Scalable methodologies for the synthesis of novel unsymmetrically substituted secondary amines

Article abstract of DOI:10.2298/JSC110408173R

Fast, easy, and scalable methodologies for the synthesis of unsymmetrically substituted secondary amines containing naphthalene, indole, pyridine and imidazole moieties through reductive amination were explored. The investigated operating procedures were

Full text of DOI:10.2298/JSC110408173R

J. Serb. Chem. Soc. 77 (2) 131–140 (2012)
UDC 547–304.2+542.913+66.095.83–916.2
JSCS–4255
Original scientific paper
Scalable methodologies for the synthesis of novel
unsymmetrically substituted secondary amines
GHEORGHE ROMAN*
Department of Inorganic Polymers, Petru Poni Institute of Macromolecular Chemistry,
41A Aleea Gr. Ghica Vodă, Iaşi 700487, Romania
(Received 8 April, revised 2 July 2011)
Abstract: Fast, easy, and scalable methodologies for the synthesis of unsym-
metrically substituted secondary amines containing naphthalene, indole, pyri-
dine and imidazole moieties through reductive amination were explored. The
investigated operating procedures were successful on a 50- to 30-mmol scale,
and present a high potential for up-scaling.
Keywords: reductive amination; imine; secondary amine; scalability.
INTRODUCTION
Medicinal chemistry depends significantly on the generation of compound
libraries for the discovery of leads, exploration of structure–activity relationship
(SAR), and optimization of physical properties. However, the scope of a com-
pound library can be limited by the commercial availability of the starting mate-
rials. Several chemical classes of starting materials, such as aldehydes and carbo-
xylic acids, are well represented commercially. Amongst other important scaf-
folds in the preparation of numerous biologically active substances, a large num-
ber of structurally diverse amines are also available. Nonetheless, the significant
use of amines as building blocks in drug-like molecules justifies the expansion of
the available entities.
1,2
3,4
In connection with previous work concerning the synthesis, reactivity,
5,6
and biological activity of Mannich bases derived from ortho-hydroxyacetophe-
nones, easy access to novel, biologically relevant secondary amines in 10-gram
quantities was required. One-pot, solution-phase reductive alkylation of a pri-
mary amine with an aldehyde or a ketone is one of the most widely utilized me-
thods for the synthesis of secondary amines. One of the drawbacks of this ap-
proach is the necessity for the removal (usually by column chromatography) of
the unreacted primary amine along with other potential by-products, especially
*E-mail: gheorghe.roman@icmpp.ro
doi: 10.2298/JSC110408173R
131
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the alcohol related to the initial carbonyl compound. Both solid-phase synthesis
and solution-phase synthesis with resin-bound scavengers/reagents have been
7
used to circumvent the shortcomings of the classical solution-phase synthesis.
Although these methodologies allow fast preparation of a virtually infinite num-
ber of pure secondary amines (either individually or in parallel synthesis) on a
very small scale, the cost of the resins employed makes large- or even medium-
scale synthesis prohibitive. Therefore, low-cost, classical, solution-phase synthe-
tic strategies that are amenable to scaling up without the need for chromategra-
phic separation were considered for the achievement of this synthetic goal. In this
paper, two of such strategies were employed for the multi-gram preparation of
unsymmetrically substituted secondary amines having naphthalene, indole,
pyridine and imidazole moieties in their structure; in addition, the potential for
scale-up of these two strategies was explored.
EXPERIMENTAL
All chemical reagents were obtained from Sigma–Aldrich and were used without prior
purification. Analytical thin-layer chromatography was performed on glass-backed SiliCycle
precoated silica gel 60 F254 plates, and the compounds were visualized by UV illumination
(254 nm). Melting points were taken on a Mel-Temp II apparatus and are uncorrected. Ele-
mental analysis was conducted in-house, on a PerkinElmer 2400 Series II CHNS/O system.
1
The H- and 13C-NMR spectra were recorded on a Bruker Avance 400-MHz spectrometer.
The signals owing to residual protons in the deuterated solvents were used as internal stan-
1
dards for the H-NMR spectra. The chemical shifts for the carbon atoms are given relative to
CDCl3 (δ = 77.16 ppm), CD3OD (δ = 49.00 ppm), or DMSO-d6 (δ = 39.52 ppm). The high-re-
solution mass spectra were obtained on an Applied Biosystems/MDS Sciex QSTAR XL
spectrometer equipped with an Agilent HP1100 Cap-LC system in the electrospray ionization
(ESI) mode.
