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20th December 2016 @ 16:45

Aim:

The Pd(dba)2 catalyst used during the synthesis of ID-1-006 was replaced with Pd(OAc)2 and Cs2CO3 as an alternative base. Pd(OAc)2 is less air sensitive which suits the preparation of the experiment; a success of the experiment could of concluded that the Pd(dba)2 air sensitivity  catalyst was a possible downfall of previous coupling reactions throughout the project. Cs2CO3 has been rendered a useful base in palladium chemistry such as the Heck, Suziki and Sonogashira reactions [8]. Pyrrolidine was not available hence piperdine (difference of a CH2 group) was used instead.

 

Preparation:

Material

Equivalent

Mw (gmol-1)

Moles (mmol)

Quantity

2-(3-bromophenyl)-1,3-dioxolane

1.0

185.02

0.6

142.7mg

Piperidine

1.2

85.15 gmol−1

0.72

61.31mg

Pd(OAc)

2.0

224.5 gmol-1

0.0118

2.65mg

BINAP

2.5

622.67

0.015

9.34mg

Cs2CO3

1.5

325.82

0.9

293.24mg

Ethyl acetate

-

‎88.106 

 

-

15mL

HCl (95%)

-

-

-

15mL

Toluene (solvent)

-

92.14

-

15mL

 

Experimental Procedure:

In a 100ml RBF with Toluene (15mL) and 2-(3-bromophenyl)-1,3-dioxolane (142.7mg, 0.6mmol) was charged Piperidine (61.31mg, 0.72mmol) and the base Cs2CO3 (293.24mg, 0.9mmol). The mixture was bubbled with Nitrogen gas and degassed of oxygen for 15 minutes prior BINAP (9.34mg, 0.015mmol) and Pd(OAc)2 (2.65mg, 0.0118mmol) being charged into the flask and placing the condenser (Liebig). The reaction mixture was degassed of Oxygen for 15 minutes under a Nitrogen (inert) atmosphere. Reaction apparatus was set up as previous cross-coupling experiments; reaction was heated at 70-100 °C and stirred overnight (16hrs).

 

TLC (MP Pet. Ether : EtOAc) plates of 3:1 and 9:1 ratios of MP indicated the absence of some starting materials in the crude indicating completion in the reaction and possible product. Following the TLC, crude mixture was worked up with Brine and extracted with Ethyl acetate in a 200mL separating funnel (25mL). 

      

 Pet.Ether:EtOAc 3:1 & 9:1 MP respectively

 

 After being under reduced pressure, crude had Toluene evaporated off resulting in a yellow liquid with a yield of 0.256g (256mg, 0.14%) of ID-2-006.

ID-2-006


Chemical Analysis:

As ID-1-006, it was evident from 1H-NMR that starting materials still dissolved in Toluene and the reaction was also not a success. At this point a new synthesis was not considered and the coupling reactions across the project were most probably subject to operator errors with a strong reason being the handling of the catalyst was poor and a lack of specific equipment[8] ; future work to consider selective synthesis for our experiments (i.e equipment) and further research into working around the parent starting aldehyde to form our ultimate aldehyde 3-(Prryolidin-1-yl)-1,3-dioxolane. Final conclusions of failure of experiments will be further discussed, investigated and deduced in the final project report. 

 

  

Our next experiment would focus on proving the Buchwald-Hartwig coupling actually works as seen in the literature with simple, less selective and specific starting materials. (cross coupling of para-iodo-4-nitrobenzene and piperidine)

 

References:

[8] F. Lehmann, Cesium Carbonate (Cs2CO3), Synlett, 2004, 13, 2447–2448

Attached Files
6th December 2016 @ 19:23

Aim:

ID-1-005 was coupled with pyrrolidine via Buchwald-Hartwig coupling in an identical manner to the synthesis of ID-1-001. The aim was to yield a substituted-pyrrolidine group on the phenyl group, before deprotection of the dioxolane, in order to yield our target aldehyde 3-(Prryolidin-1-yl)benzaldehyde. 

A scaled reaction was prepared and our aldehyde was protected cf. to the literature used in aldehyde synthesis 1[1] and accordance to a cross-coupling guide by sigma Aldrich[6].

