Experimental considerations

Reagents for the synthesis were commercial available from Aldrich, Fluka, Lancaster, Avocado, Reeve angel Scientific Ltd. and BDH Chemical.

THF and CH2CI2 used such as reagent solvents, were distilled under inert atmosphere of dry-Argon immediately prior to use. For THF were distilled from sodium and benzophenone and CH2CI2 from calcium hidrate.

Analytical thin layer chromatography (tic) was performed using Sigma- Aldrich tic plates aluminium particle size <60 pm and the flash column chromatography using BDH flash silica gel o f particle size 30-50 pm or Aldrich 60 flash silica gel of particle size 40-60 pm as a stationary phase.

All solvents and reagents were obtained fi'om commercial available sources and used without further purification. The glassware and syringes for moisture- sensitive reactions were dried in an oven at 130 °C before used.

The Melting points were measured using Electrothermal melting point apparatus. IR spectra were recorded on a Perkin Elmer 1600 series FTIR The mass spectra were recorded on a VG7070H mass spectrometer at University College London and UIUC School of Chemical Science (New York).

Molecular Mechanics calculations have been run on a Silicon Graphics workstation (Radon.chem.ucl.ac.uk) based on standard MM3 and MM2 force field parameters Ab initio and semi-empirical PM3 calculations have been run on the PC with Pentium IV processor running under Linux (128.40.76.85) using a Gaussian-98 program^^. The visualisations o f the structures in 3D have been carried out with a PCmodel 7.0"^^ version and Chem-3D 6.0 version^^^ run on Pentium II Toshiba notebook.

Simulation of ^H NMR spectra for chapter 4, has been done in a Pc with Pentium II processor (350 MHz, 128.40.76.133) at UCL NMR lab using the program SpinWorks Version 1.2^"^\

NMR studies have been carried out on a Bruker DRX-500 MHz with a gradient unit system, Bruker AMX 400 MHz, automatic Bruker AMX 300 MHz and Bruker MSL 300 MHz solid state spectrometer. The data was processed using XWINNMR on a Silicon Graphic workstation with IP address oxygen, nitrogen and carbon in NMR lab Chemistry department of UCL and the plot o f the spectra

were either carried out from XWESfNMR program or transfer to XWINPLOT for further graphics processes. The variable temperature experiments were controlled with a Bruker Eurotherm BVT 2000 in the case of the 400 MHz and Bruker Eurother BVT 3000 Digital in the case of the 500 MHz. NMR solutions were approximately 0.1 M. The CDC13, CD2CI2 and d-toluene were obtained from Aldrilch. The calibration o f the spectra were carried out using the reference of the solvent respect to TMS: 7,24 ppm for ^H and 77.0 ppm for o f CDCI3, 5.32 ppm for ^H and 53.8 ppm for of CD2CI2, 2.03 ppm for ^H and 20.4 ppm for d- toluene. When the analysis o f Silyl ether were carried out in chlorinated solvents, small amount of K2CO3 was added to the solution to avoid any small traces of acid present in the solution.

Crystal structure statistical analysis was carried out on Cambridge Crystallographic Database^ using version 5.21 with 233.218 entries. The software available for the study was Quest, Vista and Pluto program.

6,2 Experimental part

6.2.1 Experimental vart: Chapter 2

All the compounds have been made following the procedure proposed by Stevens et

General procedure ! : Synthesis of formate derivatives:

The reaction was carried out under inert atmosphere o f argon. 1.2 equivalents o f formic acid were added with stirring to an equimolar amount of acetic anhydride. The mixture was stirred at 45° for one hour and then allowed to cool to room temperature and at which point 1.0 equivalent o f alcohol was added dropwise whilst maintaining the temperature below 20°C. After the addition was completed, the reaction was stirred 16 hours at room temperature. The reaction mixture was then poured into saturated sodium carbonate solution (50ml), and the organic compound was extracted with ethyl acetate (3 x 25ml). The combined

o rg an ic layer w as w ashed w ith w a te r (25m i), dried w ith an hydrous sodium sulfate, filtered and then c o n c en trate d in vacuo.

