Kurdistan Region-Iraq

Ministry of Higher Education & Scientific Research

Salahaddin University-Erbil

Synthesis of Betti Base as a Potential Drug

A Report

Submitted to the Scientific Committee of the Chemistry

Department - College of Sciences / Salahaddin University - Erbil

in Partial Fulfillment Requirements for the Degree of Bachelor

in Chemistry Science

By:

Muhammad Askandar Hamadamin

Supervised by:

Asst. Prof. Dr. Media Noori Abdullah

April-2021

Aim of the project:

The aim of the project is to study the synthesis and the importance of Betti

Base in pharmaceutical chemistry because of their bioactivity properties, and as a

valuable ligand in asymmetric synthesis.

Abstract

The multicomponent reaction between 2-naphthol, arylaldehydes and ammonia

yields aminobenzylnaphthols in a process known as the Betti reaction, which was

first revealed at the beginning of the 20th century. Various methods have been

reported for the synthesis of aminobenzylnaphthol derivatives (Betti base) using

various types of naphthols, aromatic amines, heteroaromatic amines, and aliphatic

and cyclic amines instead of ammonia and aliphatic and aromatic aldehydes

compounds under various conditions in recent years. Betti bases are importance in

pharmaceutical chemistry because of their bio-activities, including anti-bacterial,

antipain, antihypertensive and bradycardic activities. The aminobenzylnaphthols

could be easily resolved into their enantiomers, as a result, novel applications of the

Betti reaction was to produce new chiral aminobenzylnaphthols together with the

evaluation of these chiral bases in asymmetric synthesis.

Table of content:

1- Introduction

1.1. History

1.2. Describe of Betti base

1.3. Derivatives of Betti base

1-Introduction

1.1-History

Mario Betti (1875–1942) was a distinguished Italian chemist, (Naso F.et. al.

2017) very active at the beginning of the 20th century. He worked at the Universities

of Florence, Cagliari, Siena, Genoa and finally Bologna, where he was the successor

of Giacomo Ciamician. His main research interests in stereochemistry were directed

towards the resolution of racemic compounds, the relationship between molecular

constitution and optical rotatory power, and asymmetric syn- thesis with the aid of

chiral auxiliaries or in the presence of circularly polarized light. In 1939, he was

appointed as the Senator of the Kingdom of Italy Noyori considered him to be the

real pioneer of the asymmetric synthesis, (Noyori R. al.1994) since Betti reacted

methyl magnesium iodide and benzaldehyde in the presence of N, N-

dimethylbenzylamine. The reaction yielded a product with a modest specific

rotation, which was also questioned.( Noyori R. al.1994) However, the original

synthetic idea proved to be valid, as witnessed by the many similar enantioselective

reactions of organometallic reagents that have been reported in contemporary times

with excellent yields and ee values.( Noyori R. al.1994) With respect to the other

research topics, Mario Betti is known for the so-called Betti reaction(Betti M. al.

1941)and for the resulting aminobenzylnaphthol 1 (Fig. 1)( Betti M. al. 1906) that

was called the Betti base.

Figure 1. Betti Base

1-(amino(phenyl)methyl) naphthalen-2-ol

1.2-Describe of Betti base

The study of the chemistry of the Betti bases was started when Betti reported a

straight forward synthesis of 1- (α-amino benzyl)-2-naphthol (Ghandi et. al. 2008).

At the beginning of the 20th century, Mario Betti discovered the three-component

reaction of 2- naphthol, aryl aldehydes and ammonia or amines for the synthesis of

aminobenzylnaphthols. Now, this process has been known as the Betti reaction and

the aminonaphthol product known as a Betti base. (betti M. al. 1941) synthesis of

substituted Betti base derivatives have become an important area of synthetic

chemistry. the Betti reaction to produce new chiral amino benzyl naphthol’s were

reported together with the evaluation of these chiral bases in asymmetric synthesis

(Cardellicchio C. al. 2010).