Preparation:

Material

Equivalent

Mw (gmol-1)

Moles (mmol)

Quantity

2-(3-bromophenyl)-1,3-dioxolane

1.00

185.02

0.43

100mg

Pyrrolidine

1.2

71.12

0.53

0.042mL

Pd(dba)(0)

0.75%

575.00

3.2x10-4

1.9mg

BINAP

0.75%

622.67

3.2x10-4

2mg

Sodium tert-butoxide

1.2

96.10

0.53

0.05g

Toluene (solvent)

-

92.14

-

15mL


Experimental procedure:

In a 100ml RBF with Toluene (15mL) and 2-(3-bromophenyl)-1,3-dioxolane (100mg, 0.43mmol) was charged Pyrrolidine (0.042mL, 0.53mmol) and the base NaO-tBu (0.05g, 0.53mmol). The mixture was bubbled with Nitrogen gas and degassed of oxygen for 15 minutes prior BINAP (2mg, 3.2x10-4mmol) and Pd(dba)2 (1.9mg, 3.2x10-4mmol) being charged into the flask and placing the condenser (Liebig). The reaction mixture was degassed of Oxygen for 15 minutes under a Nitrogen (inert) atmosphere. Reaction apparatus was set up as shown below; reaction was heated at 70-100°C and stirred overnight (16hrs).

    

 apparatus set up of reaction                     reaction mixture before heating

 

TLC of the reaction in 3:1 and 9:1 solutions of Pet. Ether : EtOAc mobile phase showed some starting material still remained. The starting material (R) in the 3:1 mobile phase was diluted in Ethyl acetate while in the 9:1 mobile phase it was diluted in Toluene. The former plate indicates the absence of 2-(3-bromophenyl)-1,3-dioxolane at the P spot cf. to the R spot however pyrrolidine and some reagents (and solvent) still remained, evident by the reaction mixture spot (R/P). The latter further concluded this observation as the separation spots of P indicated the reagents were still dissolved in toluene ca. to the large spots on R/P and R. TLC confirmed the absence presence of new material.

         

Pet.Ether : EtAcO            Pet.Ether : EtAcO
9:1 MP                           3:1 MP

 

Chemical Analysis:

Yield of crude (pale brown) ID-1-006 (0.145g, 192%) is a consequence of Toluene not removed completely, under reduced pressure, as contents evaporated away with solvent; it was anticipated that 3-(Prryolidin-1-yl)benzaldehyde would be present in the reaction mixture.

product after reduced pressure

 

It was evident from 1H-NMR that starting material ID-1-005 and reagents were still dissolved in Toluene. Also no change in viscosity or solubility was observed in the crude. 3-(Prryolidin-1-yl)-1,3-dioxlane peaks were absent. Reaction was unsuccessful. 

 

 

A new less air-sensitive catalyst would be used instead (Pd(OAc)2) as we concluded the colour of the solution was indicative of catalyst death. 

References:

[1] J. Med. Chem., 2008, 51, 1333–1343

[6] Cross-Coupling Reaction Manual: Desk Reference, Dr Nick Bruno, Add Adlrich, http://www.sigmaaldrich.com/chemistry/chemical-synthesis/learning-center/cross-coupling-guide.html, accessed on 08/11/2016





 

Attached Files
4th November 2016 @ 17:56

Aim:

After an inconclusive synthesis of ID-1-002, the synthesis was repeated[5] via The Dean Stark method. An azeotrope of water was set up with Toluene with the same starting materials but reduced quantity. The extraction and work up of the organic crude was identical to the synthesis of ID-1-002 excluding the Brine.
 

Preparation:

Material

Equivalent

Mw (gmol-1)

Moles (mmol)

Quantity

3-Bromobenzaldehyde

1.00

185.02

6.75

1.25g

95% Ethylene glycol

5.00

62.07 

 

33.75

2.10mL

TsOH.H20

0.05

190.22

0.54

0.093g

Toluene (solvent)

-

92.14

-

30mL +

Ethyl acetate

-

88.11 

-

25.00  mL

(Saturated) Sodium hydrogen carbonate

-

84.01

-

20.00 mL (0.15gmL-1)

(Anhydrous) Magnesium Sulphate

-

120.366

 

-

-

Aluminium foil

-

-

-

-

Cotton wool

-

-

-

-


Experimental Procedure:


Into a dry 250mL round bottom flask was first charged 3-Bromobenzaldehyde (1.25, 6.75mmol), Ethylene glycol (2.10mL, 33.75mmol), Toluene (30mL) and lastly TsOH.H2O (0.093mg, 0.54mmol). A Dean-stark apparatus was set up as shown (below) prior preparing mixture. Aluminium foil and cotton wool covered the distillation trap component; the side-arm (burette component) was filled with Toluene. Water flow was switched on allowing a reflux to occur at 120-150 oC induced by an electrical hot plate.
The set-up as a whole would allow the reaction vapour (toluene and water) to travel up and cool into the Burette component. Toluene is less dense than water so an immiscible bottom layer of water was expected. Overnight, distilled mixture was cloudy indicating a successful azeotrope but minimal amount of water being produced during the reaction.

