see experimental and

appendices A and B). The theoretical and experimental analyses were in agreement and theIR showed a peak at 1106.94 cm-1, characteristic of the C=S stretch20. The NMR showed a

characteristic singlet at 4.36 ppm, corresponding to the methylene of 16, as well as the

multiplets characteristic of morpholines: one at 3.46 ppm and one centred on 3.6 ppm.

4-morpholino-2-phenylthioacrylic acid morpholide 17

The formation of a new C-C bond was effected with HC(OEt) 3, and subsequent reaction with

morpholine yielded the thioacrylamide. 16 was reacted with morpholine and triethyl

orthoformate, both in excess to act as both reagent and solvent. EtOH was removed by

distillation to drive the reaction to completion and 17 was obtained as a yellow solid in 72%

yield after recrystallisation from MeOH and chloroform (1:5 ratio). The reaction took 9-10 h

for completion and was monitored by TLC on silica gel, mobile phase EtOAc-Pet. ether

(1:2).


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Mechanism

The mechanism is shown in Scheme 6. The orthoester cleaves on heating to yield ethoxide

and an oxonium in situ. Ethoxide attacks 16 producing the thioenolate which then reacts with

the oxonium species in a conjugate type addition. This subsequently reacts with morpholine

and tautomerisation leads to the enamine.


17 was characterised by elemental analysis, IR and 1H NMR spectroscopy. The theoretical

and experimental analyses were in agreement and the IR showed a C= peak at 1141.65 cm -1.

The 1H NMR spectrum showed a singlet at 7.4 ppm, characteristic of the methylene group, as

well as a multiplet at 3.4-3.8 ppm, integrating to 16 protons and therefore characteristic of the

morpholine substituents.

5-(4-bromobenzoyl)-2-(4-morpholino)-2-phenylthiophene, 5

Equimolar amounts of 17 and 18 were dissolved in MeOH and heated to reflux. The SN2

reaction was facile, due to the sulfur nucleophile, primary carbon, bromide leaving group and

adjacent carbonyl. The sulfonium salt was not isolated since cyclisation could be effected

Scheme 6


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immediately with Et3N. As expected, aromaticity followed swiftly and yellow 5 was obtained

in good yield (85%) and as the pure product; no further purification was necessary.

Mechanism

The mechanism is straight forward (Scheme 7); SN2 is followed by attack of triethylamine,

forming the enolate which readily cyclises to the thiophene with loss of morpholine.


Again, elemental analysis, IR and 1H NMR spectroscopy was used. The experimental and

theoretical analyses were in agreement and the only peak of note in the IR is the carbonyl

C=O at 1616.06 cm-1. The NMR showed the morpholine resonances at 3.8 ppm while the

characteristic singlet of the thiophene proton in the aromatic region was found at ~7.4 ppm

Scheme 7

.

13C NMR spectra

There were no major problems in the experiment; however, as can be seen from appendices

C, F and I (the 13C spectra of16, 17 and 5 respectively), only the solvent peaks are clearly

visible. At least 50 mg sample was used in the analysis, but evidently this was not sufficientand after other analyses and subsequent steps in the experiment were undertaken, there was


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not enough remaining sample to repeat the experiments (it was assumed that using < 50 mg

would be fruitless).Therefore, these spectra could not be used for characterisation purposes.

Conclusions

In summary, the total synthesis of 5 was achieved with 27% overall yield in 3 steps. The

synthetically versatile Willgerodt-Kindler reaction was employed, followed by the

orthoformate method of forming C-C bonds to incorporate a methylene group; finally, an SN2

followed by cyclisation gave the final thiophene product.

The synthetic sequence presented no major problems, required no non-standard laboratory

equipment and has a moderate overall yield. Thus, it is a good route to this potential

pharmaceutically important class of molecules, allowing for fairly efficient synthesis and its

possible application to a wide range of substrates means it could also be used for the

preparation of the analogous substituted thiophenes currently under investigation for use as

anti-inflammatories. Further modifications of the experimental procedures (recycling of

solvents, for instance) would enhance the green credentials of this experiment, something

which the pharmaceutical industry is acutely aware that more focus is needed on.


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Experimental

All reagents were commercially available and used without further purification. Elemental

analyses was performed by the University of Liverpool Chemistry Department; infra red

spectra were run neat on a Jasco FT/IR 4200 spectrometer; 1H- and 13C-NMR spectra were

recorded on a Bruker ARX 250 spectrometer using deuterated solvents and TMS as an

internal standard; melting points were determined on a Gallenkamp melting point apparatus

and TLCs were run on Sigma-Aldrich silica gel 60 F254 plates, mobile phase 1:2 ethyl acetate:

pet. ether (40-60oC fraction).

Step 1

Acetophenone (3.0 mL, 26 mmol), morpholine (4.6 mL, 52 mmol), sulfur (0.84 g, 26 mmol)

and p-toluene sulfonic acid monohydrate (0.13 g, 0.67 mmol) was heated to reflux (T~

130o

C) for 3 h. The red-brown solution was poured into 13 mL hot (T~60o

C) methanol andthe precipitate isolated after cooling in an ice-water bath. The crude product was suspended

in 3 mL methanol and 3mL water, heated to reflux and methanol added dropwise until

complete solution occurred. The almost colourless pure product 1 was collected after cooling

and dried in the open air (2.52g, 44%), mp 76-77oC (MeOH-water). (Anal. Calcd. for

C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C, 65.10; H, 6.89; N, 6.32; max(neat)/cm-1

1106.94 (C=S); H (250 MHz; CDCl3; Me4Si, p.p.m.) 7.319 (5H, m, Ph), 4.364 (2H, m,

morpholide-CH2), 4.364 (2H, s, PhCH2CS), 3.725 (2H, m, morpholide-CH2), 3.484 (2H, m,

morpholide-CH2), 3.370 (2H, m, morpholide-CH2).