In recent years, the efforts were done to synthesize the Betti’s base derivatives

in organic solvents such as EtOH or MeOH at room temperature or thermally under

solventless condition (Saidi M. R. & Azizi N. al. 2003). Various heterogeneous

catalysis has been prepared and screened for the synthesis of Betti base in an attempt

to reduce the environmental hazards (Dindulkar S. D. et. al. 2012). Betti base with –

NH2 and –OH groups at 1 and 3 position, respectively, is expected to act as an

excellent ligand for coordination with transition metal ions, and Cu (II) complex with

Betti base has been reported (Heydenreich M. et. al. 2006).

1.3-Derivative of Betti base

Preparation of the substituted Betti base derivatives via the modified Manniche

reaction has subsequently become of considerable importance because of C–C

bond formation under mild experimental conditions. In recent years, attention has

been paid to the Betti reaction, and a similar reaction, can be performed by either

using other naphthol’s (Pirrone F. al.1940) or quinolinols, or by replacing ammonia

with alkyl amines. (Littman J. B. & Brode W. R. al. 1930) In addition, a variety of

racemic structures related to the Betti bases have recently been prepared by

addition of naphthol’s to the preformed iminium salts. (Grumbach H. J. et. al.1996)

Traditionally, the Betti base derivative synthesis is carried out in organic solvents

such as EtOH, MeOH, and Et2O at room temperature for long times or thermally

under solventless conditions. As such, utilization of environmentally friendly water

as solvent not only provides the product in an easy workup procedure (vide infra)

but also is in accord with green sustainable chemistry principles. The racemic Betti

bases have been used for transformation into pro- ducts with antibacterial activity.

2- Mechanism of Betti base:

Mechanism. Once the imine is produced, it reacts with phenol in the

presence of water to yield an α-aminobenzylphenol. First, the lone-pair on the

nitrogen of the imine deprotonates the phenol, pushing the bonding electrons onto

the oxygen.

3-The Betti reaction

This synthetic strategy originated between the end of the 19th and the beginning

of the 20th century when research in several laboratories was performed on reactions

between ammonia, or amines, formaldehyde and enolisable carbonyl compounds.

(Blicks, F. F. al.1942) The first two components yield an imine that reacts with the

carbonyl compound. These procedures are commonly classified as Mannich

aminoalkylations, after the systematic work of the latter author, which began in

1912, thus subsequent to the Betti research. (betti M. al. 1906) In 1900, (betti M. al.

1900) Betti had hypothesized, and later proved that 2-naphthol should be a good

carbon nucleophile towards the imine produced from benzaldehyde and aniline, as

represented in Scheme 1.

Later, (betti M. al. 1900) Betti also reported that product 3 (Scheme 2) could be

obtained from a three-component condensation of 2-naphthol, an ethanolic solution

of ammonia and 2 equiv of benzaldehyde (91%yield).

Actually, the product of the reaction, as later proved, (Smith H. E., & Cooper N. E.

al.1970) is rep- resented by the forms 3a and 3b in equilibrium. The intermediate 3

was treated with hydrochloric acid to obtain the salt of the Betti base 1HCl (91%

yield, Scheme 3). Addition of a solution of sodium hydroxide to chloride, yielded

Betti base 1 (75% yield). (Betti, M. al.1941) Along the lines presented in Scheme

1, (Betti, M. al. 1900) Scheme 4 reports the reaction of ammonia and

benzaldehyde to yield the corresponding imine, that subsequently reacts with 2-

naphthol. In the presence of benzaldehyde, Betti base 1 produces

the imine/oxazine 3 (Scheme 5). Betti base 1 was successfully resolved into two

isomers using tartaric acid. (Betti, M. al. 1906) The Betti reaction, that is, a simple

and straight for- ward condensation between 2-naphthol, aryl aldehydes and

ammonia, or amines could be used to synthesis more complex

molecular structures by assembling these three-simple components. However, a

long period of silence occurred after an initial interest that included the work

performed by Littmann and Brode, who used different amines instead of ammonia.

