Selective synthesis of mono- and di-methylated amines using methanol and sodium azide as C1 and N1 sources

Article abstract of DOI:10.1039/c8gc00863a

A Ru(ii) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using methanol as a methylating agent is reported. This methodology was successfully applied for a one-pot reaction of bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed by preparative scale reactions with different organic azides and synthesis of an anti-vertigo drug betahistine. Several kinetic experiments and DFT studies were carried out to understand the mechanism of this transformation.

Full text of DOI:10.1039/c8gc00863a

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Selective Synthesis of mono- and di-Methylated Amines using
Methanol and Sodium Azide as C1 and N1 Sources
Kaushik Chakrabarti,a Anju Mishra,a Dibyajyoti Panja,a Bhaskar Paul a and Sabuj Kundu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A Ru(II) complex mediated synthesis of various N,N-dimethyl and N-monomethyl amines from organic azides using
methanol as a methylating agent is reported. The methodology was successfully applied for the one-pot reaction of
bromide derivatives and sodium azide in methanol. Notably, by controlling the reaction time several N-monomethylated
and N,N-dimethylated amines were synthesized selectively. The practical applicability of this tandem process was revealed
by preparative scale reactions with different organic azides and synthesis of anti-vertigo drug betahistine. Several kinetic
experiments and DFT studies were carried out to understand the mechanism of this transformation.
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simple and state forward protocols.26, 27 Staudinger reaction,28,
29
Introduction
Schmidt reaction,30, 31 Curtius rearrangement32 and azide-
alkyne Huisgen cycloaddition33-35 are the most common
Utilization of inexpensive and abundant methanol as a fuel,
hydrogen storage medium and feedstock to produce various
value-added chemicals such as biofuels, amino acids, and
polymers became highly relevant in recent years as the crude
oil reserves are depleting rapidly.1-3 In addition to this,
sustainable transformation of methanol as C1 building blocks
also received significant attention in organic synthesis.4, 5 In
this prospect some remarkable advancements were achieved
for the utilization of methanol in many eco-friendly reactions
classical organic reactions using azides. The reduction of azides
to amines is quite well known in literature and recently few
efficient methods also developed using softer reducing
agents.36-42 Multistep transformations of organic azides to N-
methylated
amines
using
toxic
MeI
or
44
paraformaldehyde/NaBH4 is known in literature.43,
Remarkably, Hong group demonstrated Ru(II) complex
catalyzed synthesis of amide from azide and alcohol which is
the only example known till date for the azide alcohol
coupling.45
such
as
C/N-methylation,6-12
C-methoxylation,13
N-
formylation,14-16 and methoxycarbonylation.17
N-methylated amines are considered as an essential unit in
numerous biologically active compounds and also serve as key
intermediates in the preparation of various natural products,
dyes, agrochemicals, bulk and fine chemicals.18, 19 Traditionally
for the N-methylation of amines carcinogenic methyl iodide,
dimethyl sulphate, trimethyloxonium tetrafluoroborate or
diazomethane, etc. were employed which generate
stoichiometric amount of toxic waste.20-22 Recently, trimethyl
orthoformate, dimethyl carbonate, and dimethyl sulfoxide
were also scrutinized as methylating agent but the efficiency
and selectivity was poor.23-25 Hence, for the development of
sustainable methylation process utilization of methanol as a
methylation agent is highly desirable.
Scheme 1 Methodology for synthesis of N-Methylated amines.
In our continued interest to develop atom-economical and
environmentally benign protocols to construct new C-C and C-
N bonds by alcohol activation, herein we report a Ru(II)
complex catalyzed tandem transformation of various aromatic
and aliphatic azides into the corresponding N-methylated
amines. To the best of our knowledge, direct conversion of
organic azides to N-methylated amines using methanol is not
Organic azides are highly important and versatile class of
compounds in synthetic chemistry which received notable
interest in last two decades due to their broad synthetic
applicability as well as their easy accessibility via numerous
reported yet (Scheme 1).
Result and Discussion
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Initially, reaction of benzyl azide with methanol was tested as
a model reaction in presence of various 1,10-phenanthroline
based tridentate NNN pincer Ru(II) complexes (2 mol %) which
showed 23-40% yields of N,N-dimethylbenzyl amine after 24 h
(Table 1, entries 1-4). Compared to our previous studies with
methanol activation,7 among the phen-py based Ru(II)
10
11
E
E
E
NaOH (1.0)
NaOH (1.5)
NaOH (1.5)
61
67
98
12b
aReaction conditions: azide (0.375 mmol), Cat. (2 mol %), base
(equiv.), methanol (1.5 mL), 24 h, 125 °C (oil bath
temperature). GC yields. b3 mol % Cat.