-Methyl formate (2.10)71

-F rom Fluka R eference num ber: 06546. C atalo g u e 1999/2000. C o lo u rless oil. B efore u sed , th e sam ple w as distilled ( bp= 3 1-33°, 760m m Fig)

-5 0 0 M H z' H N M R (C D C b ) 0/ppm 8,04 (s, IH ), 3.71 (s, 1H '). -1 2 5 .7 M H z '^ C N M R (CDCl., ) 5/ppm 161.2 ( C = 0 ) , 50.5 (C ').

IR: (n e a t) v/ cm ' 29 5 5 .5 (C -H st), 1750.5 ( C = 0 st), 1436.1, 1172.0 ( C - 0 st), 9 1 1 .1 , 767.0.

-IsDpropvl formule ( 2 . 1 1 > '

S ynthesis o f isopropvl fo rm ate

T o acetic anhydride (2.9 ml, 30.7 m m ol), form ic acid (1 ,2 ml, 31.8 m m ol) w as ad d ed and follow ing p ro c e d u re -1, 2-propanol ( 2 ml, 26.1 m m ol) w as added.

A fter stirred 16 h o u rs and th e w o rk up w as carried o u t follow ing p ro c e d u re -1 to afford isopropyl fo rm a te (0 .9 g, 39 % ), as a co lo u rless oil.

-4 0 0 M H z ' H N M R (C D2CI2) 5/ppm 7.99 (s, IH ), 5.08 (se p tu p lât, 6.3 Hz,

1H '), 1.25 (d , 6.3 H z, 6H").

-I R : (n e at) v/ cm"’ 29 6 8 ,0 (C -H st), 1750.4 ( C = 0 st), 1166.2 ( C - 0 st), 9 1 2 .7 , 744.6. -2,4-dimethylpentyl formate (2.12) C ,H C H C H

S ynthesis o f 2,4-dim ethylpentvl fo rm ate

T o acetic anhydride (8.0 ml, 84.7 m m ol), addition o f form ic acid (3 .2 ml, 84.8 m m ol) w as carried out follow ing the p ro c e d u re -1, and th en 2,4 - dim ethylpentanol (10 ml, 71.3 m m ol) w as added. A fter stirred 16 h o u rs th e w o rk up o f th e re actio n g aye 2,4-dim ethylpentyl fo rm a te (9. Ig, 82.5 % ), as a co lo u rless oil.

-4 0 0 M H z H N M R (C D2CI2) 5/ppm 8.16 (s, IH ), 4 .6 2 (t, J V h - 6.1 H z, IH*),

1.93 (se p tu p let, J^h-h = 6.4 Hz, IH^), 0.88 (t, J^h-h = 6 . 8 H z, 12H^).

-1 0 0 . 6 M H z N M R (C D2CI2 ) 5/ppm 161.6 ( C = 0 ) , 83.2 (C*), 29.5 { C \ 19.6

( C ') , 17.3 (C ').

- I R : (n e at) v/ cm * 29 6 8 .8 (C -H st), 1724.3 ( C = 0 st), 1468.9, 1389.0, 1182.2 ( C - 0 st), 9 3 5 .4 , 887.9.

Synthesis o f (cis. /ra».s)-4-/m-butvlcvclohexvl formate

To acetic anhydride (2.6 ml, 27.5 mmol), formic acid (1,1 ml, 29.1 mmol) was added and following the procedure-1 {cis, /rw7.s2-4-/(?r/-butylcyclohexanol (3.6 g, 23 .0 mmol) was added. After stirred 16 hours and the work up o f the reaction mixture gave (cfs,//w/x)-4-/(^/V-butylcyclohexyl formate (3.7 g, 87.1 %) as a colourless oil. -5 0 0 M H z ' H N M R (C D C b ) 5/ppm 8,00 (dd, JV ii = I I H z, j V h = 11 H z, IH '" ) , 7.95 (d, J \ . „ = 1,1 H z, 1H"“ ), 5,10 (tt, 2,9 H z, J \,.h = 2 ,9 H z, I H i Ô , 4 ,6 9 (tt, 11,3 H z, J^,.ii= 4,5 H z, 1 H ,„ ‘" “ ), 2,03 (m, 1 H^e.'” "*), 1,95 (m, lH 2 ,,n . 1.81 (m, IHjec,™"), 1,59 (m, IH ,^ '" ), 1,50 (ni, I H :./" ) , 1 3 3 (m, 2H H , . , " '! ) , 1,12 (m, 3 H ,a™ * ), 1.04 (m, 2 H |H r '" , 1 4 ^ } ) , 0,85 (s, 9H , H,,“ '), 0 ,8 4 (s, 9H , H Z '"") -1 2 5 ,7 M H z " c N M R (C D C l,) 5/ppm 160,7 ( C = 0 , cis), 160,7 ( £ = 0 , tran s), 73,3 ( C ‘, tran s), 6 9 ,4 ( C ', cis), 4 7 ,4 ( C \ cis), 4 7 ,0 ( C \ tran s), 3 2 ,4 ( C \ cis), 32,3 ( C \tr a n s ) , 31,9 ( C \ tran s), 30,4 ( C \ cis), 27,5 ( C \ tran s), 27,4 ( C \ cis), 25,3 (C ^ tran s), 21,4 (C^, cis),