Step 2

1 (1.43 g, 6.47 mmol), morpholine (1.2 mL, 12.9 mmol) and triethyl orthoformate (4.3 mL,

26 mmol) were added to a distillation apparatus and heated for 10 h (until TLC of the

reaction mixture showed no remaining 1, stationary phase 1:2 EtOAc: pet. ether), during

which time ethanol was removed by distillation. The orange mixture was evaporated in vacuo

(bath T~80oC) and the orange-yellow precipitate recrystallised from chloroform and


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methanol (1:5, methanol was added until complete solution occurred). The pure yellow

product 2 was isolated by filtration, washed successively with cold methanol and ether and

dried in air (1.49g, 72%), mp 153-154oC (chloroform-MeOH). (Anal. Calcd. for

C17H22N2O2S: C, 64.12; H, 6.96; N, 8.80. Found: C, 63.80; H, 6.77; N, 8.91; max(neat)/cm-1

1114.65 (C=S); H (250 MHz; CDCl3; Me4Si, p.p.m.) 7.4 (5H, m, Ph), 6.4 (1H, s, methyne),

3.8 (16H, m, morpholine).

Step 3

2 (1.24 g, 3.88 mmo) and 1-4-dibromoacetophenone (1.08 g, 3.88 mmol) were suspended in

methanol (19 mL) and the mixture was heated to reflux. Triethylamine (0.54 mL, 3.88 mmol)

in methanol (3.9 mL) was added and the mixture refluxed for a further 10 minutes. Cooling

and filtration yielded the target compound 3 as a yellow solid (1.41g, 85%), mp 174-175oC.

(Anal. Calcd. for C21H18BrNO2S: C, 58.88; H, 4.24; N, 3.27. Found: C, 57.81; H, 4.28; N,

3.27; max(neat)/cm-1 1616.06 (C=O), 1234.22 (C-O); H (250 MHz; CDCl3; Me4Si, p.p.m.)

7.2-7.8 (10H, m, Ph), 7.5 (1H, s, thiophene), 3.75 (4H, m, morpholine), 3.1 (4H, m,

morpholine).

References

1. M. W. Whitehouse, Curr Med Chem, 2005, 12, 2931-2942.2. K. I. Molvi, K. K. Vasu, S. G. Yerande, V. Sudarsanam and N. Haque, Eur J Med Chem, 2007,

42, 1049-1058.

3. S. Raju, P. R. Kumar, K. Mukkanti, P. Annamalai and M. Pal, Bioorg Med Chem Lett, 2006, 16,

6185-6189.

4. E. Abele and E. Lukevics, Chemistry of Heterocyclic Compounds, 2001, 37, 141-169.

5. R. L. Jarvest, I. L. Pinto, S. M. Ashman, C. E. Dabrowski, A. V. Fernandez, L. J. Jennings, P.

Lavery and D. G. Tew, Bioorganic and Medicinal Chemistry Letters, 1999, 9, 443-448.

6. K. E. Schulze, P. R. Cohen and B. R. Nelson, Dermatol Surg, 2006, 32, 407-410.

7. I. Opsenica, V. Filipovic, J. E. Nuss, L. M. Gomba, D. Opsenica, J. C. Burnett, R. Gussio, B. A.

Solaja and S. Bavari, Eur J Med Chem, 2012.

8. A. D. Pillai, P. D. Rathod, P. X. Franklin, M. Patel, M. Nivsurkar, K. K. Vasu, H. Padh and V.Sudarsanam, Biochem Bioph Res Co, 2003, 301, 183-186.

9. A. D. Pillai, S. Rani, P. D. Rathod, F. P. Xavier, K. K. Vasu, H. Padh and V. Sudarsanam,

Bioorgan Med Chem, 2005, 13, 1275-1283.

10. A. Noack and H. Hartmann, Tetrahedron, 2002, 58, 2137-2146.

11. J. Liebscher and B. Abegaz, Synthesis-Stuttgart, 1982, 769-771.

12. C. Heyde, I. Zug and H. Hartmann, Eur J Org Chem, 2000, 3273-3278.

13. A. Rolfs and J. Liebscher, Synthesis-Stuttgart, 1994, 683-684.

14. A. Rolfs and J. Liebscher, Org. Synth. , 1997, 74.

15. J. A. King and F. H. Mcmillan,J Am Chem Soc, 1946, 68, 525-526.

16. E. V. Brown, Synthesis-Stuttgart, 1975, 358-375.

17. J. A. King and F. H. Mcmillan,J Am Chem Soc, 1946, 68, 632-636.18. D. F. Detar and M. Carmack,J Am Chem Soc, 1946, 68, 2025-2029.


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19. T. Kanbara, Y. Kawai, K. Hasegawa, H. Morita and T. Yamamoto, J Polym Sci Pol Chem, 2001,

39, 3739-3750.

20. E. Spinner,J Org Chem, 1958, 23, 2037-2038.

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