E was used.
complexes
complex
(
A-D), 2-hydroxypyridine moiety containing
A
did not show better activity which suggested that
After optimizing the reaction conditions with benzyl azide
this methodology was extended to different benzyl, aryl,
aliphatic and carbonyl azide substrates. Different benzyl azide
substrates with electron donating and withdrawing groups at
the para, meta and ortho positions were effectively converted
the metal-ligand cooperativity was not the dominating factor
in this reaction. To improve the catalytic activity and make the
ligand more electron rich, different substituted pyrazole46, 47
units were introduced at the 2-position of the 1, 10-
phenanthroline moiety which yielded stable NNN-pincer
ligands. The corresponding Ru(II) complexes were synthesized
in good yields by reacting an equimolar amount of phen-pyra
ligands (1b-1d) with RuCl2(PPh3)3 in refluxing methanol under
inert atmosphere followed by anion metathesis with NH4PF6
(SI, Scheme S1 and S2). These complexes were fully
characterized by different spectroscopic techniques and the
to
phenylmethanamine derivatives (Table
Naphthalene, 1,3-dioxolyl, and ester substituted azides were
effectively converted to the preferred products (Table
entries 10a 12a). Challenging heteroatomic, aliphatic, tertiary
the
corresponding
substituted
N,N-dimethyl-1-
2
, entries 1a 9a).
-
2,
-
and secondary azides also responded well in this reaction
conditions and produced the respective N,N-dimethyl amines
solid state structure of complex
around the Ru center. Afterward, these new Ru(II) complexes
I) were also screened and we were pleased to find that
complex delivered the highest yield of N,N-dimethylbenzyl
amine among all the Ru(II) complexes (Table 1, entry ).
Different weak and strong bases were screened with complex
and NaOH (1.5 equiv.) gave the best yield (67%) of N,N-
E also confirmed the geometry
in moderate to good yields (Table
2, entries 13a-20a).
Additionally, different aromatic and sulfonyl azides were also
smoothly converted to the N-monomethylated products
(E-
E
following this protocol (Table
2, entries 21a-25a).
5
Table 2 Synthesis of N,N-dimethylated amines from azidesa
E
°
dimethylbenzyl amine at 125 C within 24 h (SI, Table S2).
Common Ru(II) precursors like Ru(H2)(CO)(PPh3)3,
Ru(H)(Cl)(CO)(PPh3)3, RuCl2(PPh3)3 were also tested, which
displayed lower activity compared to the complex (SI, Table
E
S1). There was no product formation in the absence of any
Ru(II) complex. When the catalyst loading was increased up to
3 mol %, to our delight complex
E delivered the desired amine
1a in 98% yield (Table 1, entry 12).
Table 1 Transformation of benzyl azide to N,N-dimethyl-1-
phenylmethanaminea
aReaction conditions: Azides (1.13 mmol), Cat.
NaOH (1.69 mmol), methanol (4.5 mL), 24 h, 125 C (oil bath
E (3 mol %),
°
b
temperature). 4 mol % Cat.
Entry Catalyst Base (equiv.) Yield of 1a (%)
E was used and heated for 36 h.
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
KOtBu (1.0)
26
37
40
23
50
42
32
28
29
cKOtBu (1.5 equiv.) was used as base. GC yields (isolated yields
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
in parenthesis).
Notably, following the same protocol with benzyl azide at
shorter reaction time (2h) formation N-methyl-1-
phenylmethanamine was detected as a major product. Next,
utilizing this methodology complex
synthesis of N-monomethylated amines from organic azides
was investigated by controlling the reaction time (Table ).
E catalyzed selective
G
H
I
3
Both electron donating and withdrawing group containing
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azide substrates responded well in this condition (Table
ARTICLE
3,
yl)ethanamine (betahistine) which is used as a drug for the
entries 2b-10b). Additionally, naphthalene, 1,3-dioxolyl and treatments of Meniere’s disease and vertigo symptoms
ester substituted azides were selectively converted to the (Scheme 2c, entry 3c).48, 49
desired monomethylated products in good yields (Table
entries 11b 13b). Secondary and heteroatomic azide dependent product distribution during the tandem
derivatives delivered good yields of the corresponding transformation of azides to N-methylated amines was
products under this reaction condition (Table , entries 14b monitored (Figure ). Within 30 minutes, benzyl azide was
3,
To shed some light on the mechanism of this reaction, time
-
3
-
1
16b). Whereas with aliphatic and tertiary azides yields of the
respective N-monomethylated amines were moderate (Table
3, entries 17b-20b).
Table 3 Scope of N-monomethylationa
aReaction conditions: Azides (1.13 mmol), Cat.