(Littman, J. B. & Brode W. R. al.1930) For example, the use of dimethylamine

yielded the dimethylamino-derivative of the Betti base 4 in a one-pot

multicomponent process (71% yield, Scheme 6). On the other hand, the use of

piperidine gave 1-(1-piperidylbenzyl)-2-naphthol (73% yield, Scheme 7) 5a.

(Littman, J. B. & Brode W. R. al.1930) This compound was also resolved into its

enantiomers with the aid of camphor sulfonic acid. A different mechanism should

be operative in these reactions. According to Littmann and Brode, (Littman, J. B. &

Brode W. R. al.1930) secondary amines should react with benzaldehyde via the

formation of a benzylidinediamine, as shown in Scheme 8. This intermediate attack

the 2-naphthol and yields aminobenzylnaphthol, after the elimination of an amine

molecule. However, in principle the alternative mechanism represented in Scheme

9, based upon the reaction between the amine and an ad- duct formed between 2-

naphthol and benzaldehyde cannot be ruled out.

A decade ago, (Cardellicchio C. al.1999) we decided to ‘awaken’ the Betti

base, due to our firm belief that its structure and all of the possible variations on the

theme could be of special interest for organic chemists working in the field of ligand–

metal catalyzed reaction. (Noyori R. al.1994) The possibility of accomplishing in a

straightforward manner the resolution of the Betti base 1 was considered a great

advantage. In our work, (Cardellicchio C. al.1998) the original synthetic procedure

was reconsidered and extended to other reactants; the absolute configuration of the

Betti base hydro- bromide was determined by an X-ray experiment (Fig. 3) and the

configurations of the other bases were determined by chemical correlations with 1.

Finally, we reported the first application of the aminobenzylnaphthols

produced in asymmetric synthesis. (Cardellicchio C. al.1999) Since then, many other

research groups in the world have investigated this reaction. However, reviews on

the topic remain scarce. A short report was published in 2004, (Szatmári I. & Fulop

F. al.2004) and a few features of the Betti bases are present in work dealing with

aminobenzylphenols. (Cimarelli C. & Palmieri G. al. 2009) Herein we report the

current state of the art and recent research concerning this use- full reaction and the

bases produced that will be generally called Betti bases.

4-Synthesis of new Betti bases

4.1-Transformation of the original Betti base

New chiral molecules were synthesized starting from the Betti base. In our

investigations, (Cardellicchio C. etc. al.1998) we observed that simultaneous N-, and

O-methylation of the Betti base could be accomplished by a simple treatment with

NaOH/CH3I (90% yield, Scheme 11).

Selective O-methylation was achieved by protecting the nitro- gen atom.

(Cardellicchio C. etc. al.1998) Towards this end, we used the imine/oxazines 3

(Scheme 12) as a starting material that was subjected to methylation; the

subsequent hydrolysis led to the final O-methylated Betti base (64% yield).

N-Substituted amines were produced by following a two-step procedure.

(Cardellicchio C. etc. al.1999) For example, Betti base 1 (Scheme 13) was treated

with an aldehyde to give imine/oxazine 11 (68% yield). Then, this intermediate

was subjected to reduction with hydrogen or NaBH4 yielding the N-alkyl

substituted amine 12 (60% yields)

5-Spectroscopy of Betti base

5.1. 1H-NMR of Betti Base or ( 1-(amino(phenyl)methyl)naphthalen-2-ol):

6-Biological activity of Betti bases

Little attention has been paid to the Betti bases as far as their biological

activity is concerned. (Desai, et al. 1984) examined the in vitro antituberiostatic

activity of 1-aryl-3- [α-(2-hydroxy-1- naphthyl)-benzyl] and 2-aryl-3- [α-(2-

hydroxy-1- naphthyl)-benzyl]-4-thiazolidinones against the H37RV strain of

Mycobacterium tuberculosis in Lowenstein-Jensen egg medium at 0.02 mg/ml.

