Microwave-promoted synthesis in water

Transcription

1 Microwave-promoted synthesis in water icholas E. Leadbeater

2 Outline of what we do Synthesis / Methodology / ew techniques Pure organic synthesis eg. Baylis-Hillman eaction Pure organometallic synthesis eg. Making organometallic polymers and other functional materials Organometallic and inorganic chemistry focused towards organic synthesis

3 Microwave-promoted synthesis Growing interest in microwave synthesis Many papers and reviews coming out in 2002, 2003 and now 2004 Enhanced reaction times and product yields Minutes instead of hours ew avenues for chemistry Using microwaves, chemists are finding that they can do new chemistry

4 Microwave reactions using aryl halides Aryl halides are widely used to form new carbon-carbon and carbon-heteroatom bonds Also useful in nucleophilic displacement reactions and substituted aryl halides are most reactive, however analogues are cheaper and more readily available

5 Halogen exchange reactions in aryl halides Shorter times mean starting material remains Optimum reaction time = 5 min Lower temperature means longer reaction time and lower product yields Optimum microwave power = 100 W Optimum temperature = 170 C + i 2 µw, x min, y C DMF 44 % isolated yield Optimum quantity of i 2 = 2 equiv. Best solvent = DMF Optimum volume = 0.5 ml Use of 1 equiv has the effect of lowering product yield considerably

6 Halogen exchange reactions in aryl halides Methodology is suitable for a range of halide exchanges i 2 i 2 i 2 i 2 yield (%) yield (%) yield (%) yield (%) COMe 43 COMe 70 COMe 97 COMe 99 OMe 45 OMe 68 OMe 95 OMe 99 CHO 41 O 2 72 CO 2 H 94 MeO 94 99

7 Latest developments Tetrabutylammonium halides can be used as halogen sources + TBAB 10 mol % i 2 µw, DMF 72% yield O O + TBA 10 mol % i 2 µw, DMF 50% yield O O

8 Cyanation of aryl halides Aryl nitriles are valuable intermediates in organic chemistry Form integral parts of of dyes, herbicides, natural products and pharmaceuticals Many methodologies have been developed over the years Most direct and versatile method found so far is transition-metal catalyzed cyanation of aryl halides Microwave promotion has been used as a tool for the Pd-mediated cyanation of aryl bromides (J. Org. Chem. 2000, 65, 7984)

9 Cyanation of aryl halides Use of nickel cyanide We have developed a fast, easy methodology using nickel cyanide as a reagent X i(c) 2 or i 2 + ac C X =,,. K. Arvela and. E. Leadbeater, J. Org. Chem., 2003, 68, 9122

10 Cyanation of aryl halides Shorter times mean starting material remains Optimum reaction time = 10 min Lower temperature means longer reaction time and lower product yields Optimum microwave power = 100 W Optimum temperature = 200 C + i(c) 2 µw, x min, y C MP C 99 % isolated yield Optimum quantity of i(c) 2 = 0.6 equiv. Best solvent = MP Optimum volume = 1 ml Use of 0.5 equiv has the effect of lowering product yield considerably

11 Cyanation of aryl halides Using i(c) 2 Conditions suitable for a wide range of substrates + i(c) 2 µw MP C SOLATED YELDS (%) COMe OMe O 2 CO 2 H CHO H 2 MeO S

12 Cyanation of aryl halides Using i 2 and ac Form i(c) 2 in-situ Can effect a tandem halide exchange / cyanation of aryl chlorides + µw i 2 + ac C 93% yield MP + i 2 + ac µw MP C SOLATED YELDS (%) COMe OMe CO 2 H OH

13 Water as a solvent for microwave chemistry n principle, water is a good solvent for use in synthesis Cheap eadily available on-toxic on-flammable Suitable for scale-up Microwaves interact well with it There are however problems Solubility of reagents and catalysts Unwanted side reactions

14 The Suzuki reaction Suzuki couplings are used on a small and multi-ton scale and are big business Millions of $ / / spent every year on Pd catalysts and ranges of ligands for performing this reaction Biaryl units are found in: Pharmaceuticals Herbicides Conducting materials Liquid crystals

15 Water as a solvent for the Suzuki reaction Water has been used as a solvent with ligandless palladium catalysts One of the first examples was with water-soluble aryl iodides (Tetrahedron 1997, 53, 14437) + B(OH) 2 Pd 2,a 2 CO 3 H 2 O = OH, COOH

16 Water as a solvent for the Suzuki reaction Tetrabutylammonium bromide (TBAB) has been used as an additive for couplings in water using conventional heating (J. Org. Chem., 1997, 62, 7170) Acts as a phase-transfer agent to aid substrate solubility Activates boronic acid to reaction + B(OH) 2 Pd(OAc) 2,a 2 CO 3, TBAB H 2 O Generally, activated aryl bromides used