E (3 mol %), Scheme 2 Practical applicability of the methodology: 2a) One-
°
NaOH (1.69 mmol), methanol (4.5 mL), time, 125 C (oil bath Pot methylation of bromide derivatives; 2b) Preparative scale
temperature). GC yields (isolated yields in parenthesis). b4 mol synthesis of N-methylated amines; 2c) Synthesis of betahistine.
% Cat. E was used.
consumed and benzyl amine appeared as a major product
To reveal the practical applicability of this methodology one- along with a small amount of N-methyl-1-phenylmethanamine
pot N,N-dimethylation and N-monomethylation of several (Figure 1a). Then, gradually benzyl amine was converted to N-
benzyl and aliphatic bromides using sodium azide and methyl-1-phenylmethanamine and within 2 h its concentration
methanol were investigated. For this purpose, benzyl bromide reached
the
maxima
(~84%).
N,N-dimethyl-1-
was taken as a model substrate and the reaction was carried phenylmethanamine concentration was considerably low
out in the presence of NaN3 (1.1 equiv.) in methanol at room within first 2 h which slowly increased during the course of the
temperature for 16 h followed by addition of Ru(II) catalyst (
and NaOH which furnished the N,N-dimethyl-1- clearly implies that rate of the N-monomethylation reaction
phenylmethanamine in excellent yields (SI, Table S8). was much faster than the N,N-dimethylation reaction.
Afterward, this one-pot protocol was successfully applied to a The formation of phenylmethanimine intermediate during
wide range of benzyl bromide derivatives, heteoatomic the conversion of benzyl azide to benzyl amine is well
E
)
reaction and reached maxima after 24 h (Figure 1b). This
51
substrates as well as aliphatic substrates which delivered the documented
desired products in good to excellent yields (Scheme 2a). phenylmethanimine intermediate in our reaction condition we
Next, we extended this sustainable protocol to preparative monitored the conversion of benzyl azide in presence of Cat.
in
literature.50,
To
detect
the
E
scale synthesis of methylated amines. Aromatic, aliphatic and in 2-propanol up to seven days at room temperature and as
°
heteroatomic azide substrates were successfully converted to well as after heating at 85 C for 12 h. However, under both
the respective mono and dimethylated amine derivatives in conditions we did not detect any phenylmethanimine. Hence,
good to moderate yields (Scheme 2b). Moreover, this we synthesized the active Ru-H complex (Cat. EH) by treating
with NaOiPr in 2-propanol/dichloromethane
methodology was employed in the N-monomethylation of 2- the precatalyst
E
°
(2-azidoethyl)pyridine to synthesize N-methyl-2-(pyridin-2- mixture (2:1) at 82 C (SI, page 22). This Ru-H species (Cat. EH
)
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was characterized by 31P and H NMR spectroscopy (SI, Figure proposed similar 1,3-deuteride migration to imine.53-56 We
S3 and S4). The 31P NMR resonance of the complex EH was hypothesized that in presence of complex
benzyl azide would
observed at
= 50.18 ppm and in 1H NMR spectroscopy it gave smoothly convert to phenylmethanimine which is well
a hydride resonance at
= -5.88 ppm (t, JH-P = 24.6 Hz). documented in the literature.51, 52, 57 In addition, the reaction
Afterward, the same experiment for the detection of of N-methylbenzyl amine and N-methylene-1-
phenylmethanimine intermediate was repeated with this Ru-H phenylmethanamine in methanol-d4 yielded partially
E
δ
δ
species (Cat. EH) at room temperature and the reaction was deuterated products
S
and
T. On the basis of these kinetic and
monitored up to seven days (SI, Figure S5). After three days at deuterium experiments
a
probable catalytic cycle was
room temperature stirring 15% conversion of benzyl azide to proposed for this system (SI, Scheme S10).
phenylmethanimine (7%) and N-benzylidene-1-
phenylmethanamine (8 %) was detected (SI, Figure S5). Due to
high reactivity of the phenylmethanimine it was readily
coupled with in-situ generated benzyl amine and formed N-
benzylidene-1-phenylmethanamine (SI, Scheme S9).51 For that
reason although the conversion of benzyl azide after seven
days was 30% the effective concentration phenylmethanimine
was never increased beyond 11% (SI, Scheme S9 and Figure
S5). Similar phenomenon was also observed when this reaction
°
was carried out at 85 C in 2-propanol (SI, Scheme S9 and
Figure S6). This experiment clearly suggested the involvement
of the Ru-H species (Cat. EH) in the conversion of benzyl azide
to phenylmethanimine which is the intermediate for the
formation of benzyl amine.50-52
Scheme 3 Mechanistic studies using methanol-d4.