The retardation of the growth rate was studied for up to six weeks at 37 °C. The

antibacterial activities of 1-aryl-3- [α-(2-hydroxy-1- naphthyl)-benzyl] and 2-aryl-

3- [α-(2-hydroxy-1- naphthyl)-benzyl]-4-thiazolidinones were tested by means of

an N-agar pour-plate method in DMF, and they proved to be active against

Escherichia coli and S. aureus. It was found that 1-aryl-3- [α-(2-hydroxy-1-

naphthyl)-benzyl] does not possess significant antimycobacterial activity; the

presence of a thiazolidine nucleus is necessary for good antituberculotic activity,

and the presence of halogen atoms enhances the antibacterial activity (István and

Ferenc. 2004)

7-Betti base as Drug

Betti bases (aminobenzylnaphthols) have not been studied extensively to

explore their possible pharmacological applications. Our group prepared a small

and focused library of twenty-three Betti bases from the multicomponent reaction

of 2-naphthol with primary or secondary cyclic amines and representative aromatic

aldehydes. The compounds were prepared in 52-90% yield using environmentally

friendly procedures. The E-factor and the atom economy for our process were 3.92

and 94%, respectively. The study of the anti-proliferative activity against human

solid tumor cell lines pointed out that these Betti bases represent privileged

scaffolds and could be used for the development of pharmacologically-active

compounds in cancer therapeutics. The 50% growth inhibitory (GI50) values of the

most potent compounds were in the low micromolar range. Fourteen of these Betti

bases were less active in HBL-100 breast cancer cells than towards the breast

cancer cell line T-47D. A subset of these Betti bases was further tested against the

human breast cancer cell lines MCF-7 and MDA-MB-453. The results indicated a

correlation in the sensitivity of T-47D cells to Betti bases. We explored

computationally the interaction of the Betti bases with SLC6A14, a Na+- and Cl--

dependent influx transporter of both neutral and cationic amino acids that is

overexpressed in T-47D cells. SLC6A14 is inhibited by α-methyl-tryptophan,

which blocks cell growth via deprivation of amino acid influx. The docking studies

indicated that our Betti bases might behave as tryptophan mimetics, blocking this

solute carrier transporter and inducing the anti-proliferative effects. Importantly,

these Betti bases showed good cytotoxic selectivity towards cancer cells with no

activity against normal human fibroblast cells BJ-hTERT.

8-Application of Betti bases

8.1-Organozinc chemistry

8.1.1-Addition of diethylzinc to aryl aldehydes

The enantioselective addition of organozinc reagents to aldehydes in the presence

of a chiral ligand is a very useful synthetic method leading to chiral alcohols. (Pu,

L., & Yu, H. B. al. 2001) This reaction requires the presence of a suitable ligand of

the metal that can be also used on a catalytic scale (the ratio between the substrate

and the chiral ligand is in the range 20:1–5:1). The process is very commonly used

in asymmetric synthesis to test the capability of the chiral, but void of phosphorus,

ligands. Enantiopure amines, alcohols, amino alcohols, Sulphur compounds, and

many other molecules were tested with this easy and useful reaction (Pu, L., & Yu,

H. B. al. 2001) as soon as they were synthesized. Accordingly, several

aminobenzylnaphthols obtained with a Betti protocol were tested as chiral ligands

for the first time in this standard reaction (Scheme 35). The results that were reported

can be considered to be of special interest taking into account the ready accessibility

of the chiral ligand.

In fact, we performed the addition of diethylzinc to aryl aldehydes in the

presence of Betti base 1, N-butyl-Betti base 12, and N, N-dimethyl-Betti base 4.

