synthesis of betti base as a potential drug
TRANSCRIPT
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
References:
1. Naso, F. (2017). Mario Betti: A Giant in the Chemistry Scenario of the Twentieth
Century. Substantia, 1(2).: 111-121
2. Rosini, G. Rendiconti (2003), Accademia Nazionale delle Scienze, Memorie di Scienze
Fisiche e Naturali , 27, 1–35
3. Noyori, R. (1994) asymmetric catalysis in organic synthesis (No. 547.2 N6)
4. Betti, M. Org. Synth. Collective 1941, 1, 381–383.
5. Betti, M. Gazz. Chim. Ital. 1900, 30 II, 310–316.
6. Betti, M. Gazz. Chim. Ital. 1900, 30 II, 301–309
7. Betti, M. Gazz. Chim. Ital. 1906, 36 II, 392–394.
8. Ghandi, M.; Olyaei, A.; and Raoufmoghaddam, S. (2008), One- pot, three-
component uncatalyzed quantitative synthesis of new aminonaphthol’s (Betti Bases) in water;
synthetic communications, V.38, pp. 4125 - 4138
9. Betti M., β-naphthol phenyl aminomethane (1941), Org. Synth. Coll. Vol.1, pp. 381–384
10. Cardellicchio, C., Capozzi, M. A. M., & Naso, F. (2010). The Betti base: the awakening of a
sleeping beauty. Tetrahedron: Asymmetry, 21(5), 507-517.
11. Saidi, M. R., & Azizi, N. (2003). Highly diastereoselective amino alkylation of naphthol’s
with chiral amines mediated by lithium perchlorate solution in diethyl ether. Tetrahedron:
Asymmetry, 14(3), 389-392.
12. Dindulkar, S. D., Puranik, V. G., & Jeong, Y. T. (2012). Supported copper triflate as an
efficient catalytic system for the synthesis of highly functionalized 2-naphthol Mannich bases
under solvent free condition. Tetrahedron Letters, 53(33), 4376-4380.
13. Heydenreich, M., Koch, A., Klod, S., Szatmári, I., Fülöp, F., & Kleinpeter, E. (2006).
Synthesis and conformational analysis of naphth [1′, 2′: 5, 6] [1, 3] oxazino [3, 2-c] [1, 3]
benzoxazine and naphth [1′, 2′: 5, 6] [1, 3] oxazino [3, 4-c] [1, 3] benzoxazine
derivatives. Tetrahedron, 62(48), 11081-11089.
14. Pirrone, F. (1940). Hydroxyquinolines Amino derivatives of 7-benzyl-8-hydroxyquinoline. 7-
[a- (p-nitroanilino) benzyl] -8-hydroxyquinoline. Gazzetta Chimica Italiana, 70, 520-527.
15. Littman, J. B., & Brode, W. R. (1930). CONDENSATIONS OF SECONDARY AMINES
WITH ALDEHYDES AND NAPHTHOLS1. Journal of the American Chemical Society, 52(4),
1655-1659.
16. Szatmári, I., Martinek, T. A., Lázár, L., & Fülöp, F. (2003). Substituent effects in the ring-
chain tautomerism of 1, 3-diaryl-2, 3-dihydro-1H-naphth [1, 2-e][1, 3]
oxazines. Tetrahedron, 59(16), 2877-2884.
17. Grumbach, H. J., Arend, M., & Risch, N. (1996). Aminoalkylation of electron-rich aromatic
compounds using performed iminium salts derived from aldehydes other than
formaldehyde. Synthesis, 1996(07), 883-887.
18. Blicks, F. F. (1942) The Mannich reaction in Organic Reactions; Springer: New
York, Vol. 1.
19. Smith, H. E., & Cooper, N. E. (1970). Ring-chain tautomerism of derivatives of 1- (. alpha. -
aminobenzyl)-2-naphthol with aromatic aldehydes. The Journal of Organic Chemistry, 35(7),
2212-2215.
20. Cardellicchio, C., Ciccarella, G., Naso, F., Schingaro, E., & Scordari, F. (1998). The Betti
base: absolute configuration and routes to a family of related chiral nonracemic
bases. Tetrahedron: Asymmetry, 9(20), 3667-3675.
21. Cardellicchio, C., Ciccarella, G., Naso, F., Perna, F., & Tortorella, P. (1999). Use of readily
available chiral compounds related to the Betti base in the enantioselective addition of
diethylzinc to aryl aldehydes. Tetrahedron, 55(51), 14685-14692.
22. Szatmári, I., & Fulop, F. (2004). Syntheses and transformations of 1-(α-aminobenzyl)-2-
naphthol derivatives. Current Organic Synthesis, 1(2), 155-165.
23. Cimarelli, C., & Palmieri, G. (2009). Synthesis of enantiopure 2‐(aminoalkyl) phenol
derivatives and their application as catalysts in stereoselective reactions. Chirality: The
Pharmacological, Biological, and Chemical Consequences of Molecular Asymmetry, 21(1), 218-
232.
24. István, S. and Ferenc, F. (2004). Syntheses and transformations of 1-(α-amino benzyl)-2-
naphthol derivatives. Curr. Org. Synth. V.1. 155-165.
25. Pu, L., & Yu, H. B. (2001). Catalytic asymmetric organozinc additions to carbonyl
compounds. Chemical Reviews, 101(3), 757-824.
26. Periasamy, M., Reddy, M. N., & Anwar, S. (2004). Synthesis and resolution of 1-(α-
pyrrolidinylbenzyl)-2-naphthol and its application in the resolution of 2, 2′-dihydroxy-1, 1′-
binaphthyl. Tetrahedron: Asymmetry, 15(11), 1809-1812.
27. Palmieri, G. (2000). A practical o-hydroxybenzylamines promoted enantioselective addition
of dialkylzincs to aldehydes with asymmetric amplification. Tetrahedron: Asymmetry, 11(16),
3361-3373.
28. Cimarelli, C., Palmieri, G., & Volpini, E. (2002). A practical stereoselective synthesis of
secondary and tertiary aminonaphthols: chiral ligands for enantioselective catalysts in the
addition of diethylzinc to benzaldehyde. Tetrahedron: Asymmetry, 13(22), 2417-2426.
29. Liu, DX, Zhang, LC, Wang, Q., Da, CS, Xin, ZQ, Wang, R., ... & Chan, AS (2001). The
application of chiral aminonaphthols in the enantioselective addition of diethylzinc to aryl
aldehydes. Organic letters, 3 (17), 2733-2735.
30. Szatmári, I., Sillanpää, R., & Fülöp, F. (2008). Microwave-assisted, highly enantioselective
addition of diethylzinc to aromatic aldehydes catalyzed by chiral aminonaphthols. Tetrahedron:
Asymmetry, 19(5), 612-617.
31. Radosevich, A. T., Chan, V. S., Shih, H. W., & Toste, F. D. (2008). Synthesis of (−) ‐
Octalactin A by a Strategic Vanadium‐Catalyzed Oxidative Kinetic Resolution. Angewandte
Chemie International Edition, 47(20), 3755-3758.
32. Ji, J. X., Qiu, L. Q., Yip, C. W., & Chan, A. S. (2003). A convenient, one-step synthesis of
optically active tertiary aminonaphthol and its applications in the highly enantioselective
alkenylations of aldehydes. The Journal of organic chemistry, 68(4), 1589-1590.