17 Water as a solvent for the Suzuki reaction Microwaves have been used for Suzuki couplings Using water / organic solvent mixtures (J. Org. Chem., 1996, 61, 9582) + B(OH) 2 Pd(PPh 3 ) 4, µw EtOH, DMF, H 2 O xn time with microwave = 3.6 min Product yield = 55% xn time conventionally = 6 h Product yield = 88% Using water soluble aryl iodides (J. Org. Chem., 1999, 64, 3885) + B(OH) 2 = COOMe or PEG-based polymer support µw Pd(OAc) 2, a 2 CO 3 H 2 O or PEG xn time = 2-5 min

18 Water as a solvent for the Suzuki reaction We wanted to couple the advantages of microwaves and TBAB Can we form biaryls rapidly in neat water and activate aryl iodides, bromide and chlorides? X =,, X + B(OH) 2 µw Pd(OAc) 2, a 2 CO 3 TBAB, H 2 O. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973

19 Water as a solvent for the Suzuki reaction Conditions suitable for a wide range of substrates X + B(OH) 2 µw Pd(OAc) 2, a 2 CO 3 TBAB, H 2 O SOLATED YELDS (%) O 2 CO 2 Me COMe CHO OH COOH OMe MeO OH COOH OMe

20 Using water as a solvent in other reactions Sonogashira coupling reactions Like the Suzuki reaction, the Sonogashira coupling finds used in a range of applications Usually a catalyst mixture of a Pd complex and Cu is used X + H Catalyst Base X =,,

21 Sonogashira coupling reactions We have developed a rapid, copper-free methodology eaction time = 5 min or shorter Optimum microwave power = 60 W Temperature = C + H µw, x min, y C Pd 2 (PPh 3 ) 2, base TBAB, H 2 O 99 % isolated yield Best base = piperidine Optimum catalyst loading = 4 mol % Optimum volume of water = 2 ml Optimum quantity of TBAB = 1 equiv.

22 Sonogashira coupling reactions eaction times are very fast with a range of substrates eaction needs only 20 sec microwave irradiation Conventional heating can be used with reactions taking 5 min Good yields of product are obtained with aryl bromides Aryl iodides give slightly lower yields (like Suzuki couplings) O OMe µw, 60W, 5 min then 5 min cool 99% 94% 61% 90% µw, 60W, 20 sec then 5 min cool 99% 92% - 88% oil bath, 140 C, 5 min then 5 min cool 99% 93% 62% 77%

23 Sonogashira coupling reactions ot the first methodology using water but the fastest, most versatile and easiest - SO 3 O O n H PPh 2 Pd - O3 S P - SO 3 Heterocycles 2003, 59, 71 Tetrahedron Lett., 1997, 38, 7843 J. Org. Chem., 1995, 60, 6829 Tetrahedron Lett., 1998, 39, 525 ot the first copper free methodology C 6 H 4 -p- Pd OH 2 Bu - + PF 6 Tetrahedron Lett., 2002, 43, 9365 Org. Lett., 2002, 4, 1691

24 ew Suzuki-type couplings Whilst probing the microwave-promoted coupling protocol we have found that it is possible to perform Suzuki-type couplings without the need for addition of a transition-metal catalyst

25 o catalyst added Suzuki couplings X + B(OH) 2 µw a 2 CO 3 TBAB, H 2 O. E. Leadbeater and M. Marco, Angew. Chem. nt. Ed., 2003, 42, 1407

26 Latest developments Vinylboronic acids can be used in the no added catalyst protocol + B(OH) 2 µw, H 2 O + B(OH) 2 µw, H 2 O

27 Latest developments Vinylboronic acids can be used in the no catalyst added protocol + B(OH) 2 µw, H 2 O

28 Scaling in the nitiator

29 Synthesis of losartan Anti-hypertensive drug also known as Cozaar onpeptide angiotensin receptor antagonist A number of syntheses have been patented and published (eg: J. Med. Chem. 1994, 37, 542; J. Org. Chem., 1994, 59, 6391) OH H

30 Synthesis of losartan Develop a rapid synthesis with scope for diversity OH ing together several microwave steps a 3 H C a 3 H B(OH) 2 OH OH H C CuC B(OH) 2 i 2 CuC

31 Synthesis of losartan Putting the synthesis together OH DMA (HO) 2 B OH H B(OH) 2 1 OH µw CuC, TBAB, H 2 O C µw a 3, Zn 2, H 2 O H µw, 1 Pd(OAc) 2 TBAB, a 2 CO 3, H 2 O H Losartan

32 Acknowledgements acknowledge the hard work and dedication of the students who have been involved in the work presented here: iina Arvela Emilie Jolibois Maria Marco Sharon Pillsworth Erik Shanahan Bonnie Tominack Vicki Willams thank Hoffmann La oche, EvotecOA and CEM Microwave Technology for financial support of our work