(Cardellicchio C. etc. al.1999) THF, n-hexane, and toluene were evaluated as

reaction solvents and toluene was found to be superior. Lower ee values of the

secondary alcohol (35% ee) were measured with Betti base 1, but the use of 12 in

toluene gave high ee values (87% ee). The best asymmetric induction (92–>99% ee)

was obtained by using tertiary base 4 (63–94% isolated yield). In the work of Hu et

al., diethylzinc was added to aryl aldehydes in toluene in the presence of ligands 5a–

c,(Periasamy M. al.2004) and 93–96% yields of the ethyl phenyl carbinol with 73–

99% ee values were obtained. Screening of different aminobenzylnaphthols was

performed by Palmieri et al. in the same reaction. (Palmieri, G. al.2000) Ethyl phenyl

carbinol was obtained with 15–89% ee values (26–97% yields). The highest

enantioselectivity (89% ee) was observed with aminobenzylnaphthol 28d. It is

interesting to underline that the use of a similar ligand having only the stereo genic

center of the phenylethylamino moiety caused poor ee values (16%). Chan et al.

added diethylzinc to benzaldehyde in toluene in the presence of ligands 28a and 30a.

(. Liu DX. al.2001) Yields (70–97%) of the secondary alcohol were obtained (ee

values 52–100%). Tertiary amine 30a (ee >99%) worked better than secondary

amines 28a. Fulop et al. performed the addition of diethylzinc to aryl aldehydes in

the presence of bases 28 under microwave irradiation. (Szatmári I el. Al.2006) The

yields of the procedure were 94–98%, with ee values in the range of 10–92%, the

92% ee peak value being obtained with aminobenzylnaphthol 28m.

8.1.2-Alkenylation or arylation of aldehydes

The addition of diisopropenylzinc to 4-iodo-3-pentenal in the presence of ligand 30a

yielded the corresponding alcohol (68% yields, 83% ee, Scheme 36). (Radosevich

A. T. el. Al.2008)

This intermediate was used in the synthesis of octalactin A, a lactone

isolated from marine microorganisms, which showed sig-nificant cytotoxic activity

against some tumour cell lines. (Radosevich A. T. el. Al.2008) The trans metalation

of a boron reagent with readily available dialkylzinc was considered a

convenient procedure to prepare

alkenyl or aryl zinc reagents in an easy manner. The in situ produced zinc reagents

were reacted with aldehydes in the presence of Betti bases (Scheme 37). For

example, alkenyl zincs were obtained from trans metalation of dimethylzinc with a

boron reagent, prepared from the hydroboration of a terminal alkyne with

dicyclohexylborane. The alkenyl zinc reagents were added to the alkyl or aryl

aldehyde in toluene in the presence of aminobenzylnaphthol 30a. (Ji J. X. el.

Al.2003) The alcohols were obtained in high yields (77–95%) and in very high ee

values (94–99% ee) In order to perform the aldehyde arylation, Chan et al.

prepared a phenyl zinc reagent by mixing phenylboronic acid with diethyl- zinc.

The zinc reagent was added to aldehydes in the presence of aminobenzylnaphthol

30a to produce chiral diarylmethanols, as shown in Scheme 38.37 Very high yields

(87–95%) and ee values (92–99% ee) were obtained. This protocol seems to be

particularly interesting, due to low cost of both the reagents and of the chiral

auxiliary and also due to the pharmaceutical relevance of the optically active

diarylmethanols obtained. Dahmen and Lohrmann reported a different aryl transfer

to aldehydes.48 Aryl zinc was produced in situ by reacting diethylzinc with

triphenyl borane, or with stable and readily available borane complexes with

ammonia or amine. These aryl zinc species were added to alkyl or aryl aldehydes

in the presence of the aminobenzylnaphthol 28g, according to Scheme 39. The zinc

complex that originated from the triphenyl borane was highly reactive, but less

stereoselective (36% ee value). Better results were obtained when

borane/aminoethanol complexes were employed. In this case, chiral

diarylmethanols were prepared in high yields (86–97%) and high ee values (92–

98%). This synthetic strategy was successfully applied by the same authors in

some pat- ents49,50 for the synthesis of valuable pharmaceutical intermediates.

For example, a chiral precursor 42 (Scheme 40) of the analgesic Cizolirtine was

obtained by reacting diphenyl zinc (pre-pared from triphenyl borane and

diethylzinc) with pyrazolcarbaldehyde in the presence of a series of chiral ligands,

among which aminobenzylnaphthols 28a, d, g and 30g are present. Ee values in the

range of 78–85% were observed.49

In a different patent,50 the thienylation of the suitable aldehyde yielded a chiral

precursor of Duloxetine, a drug used for the treatment of depression, urinary

incontinence, and neuropathic pain.