For better understanding the reaction mechanism a detail
DFT calculations for the conversion of benzyl azide to N-
methylated amine in methanol was carried out (Figure 2). The
reaction mechanism can be divided into four parts: (a)
methanol dehydrogenation, (b) generation of imine form azide
(via 1,2-proton shift), (c) imine hydrogenation and (d) N-
methylene imine hydrogenation (Figure
methoxy complex (I1) was generated from the starting
complex via base mediated activation (Figure ). Then, one
2). Firstly, the
E
2
of the PPh3 dissociated from the intermediate I1 which
destabilized the system (I2) by 12.29 kcal/mol. Afterward, β-H
elimination (TS1) from the intermediate I2 furnished a metal-
hydride complex (I3) with the activation energy barrier of 7.7
kcal/mol which subsequently converted to the azide bound
intermediate I4 (17.50 [37.90] kcal/mol) via the substitution of
Figure 1. Time dependent product distribution studies of formaldehyde molecule. Then, N2 elimination followed by 1,2-
benzyl azide: a) 0-120 minutes, b) 2-24 hours.
proton shift provided the intermediate I5 where the imine was
bound to metal center in η2-fashion. Afterward, the insertion
Next, several kinetic experiments with benzyl azide and of the imine molecule into the metal-hydride bond through
various intermediates using methanol-d4 were performed the four membered transition state (TS2 with activation
(Scheme
3
). With benzyl azide and benzyl amine deuterated energy barrier of 3.68 kcal/mol) followed by methanolysis
) was formed as the major furnished the amine. The resulting amine was coupled with
N,N-dimethylbenzyl amine (
P
product in methanol-d4. Notably, for both of these reactions α- formaldehyde (produced from dehydrogenation of methanol)
CH2 of the final product was fully deuterated. This exchange and yielded N-methylene-1-phenylmethanamine (SI, Scheme
transpired probably through phenylmethanimine intermediate S10). Then, this N-methylene-1-phenylmethanamine was
followed by Ru(II) complex catalyzed 1,3-deuteride transfer hydrogenated by the Ru-H with activation barrier of 3.60
process (SI, Scheme S11). For the Ru(II) complex catalyzed α- kcal/mol (TS3) and produced the desired N-methylbenzyl
deuteration of amines, Szymczak and Gunanathan groups also amine product (Figure 2). This N-monomethylated amine can
4 | J. Name., 2012, 00, 1-3
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be converted to the N,N-dimethylbenzylamine following
another catalytic cycle. In this catalytic cycle methanol
dehydrogenation process required comparably higher
activation energy (7.7 kcal/mol) than the imine and N-
methylene imine hydrogenation steps.
Figure 2. Calculated Gibbs free energies and enthalpies (kcal/mol) for the formation of N-methylated amines from benzyl azide
using methanol (Hybrid functional, M06-2X was used with the LANL2DZ basis set for Ru and 6-31G** basis set for nonmetal
elements). Steps involve for the conversion of I6 to I7 are shown in SI Figure S7
.
efficient method for the selective synthesis of N-methylated
amines from azides and methanol.
Conclusions
In summary, we developed a Ru(II) complex catalyzed
tandem as well as sustainable process for the synthesis of
various N,N-dimethylated and N-monomethylated amines
from organic azides. To best of our knowledge, this is the first
example where combination of organic azides and methanol
were utilized as N1 and C1 sources respectively for the
synthesis of N-methylated amine products. Notably, following
this methodology varieties of N-methylamine and N,N-
dimethylamine were selectively synthesized in one-pot fashion
using bromide derivatives and inexpensive sodium azide in
methanol. The practical applicability of this protocol was also
explored by synthesizing methylated amines in large scale
quantity. Additionally, this methodology was successfully
employed for the synthesis anti-vertigo drug betahistine.
Several kinetic experiments and DFT studies were carried out
to understand the mechanistic aspect of this tandem
transformation. An air and moisture-stable ruthenium complex
catalyzed this alternative approach provides a practical and
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to the Science and Engineering Research
Board (SERB), India and Council of Scientific & Industrial
Research (CSIR) and Indian Institute of Technology Kanpur for
financial support. KC, BP thank UGC-India, AM thank CSIR-
India, DP thanks IITK for fellowship. We specially thank Prof.
Gourab Kanti Das (Visva Bharati University, India) for helpful
discussions on DFT calculations.
Notes and references
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Green Chemistry
View Article Online
DOI: 10.1039/C8GC00863A
TOC
Selective synthesis of various N,N-dimethylated and N-monomethylated amines from organic azides
using methanol as a methylating agent is reported.