General procedure for the synthesis of N-(naphthalen-1-ylmethylene)benzylamines 1
A mixture of the required amine (50 mmol) and 1-naphthaldehyde (7.81 g, 50 mmol) in
ethanol (20 mL) was treated with 0.5 mL of ethereal HCl and stirred at room temperature for 1
h. The mixture was refrigerated overnight, and then the solid that separated was filtered and
recrystallized.
General procedure for the synthesis of N-(naphthalen-1-ylmethyl)benzylamines 2
A solution of N-(naphthalen-1-ylmethylene)benzylamine 1 (20 mmol) in methanol (50
mL) was gradually treated with NaBH4 (2.28 g, 60 mmol) at room temperature. The mixture
was stirred at room temperature overnight, and then the solvent was removed under reduced
pressure and the residue was partitioned between water (80 mL) and ethyl acetate (50 mL).
The aqueous layer was further extracted with ethyl acetate (2× 20 mL) and the combined or-
ganic phase was washed with water and brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to give the pure secondary amine. The hydrochloride
was prepared by treating a solution of the free base in diethyl ether with an excess of ethereal
HCl. Filtration and recrystallization of the separated solid afforded the crystalline hydro-
chloride.
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133
General procedure for the synthesis of N-(arylidene)-2-(1H-indol-3-yl)ethanamines 3
A mixture of tryptamine (4.81 g, 30 mmol) and aldehyde (30 mmol) in benzene (60 mL)
was heated at reflux temperature for 4 h while the formed water was removed as an azeotrope.
At the end of the reaction time, the solvent was removed under reduced pressure to give a
residue that was recrystallized from the appropriate solvent.
Reduction of imines 3 derived from tryptamine to amines 4
Starting from imines 3 (20 mmol) and NaBH4 (2.28 g, 60 mmol), the reduction was
performed in a manner similar to the procedure reported previously for amines 2. The hydro-
chlorides were prepared as described for the N-(naphthalen-1-ylmethyl)benzylamines 2.
General procedure for the one-pot synthesis of N-(pyridin-3-ylmethyl)benzylamines 5
A mixture of 3-(aminomethyl)pyridine (3.24 g, 30.0 mmol) and aldehyde (36 mmol) in
methanol (50 mL) was stirred at room temperature for 6 h, and then NaBH4 (3.42 g, 90.0
mmol) was gradually added to the solution, and the mixture was further stirred at room
temperature overnight. The solvent was removed under reduced pressure and the residue was
partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous layer was further
extracted with ethyl acetate (2×20 mL); the combined organic phase was washed with water
(3×30 mL) and extracted with 1 M HCl (60 mL). The acid extract was washed with ethyl
acetate (2×20 mL), and then the pH of the aqueous phase was rendered alkaline with 10 %
aqueous K2CO3 solution. The separated oil was extracted in ethyl acetate (2×30 mL), washed
with water and brine, and dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure to yield the pure amine. The dihydrochlorides were prepared as described for
the N-(naphthalen-1-ylmethyl)benzylamines 2.
General procedure for the synthesis of N-(3-(1H-imidazol-1-yl)propyl)benzylamines 6
A mixture of 1-(3-aminopropyl)-1H-imidazole (1.25 g, 10.0 mmol) and aldehyde (12
mmol) in methanol (20 mL) was stirred at room temperature for 24 h, and then NaBH4 (1.14
g, 30.0 mmol) was gradually added. The mixture was further stirred at room temperature
overnight, and then the solvent was removed under reduced pressure and the residue was
partitioned between water (50 mL) and ethyl acetate (30 mL). The aqueous phase was further
extracted with ethyl acetate (20 mL), and then the combined organic phase was washed with
water (3×50 mL) and brine (20 mL) and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to give an oil that was purified by column chromatography.
The dihydrochlorides were obtained by treating the solution of the free base in diethyl ether
with excess of HCl in diethyl ether.