  
Dean-Stark method apparatus set up      A cloudy side-arm filled with Toluene  
during reaction                                      indicated azeotrope of water and toluene
                                                            was succesful; water caused the cloudiness

 

Stained TLC plates (K2MnO4) with a 7:3 and a 9:1 pet. Ether : Ethyl acetate mobile phase confirmed presence of a new compound and termination of the reaction. Separation of TlC spots was evident of a different compound formed in reaction mixture (cf. TLC plates to ID-1-001 and ID-1-002). 

   

Pet.Ether:EtOAc (7:3)               Pet.Ether: EtOAc (9:1)

 

Crude solution was worked up; organic layer extracted with Ethyl Acetate and dried with MgSO4 before evaporating Toluene off crude under reduced pressure (rotary evaporation). A pale white-yelllow oil was obtained.

  

Final product after removal of Toluene and EthOAc under reduced pressure;
a pale white-yellow (creamish) oil was obtained 

 

Chemical Analysis:

1H, 13C, 13C-DEPT, HMBC, HSQC and COSY NMR spectrums were interpreted collaboratively. The NMR analyses confirmed the presence of the desired protected aldehyde (ID-1-005) 3-Bromophenyl-[1,3]dioxolane. ID-1-005 will be used for a Buchwald-Hartwig coupling in a similar manner to the synthesis of ID-1-001 prior removing the dioxolane-protecting group to, ultimately, yield 3-(Prryolidin-1-yl)benzaldehyde

Yield: 0.5689g, 36.97%

m.p/b.p: to be uploaded

ESI Mass Spec data: (see attachements)

NMR Spec data:

1H-NMR (400MHz, CDCl3)

 

13C-NMR (100MHz, CDCl3)

 

DEPT 13C-NMR (100MHz, CDCl3)

 

COSY-NMR (100MHz, CDCl3)

 

HMBC-NMR (400MHz, CDCl3)

 

 

HSQC-NMR (400MHz, CDCl3)


References:
[5] Imidazotriazinone Compounds, Envivo Pharmaceuticals Inc., A.Ripka, G.Shapiro, A. J. Mcriner, M. Bursavich, G. Bursavich, Massachusetts, USA, 2013, PCT/US2013/031516


Attached Files
31st October 2016 @ 13:28

Aim:

After an unsuccessful attempt in cross-coupling the starting aldehyde and amine  (ID-1-001), a protection synthesis was attempted to protect the aldehyde of meta-Bromobenzaldehyde in a form of a 1,3-dioxolane[3][5]. The resulting product is known to offer more stability [4] to the aldehyde hence the Buchwald-Hartiwg coupling should be more liable between the Pyrrolidine and protected Bromobenzaldehyde.

Preparation:

Reaction mixture on reflux; Crude solution was worked up to rid of aqueous and obtain organic material

Material

Equivalent

Mw (gmol-1)

Moles (mmol)

Quantity

3-Bromobenzaldehyde

1.00

185.02

10.8

2.00g (3.17mL)

95% Ethylene glycol

5.00

62.07 

 

54

3.00mL

TsOH.H20

0.05

190.22

0.54

0.093g

Toluene (solvent)

-

92.14

-

40.00 mL

Ethyl acetate

-

88.11 

-

20.00  mL

Brine

 

 

 

10.00 mL

(Saturated) Sodium hydrogen carbonate

-

84.01

-

20.00 mL (0.15gmL-1)

 Experimental Procedure:

Into a dry 250mL round bottom flask was first charged 3-Bromobenzaldehyde (3.17mL, 10.8mmol), Ethylene glycol (3.00mL, 54mmol), Toluene (40mL) and lastly TsOH.H2O (0.093mg, 0.54mmol). A reflux was set up for the reaction using a Leibig condenser. The RBF was clamped above a hot plate inducing stirring and heating around 200 oC.

Colourless reaction mixture was left to reflux for 3 hours before switching off water flow and left at 200oC overnight to form a pale yellow solution. TLC (Pet. Ether / EtOAc 7:3) showed the formation of a new compound but poor separation indicating starting material still present in crude solution. 

final TLC plate confirming
termination of reaction as
identical to previous TLC plate


Saturated NaHCO3 was prepared (20mL, 0.15gmL-1) and added to the reaction mixture on an ice bath at 0 oC. Mixture was poured in a 250mL separation funnel and organic layer was extracted with Ethyl acetate (20mL). Extracted layer was washed with Brine and extracted again before drying with MgSO4. Under rotary evaporation (reduced pressure) a wet pale yellow solution was obtained.