-I R (n e at) v/ cm ' 29 4 8 ,8 (C -H st), 2 8 6 1 ,9 , 1719,1 ( C = 0 st), 1470,9, 1452,0, 1365,1, 1 1 8 5 ,0 ( C - O s t) , 1021,9, 924,0,

-(ciscis), (c is jr a n s ), (tra n sJ ra n s)-2 ,6 -d im e th v lc v c lo h e x v lfo r m a te (2 .14), (2.15), (2.16)

Q

S ynthesis o f (ciscis).{cis.tn in s).(tran s. /m //.v^2.6-dim ethvlcyclohexvl fo rm ate

T o acetic anhydride (1.2 ml, 12.7 m m ol), form ic acid (0.5 ml, 12.9 m m ol) w as ad d e d and follow ing the p ro c e d u re -1, th e com m ercially available m ixture o f

th re e isom ers 2,6-dim ethylcyclohexanol (1.5 ml, 11.0 m m ol) w as added. A fter stirred d u rin g 36 h o u rs and m onitoring th e reactio n by tic, the w o rk up w a s carried o u t fo llow ing p ro c e d u re- 1 to afford m ixture o f th re e isom ers 2,6-

dim ethylcyclohexyl fo rm ate (3.7g, 8 8 . 6 % ) as a yellow pale oil.

-5 0 0 M H z 'H N M R (C D C Ij) ô/ppm 8.20 (d, ’Ji,.n= 0 .8 9 H z, IH '), 8.18 (d, ’Jn.,i= 0.89 Hz, IH '), 8 . 1 0 (s, I H " ) , 5.07 (s, IH ,'). 4.67 (dd, 4.10 H z, V h = 8 . 2 0 Hz, IH i"), 4.35 (t, ’Jn.„= 10.4 Hz, IH ,'). 2.03 (m, IHz^.,"). I 83 (m, IHf,,.."), 1.73-

1.67 (m, 5H iH3e,“ , 2 ,.,', 23^.,'!), 1.62-1.58 (m, 3H {H ^,', 2 2 ,/!), 151-1.37 (m, 7H (2H2, / , H^cq", H4eq". H4, " , 2H404'! ) , 1.28-1.19 (m, 4H (2H3, / , H4. / . H4, / | ,

1. 11-0.97 (m , 4H {H ,, H , ,, " . 2 % , / } .

-1 2 5 .7 M H z " C N M R (C D C l, ) 5/ppm 161,3 ( C = 0 , a), 161,2 ( C = 0 , e), 160,9 (C =0 , ea), 83 l( C ,, e), 79.7 (C ,, ea), 77.0 (C ,, a), 37.3 (C2, e), 35.9 (C2, a), 33.7

(C,, e), 31.1 (Cf., ea), 30.9 (C2, ea), 30.7 (C,, ea), 30.1 (C5, ea), 28.3 (C4, a), 25.5

(C,, a), 2 5 . 1 (C4, e), 19.5 (C4. ea), 18 4 (C,, e), 18 2 (C;. a). 17.5 (C?, ea), 14.2 (C,.

ea).

-IR : v/ cm ' 29 2 9 .6 (C -H st), 1723.2 (C =0 st), 1457.8, 1380.0, 1187.8 ( C - 0 st), 9 5 6 .0 , 861.4.

- M S - C I , m /z 156 (M , 20 % ), 127 (M -29, 30 % ), 1 1 1 ( M '- 4 5 , 25 % ).