RESULTS AND DISCUSSION
The first methodology towards the large-scale synthesis of pure secondary
amines investigated in this paper was based on the two-step reductive alkylation
of a primary amine, an approach that entails the isolation of the intermediate
imine. This methodology is less attractive for the preparation of secondary ami-
nes than the one-pot approach owing to the additional step. However, the two-
-step reductive alkylation becomes acceptable provided that the intermediate imine
could be separated from the reaction mixture by filtration, and purified (prefe-
rably through recrystallization) prior to its reduction in the subsequent step; in
this case, the reduction of the imine could yield the secondary amine in high pu-
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rity even in bulk preparations. As a high molecular weight and the presence of
fused carbocycles or heterocyles are usually grounds for an organic compound to
be in the solid state at room temperature, it was hypothesized that imines having at
least one naphthalene moiety could be good candidates for the exploration of this
strategy. Furthermore, a naphthalene scaffold could be an interesting structural
feature, as proved by its presence in the structure of the biologically active
8
compounds that bind to a highly hydrophobic active site of an enzyme, or by its
effectiveness as a pharmacophore required for the binding to melanocortin re-
9
ceptors. A brief search of the literature showed that the available information
even on the common N-(naphthalen-1-ylmethylene)benzylamine or N-benzylide-
ne-1-(naphthalen-1-yl)methylamine is scarce, and that the corresponding secon-
dary amine is available from a limited number of commercial sources at conside-
rable cost. Encouraged by these findings, the synthesis of a series of N-(naphtha-
len-1-ylmethyl)benzylamines 2 was undertaken starting from the commercially
available naphthalene-1-carboxaldehyde and substituted benzylamines (Scheme
1). When an equimolar mixture of the starting materials in a small volume of
ethanol and in the presence of catalytic amounts of ethereal HCl was stirred at
room temperature for 1 hour and subsequently refrigerated overnight, the corres-
ponding imines 1 separated as solids. However, 4-methylbenzylamine and 4-fluo-
robenzylamine did not lead to solid imines, but produced the Schiff bases as
viscous oils that redissolved when the reaction mixture was allowed to warm to
room temperature; the experiments with these two benzylamines were not pur-
sued further. The solid imines 1 could be recrystallized from lower alcohols with
only a moderate loss of material, except for the Schiff base derived from 4-me-
thoxybenzylamine. Aside from 2-chloro-N-(naphthalen-1-ylmethylene)benzyl-
amine 1b, all other naphthalene-containing Schiff bases are novel, and were fully
characterized (the analytic and spectral data are given as supplementary mate-
1
rial). As a general feature, the H-NMR spectra of imines 1 present one singlet
integrating for one proton at approximately 9 ppm that can be associated with the
Scheme 1. Synthesis of naphthalene-containing unsymmetrically substituted secondary
amines. Conditions: a) substituted benzylamine, 36 % HCl, diethyl ether, rt for 1 h,
then –10 °C overnight; b) NaBH4, methanol, rt, overnight.
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SCALABLE SYNTHESIS OF SECONDARY AMINES
135
proton of the imine function, and one singlet integrating for two protons at
around 5 ppm, corresponding to the methylene group. The signal of the carbon
atom in the imine function just above 160 ppm and the peak of the carbon atom
of the methylene group at about 60 ppm can also serve as markers for the vali-
dation of the structure of imines 1.
As expected, the reduction of the pure imines with sodium borohydride in
10
methanol afforded the pure secondary amines 2 almost quantitatively. As the
free amines are known to age badly or form carbamic acids in the presence of
carbon dioxide from air, the novel compounds were also converted into their
hydrochlorides by treating their solution in diethyl ether with ethereal HCl. A
1
comparative inspection of the H-NMR spectra of amines 2 as free bases re-
vealed the presence of a new singlet integrating for two protons at around 4 ppm
and the disappearance of the singlet that was noticeable downfield in the spectra
13
of imines 1. Moreover, an additional peak in the aliphatic region of the C-NMR
spectra can be attributed to the aliphatic carbon atom in the naphthalen-1-ylme-
1
thyl residue. The H-NMR spectra of the hydrochlorides of amines 2 taken in
deuterated DMSO feature a broad singlet at approximately 10 ppm that integrates
for two protons. Since the addition of deuterated methanol to the NMR sample
resulted in a decrease of the integration for this peak, the signal was attributed to
the hydrogen atoms of the protonated secondary nitrogen atom.