Chemical Analysis:

1H NMR (400MHz) spectrum shows some peaks corresponding to -(3-Bromophenyl)-[1,3]dioxolane however sample (ID-1-002) is concentrated and possible impurities with some solvent residue; operator error and peaks not resolved clearly.  However synthesis looks promising; Dean-Stark apparatus should be more appropriate to maximise yield and rid of water during protection through azeotrope; purer sample than ID-1-002 should be obtained.


References:

[3] ACS Med. Chem. Lett., 2012, 3 (10), 787–787
[4] Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 308-322, 724-727.
[5] Imidazotriazinone Compounds, Envivo Pharmaceuticals Inc., A.Ripka, G.Shapiro, A. J. Mcriner, M. Bursavich, G. Bursavich, Massachusetts, USA, 2013, PCT/US2013/031516

Attached Files
27th October 2016 @ 13:58

Aim:

4-(Prryolidin-1-yl)benzaldehyde is known to be synthesised via Buchwald-Hartwig coupling using Pd20(dba)3 catalyst and para-Bromobenzaldehyde in literature[1]. The aim of this experiment was to imitate the reaction [1] but employ meta-Bromobenzaldehyde and reflux at a higher temperature; in order to compensate the slow rate of deactivation from the aldehyde group (i.e meta-directing) to yield the corresponding meta-counterpart 3-(Prryolidin-1-yl)benzaldehyde.

Preparation:

Reaction mixture maintained under inert (N2(g)) conditions

Material

Equivalent

Mw (gmol-1)

Moles (mmol)

Quantity

3-Bromobenzaldehyde

1.00

185.02

1.08

0.2g (0.126mL)

Pyrrolidine

1.00

71.12

1.08

0.088mL

Pd(dba)2 (0)

0.03

575.00

0.0216

0.0196g

BINAP

0.04

622.67

0.0432

0.0268g

Sodium tert-butoxide

1.50

96.10

1.62

0.156g

Toluene (solvent)

-

92.14

-

2.5mL

Potassium permanganate stain was used for TLC

Material

Quantity

Potassium permanganate

3.00g

Potassium carbonate

20.05g

5% Sodium hydroxide (5.18g : 100mL)

5mL

Water

300ml

Experimental Procedure:

 In a 50mL round bottom flask was first charged 3-Bromobenzaldehyde (0.126mL, 1.08mmol), dry Toluene solvent (2.5mL), then Pyrrolidine (0.088mL, 1.08mL), BINAP (0.0268g, 0.0432mmol), NaO-tBu (0.156g, 1.62mmol) and lastly Pd(dba)2 (0.0196g, 0.0216mL) while being stirred and maintained under Nitrogen. Reaction mixture was degassed for 15 minutes prior increasing temperature to 100-110 oC from an electrical hot plate. A yellow-red brown colour was observed from 1 to 3 hours of the reaction. 

degassed reaction mixture set up  set up of experiment aldehyde synthesis 1

reaction mixture being degassed             reaction at 3 hrs; set up throughout whole synthesis       


Mixture was left overnight and the crude obtained was a brown colour. TLC analysis showed completion of reaction (Pet. Ether / EtOAc 7:3). After 3 analyses, the plates all indicated starting material remained in crude solution however trails of a new compound were only seen in the B/P and P spot (Bromobenzaldehyde/Product and Product). Separation of the TLC plate also showed very low purity hence reaction already deemed unsuccessful. Crude solution was then put under reduced pressure on a rotary evaporator to remove the Toluene solvent to prepare for chemical analysis.

  

TLC plate             Crude solution after TLC on the left
confirming
reaction has
terminated


Chemical Analysis:

 

A 1H NMR (400MHZ, CDCl3, ID-1-001) spectrum indicated a substantial amount of meta-Bromobenzaldehyde and pyrrolidine in crude product, along with Toluene solvent, and irrelevant peaks not corresponding to 3-(Prryolidin-1-yl)benzaldehyde. The reaction was unsuccessful [2]

1H-NMR spectrum of product ID-1-001; target product was not obtained

 

Next experiment will focus on protecting the aldehyde group before Buchwald-Hartwig coupling with the same procedure for ID-1-001.

 

References:

[1] J. Med. Chem., 2008, 51, 1333–1343

[2] J. Am. Chem. Soc., 2015, 27, 8700-8703

Attached Files