8.2-Stereoselective reaction of organometallic reagents with Betti oxazines

The oxazines 43 could be submitted to regio- and stereoselective arylation at its a-

position (Scheme 41) by treatment with aryl- magnesium bromides to give the new

compound 44 in good yields (73–85%).51,52 The arylated oxazine derivatives 44

were reduced by LiAlH4 in good yields (84–92%) to another family of N-alkylated

Betti bases, that is, 1-[a-(2 aryl piperidyl)benzyl]-2-naphthols) 45 (Scheme 42),

which could be successfully used as chiral ligands in asymmetric reactions. When

products 45 were subjected to N-debenzylation by using palladium-catalyzed

hydrogenolysis in MeOH/CH2Cl2 (as shown in Scheme 16 for a different

product),52 the corresponding chiral 2-alkyl-piperidines, including a derivative of

(R)-()-coniine, were obtained in 90–93% yield. Organometallic reagents were

reacted with oxazine 29 by Palmieri et al. at 0 C (Scheme 43).34 Higher yields

were obtained with Grignard reagents or with n-butyllithium (58–98%). The

diastereomeric ratios observed were in the range of 80:20–97:3.

Best result was obtained with N-methyl- or N-allyl-substituted aminonaphthol’s.

Different nitrogen substitutions caused a decrease in the stereoselectivity

8.3-Tsuj–Trost allylic substitution

The Tsuji–Trost palladium-catalysed allylic substitution of 1,3- diphenylprop-2-en-

1-yl acetate with dimethyl malonate is a com- mon asymmetric induction test for

new phosphine ligands. When phosphines 36a and b were used in this reaction

(Scheme 44), interesting yields and enantioselectivities of 47 were observed (41–

99% yields, 12–70% ee). The highest asymmetric induction was observed in

methylene chloride.44

8.4-Hydrosilylation of aryl alkenes

Aminobenzylnaphthols 28a, b, and we were treated with (S)- or (R)-BINOL and

phosphorus trichloride (Scheme 45) to synthesize

the corresponding new chiral phosphoramidites 48 (32–74%

yields).53 The hydrosilylation reaction of arylethenes was performed with

phosphoramidites 48 in the presence of a palladium catalyst.53 The silane obtained

could be oxidized to the corresponding aryl methyl carbinol 49 (Scheme 46). Good

yields (65–96%) and high enantioselectivities (73–97% ee values) were observed

by using the ligands 48

8.5-Preparation of a B-chiral boronate complex

Betti base 1 was used to prepare the first stable boronated com- plex 50 (Scheme

47) that is stereo genic only at the boron centre.54 Accordingly, Betti base 1 was

reacted with glyoxylic acid and phenylboronic acid in DMF.

A chirality transfer process occurred from the stereo genic car- bon of the Betti

base to the boron atom. Complex 50 was then alkylated with benzyl bromide

(Scheme 48) with a good stereoselectivity (dr 10.5:1), to yield the amino acid

precursor 51.54

8.6-Preparation of enantiopure a-aminophosphonic acids

Imines 20 were treated with triethyl phosphite in the presence of trifluoroacetic

acid to yield benzyl aminonaphthol derivatives 52 (74–90% yields; 66–84% de).55

When compounds 52 were hydrolysed, chiral amino phosphonic acids 53 were

produced, as summarised in Scheme 49.55

8.7-Betti bases in the separation of enantiomers

Due to their easy preparation in an enantiomerically pure form, Betti bases

can be legitimately added to the chiral pool of the compounds used

in the separation of enantiomers, and also of 2884. industrial interest. For

example, 1-(pyrrolidinyl benzyl)-2-naphthol 5b and boric acid in acetonitrile were

used in an innovative methodology, that was devised for achieving the separation

of the enantiomers of the racemic BINOL ligand.22

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