The investigation was extended to a second series of secondary amines de-
rived from tryptamine and aromatic aldehydes. A few N-benzyltryptamines with
11
sedative, anticonvulsant, analgesic, and neuroleptic action, or active as tubercu-
12
lostatics have been so far obtained through the condensation of tryptamine with
aldehydes followed by the in situ reduction of the intermediate imine. On the
other hand, imines derived from tryptamine have usually been reported in con-
nection with the synthesis of tetrahydro-β-carbolines via the Pictet–Spengler re-
13
action. A brief examination of the methods described in the literature for the
synthesis of imines 3 derived from tryptamine revealed that the most efficient
method is based on the condensation of the reactants in benzene with the removal
of the by-product water as an azeotrope (Scheme 2). For example, this method
produced a 70 % yield of (2-(1H-indol-3-yl)-N-(2-thienylmethylene)ethanamine
3d after recrystallization, whereas a low yield of only 24 % was reported when
the same compound was prepared by heating the reactants in ethanol at reflux
14
temperature for 30 min. The analytic and spectral data for imines 3 are given in
1
the Supplementary material to this paper. The H-NMR spectra of the imines 3
showed two triplets around 3.1 and 3.9 ppm, attributable to the protons of the
methylene groups originating from tryptamine, whereas the imine proton and the
proton at the heterocyclic nitrogen atom were associated with a sharp singlet
usually above 8 ppm and a broad singlet at approximately 8 ppm, respectively. In
13
the C-NMR spectra of imines 3, the carbon atom of the imine function gave a
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signal downfield at about 160 ppm. In the subsequent step, the reduction of the
pure imines 3 with sodium borohydride in methanol at room temperature af-
forded, almost quantitatively, the pure secondary amines 4. Amines 4a and 4d
were crystalline compounds, whereas amines 4b and 4c were dense oils that were
characterized both as free bases and as hydrochlorides.
Scheme 2. Synthesis of tryptamine-derived unsymmetrically substituted secondary amines.
Conditions: a) (hetero)aromatic aldehyde, benzene, reflux, 4 h;
b) NaBH4, methanol, rt, overnight.
A second hypothesized strategy that could provide uncomplicated access to
multi-gram quantities of secondary amines was also explored in this study. This
strategy relies on the association of the standard one-pot reductive alkylation
with a procedure allowing the adequate separation of the desired product from
the unreacted starting materials and any potential by-products. An inexpensive,
fast separation procedure that is applicable for large-scale preparations could be
based on the differential solubility of the components in the mixture. Thus, the
simple partition of the crude reaction mixture between an organic solvent and an
aqueous acid solution would result in the extraction in the latter phase of the ba-
sic components only (i.e., the starting primary amine and the desired secondary
amine), whereas the unreacted carbonyl compound and the alcohol by-product
derived from it remain in the organic phase. Next, the mixture consisting of a
hydrophilic primary amine and a more lipophilic secondary amine could be se-
parated owing to their differential solubility in water. In order to test this hypo-
thesis, the water-soluble 3-(aminomethyl)pyridine and 1-(3-aminopropyl)imida-
zole were selected as starting materials. These two primary amines are also good
candidates for the generation of biologically active chemical entities. For example,
the 3-pyridinyl moiety is important for the activity of several types of nicotinic
15–17
acetylcholine receptor agonists,
or it is present as the pharmacophore in in-
18
19
hibitors of aldosterone synthase or cytochromes P450, whereas imidazole is
20
ubiquitous in azole antifungal agents and inhibitors of hemoenzymes, such as
nitric oxide synthase or heme oxygenase.
21
22
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SCALABLE SYNTHESIS OF SECONDARY AMINES
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Treatment of 3-(aminomethyl)pyridine with an excess of aromatic aldehydes
in methanol for 6 hours led to the formation of the corresponding imines, which,
in turn, were reduced in situ with sodium borohydride to the related secondary
amines 5 (Scheme 3). Sequential removal of the solvent and partition between
ethyl acetate and dilute hydrochloric acid allowed the separation of the basic
components from the crude reaction mixture. Subsequent release of the amine (or
amines, if unreacted 3-(aminomethyl)pyridine is still present) from their
hydrochlorides, followed by extraction with ethyl acetate afforded the pure se-
condary amine in good yield, as shown by TLC; the unreacted 3-(aminomethyl)-
pyridine, if present in the first ethyl acetate extract, appears to have remained in
the aqueous phase after the second extraction. The analytic and spectral data for
the secondary amines are given in the Supplementary material to this paper. The
NMR characterization of the isolated amines 5 confirmed their purity and sup-
ported their structure through the two singlets integrating for two protons in the
1
vicinity of 4 ppm in the H-NMR spectra and the two signals around 50 ppm in
13
the C-NMR spectra, which are associated with the two methylene groups ad-
1
jacent to the nitrogen atom. Inspection of the H-NMR spectra of the salts pre-
pared by treating the free bases of amines 5 with an excess of ethereal HCl re-
vealed that the corresponding dihydrochlorides were obtained in all cases. The
protonation of the heterocyclic nitrogen atom was supported by the displacement
of the signals of the protons in the pyridine moiety to lower magnetic fields. The
1
peak integrating for two protons noticeable above 10 ppm in H-NMR spectra of
the dihydrochlorides in deuterated DMSO confirmed the protonation of the nit-
1
rogen atom in the amine function; in contrast, the H-NMR spectrum of dihydro-
chloride 5d taken in deuterated methanol lacks this peak.
Scheme 3. Synthesis of pyridine-containing unsymmetrically substituted secondary amines.
Conditions: a) (hetero)aromatic aldehyde, methanol, rt, 6 h;
b) NaBH4, methanol, rt, overnight.
Under similar reaction conditions, the condensation of 1-(3-aminopropyl)-
imidazole with aromatic aldehydes to the corresponding imines (Scheme 4) was
less straightforward. TLC analysis of the reaction mixture after 6 h revealed sig-
nificant amounts of unreacted starting materials; extension of the reaction time to
24 h resulted in a slight improvement of the conversion. In situ reduction with
sodium borohydride followed by the separation procedure detailed for amines 5
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Scheme 4. Synthesis of imidazole-containing unsymmetrically substituted secondary amines.
Conditions: a) (hetero)aromatic aldehyde, methanol, rt, 24 h;
b) NaBH4, methanol, rt, overnight.
led to a mixture of 1-(3-aminopropyl)imidazole and secondary amines 6, that re-
quired additional column chromatographic separation in order to afford modest
yields of pure amines 6. As a result, this strategy does not seem to be appropriate
for a fast, medium-scale synthesis of amines derived from 1-(3-aminopropyl)imi-
dazole. The analytic and spectral data of the synthesized amines 6 are given in
the Supplementary material. The structure of the imidazole-containing secondary
1
amines 6 was supported by NMR analysis. In the aliphatic region of the H-NMR
spectra, a multiplet at 2 ppm and two triplets at approximately 2.6 and 4 ppm are
indicative for the propyl moiety, whereas the aromatic protons in the imidazole
ring appear at 6.87, 7.03 and 7.43 ppm. The deliquescent dihydrochlorides of com-
pounds 6a and 6b were also prepared and characterized by NMR. Again, the dis-
placement of the protons in the heterocyclic ring towards higher chemical shifts
confirmed the protonation of the imidazole, and the peak integrating for two pro-
tons at 10 ppm in the spectrum of compound 6b taken in deuterated DMSO
(which was absent in the spectrum of the compound 6a taken in deuterated me-
thanol) suggested the protonation of the nitrogen atom in the amine function.
CONCLUSIONS
Novel naphthalene- and indole-containing secondary amines were synthe-
sized by a two-step reductive alkylation process, with the separation of the inter-
mediate imine. The methodology was successfully applied to a 50-mmol scale
synthesis of these novel amines, and the procedure could be scaled up for the
production of even larger quantities. A second strategy, employing heterocyclic,
water-soluble amines, and comprising the usual reductive alkylation process
combined with an isolation procedure relying on the differential solubility of the
initial primary amine and the resulting secondary amine, was successful only in
the case of 3-(aminomethyl)pyridine; the methodology was valid on a 30-mmol
scale, and its potential for scalability was high. On the other hand, the application
of the same methodology with 1-(3-aminopropyl)imidazole as the starting mate-
rial required chromatographic separation, making the procedure unsuitable for
scaling up.
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SCALABLE SYNTHESIS OF SECONDARY AMINES
139
SUPPLEMENTARY MATERIAL
Аnalytical and spectral data of synthesized compounds are available electronically from
http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
И З В О Д
МЕТОДОЛОГИЈА СИНТЕЗЕ НОВИХ АСИМЕТРИЧНО СУПСТИТУИСАНИХ
СЕКУНДАРНИХ АМИНА
GHEORGHE ROMAN
Department of Inorganic Polymers, Petru Poni Institute for Macromolecular Chemistry,
41A Aleea Gr. Ghica Vodă, Iaşi 700487, Romania
Испитана је брза и једноставна синтеза асиметрично супституисаних секундарних ами-
на који садрже нафталенски, индолски и имидазолски структурни фрагмент. Испитане про-
цедуре успешно су примењене на скали 30 до 50 mmol и имају озбиљан потенцијал за при-
мену на већим скалама.
(Примљено 8. априла, ревидирано 2. јула 2011)
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