Synthesis of: N -methylated amines from acyl azides using methanol

Article abstract of DOI:10.1039/d0ob01303j

The transformation of acyl azide derivatives into N-methylamines was developed using methanol as the C1 source via the one-pot Curtius rearrangement and borrowing hydrogen methodology. Following this protocol, various functionalised N-methylated amines were synthesized using the (NNN)Ru(ii) complex from carboxylic acids via an acyl azide intermediate. Several kinetic studies and DFT calculations were carried out to support the mechanism and also to determine the role of the Ru(ii) complex and base in this transformation.

Full text of DOI:10.1039/d0ob01303j

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DOI: 10.1039/D0OB01303J
ARTICLE
Synthesis of N-Methylated Amines from Acyl Azides using
Methanol
Kaushik Chakrabarti,a Kuheli Duttaa and Sabuj Kundua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Transformation of acyl azide derivatives to N-methylamines is developed using methanol as C1 source following one-pot
Curtius rearrangement and borrowing hydrogen methodology. Following this protocol various functionalised N-
methylated amines were synthesized using (NNN)Ru(II) complex from carboxylic acids via acyl azide intermediate. Several
kinetic studies and DFT calculations were carried out to support the mechanism and also to find out the role of the Ru(II)
complex and base in this transformation.
respective N-methylated amines is relatively straightforward.
However, direct transformation of carboxylic acids to amines is
challenging due to their opposite reactivity and polarity and it
require several steps. In this context, development of new
mythologies for the synthesis of N-methylated amines from
carboxylic acid using methanol is very much fascinating. To the
best of our knowledge conversion of carboxylic acids to N-
methylated amines following the borrowing hydrogen
principle is not explored yet (Fig. 1).
Introduction
Development of different bond forming strategies which
promote atom economy and utilizes renewable resources
recently received considerable attention from scientific
community.1-3 Thus, for the efficient organic synthesis,
development of more improved catalytic systems become
highly desirable. Carboxylic acids are commonly available
carbon framework from natural and synthetic resources with
versatile structural diversity.4,
5
Carboxylic acids act as an
Previous reports
important synthons for various transformations among them
decarbonylative cross-coupling is immersed as a powerful
synthetic strategy for the formation of carbon-carbon and
carbon-heteroatom bonds.6-11
CH3
H
N
[M]
or
N
NH2 NO CN
R
/
/
2
CH3OH
R
CH3
R
CH3
M= Ir, Ru, Mn, Co
Our Approach : Synthesis of methylated amines from carboxylic acid
CH3
Atom economic construction of C-N bond represent a crucial
step for the synthesis of industrially relevant molecules.12-14 In
this context, N-methylated amines play a significant role in the
synthesis of various pharmaceuticals, agrochemicals, dyes, and
surfactants.15-17 Commonly used methylating reagents like
methyl iodide, diazomethane, formaldehyde, dimethyl
sulphate, etc. create severe hazardous environmental impacts.
Hence, development of greener and a relatively cheaper
methylating reagents is highly desirable and for this purpose
methanol is an attractive alternative.18
O
H
O
i) SOCl2
CH3OH
N3 [Ru]
N
or
N
CH3
R
R
CH3
N
ii) Na
R
R
OH
3
Curtius Rearrangement
Fig. 1 Synthesis of N-methylated amines.
Borrowing Hydrogen Principle
Amine group can be introduced in place of carboxylate group
by following various celebrated rearrangement strategies such
as Schmidt, Hofmann, Curtius and Lossen reactions.35,
36
Additionally, direct conversion of carboxylic acids to amines by
using ammonia was reported by Rauch et al. using CuO as
catalyst at 220 °C .37 However, all these protocols are not
effective towards the synthesis of functionalised di- and tri-
substituted amines. In literature, for converting carboxylate
derivatives to di and tri-substituted amines, decarbonylative
cross-coupling with substituted amines are known with
elimination of CO2 or CO.38-41 However, synthesis of
functionalized methylated amines by cross-coupling of
carboxylate derivatives with volatile methylamines or other
methylating agents are extremely rare and challenging. Acyl
azides have been traditionally used as an aminating synthons
following the Curtius rearrangement.42 In this rearrangement,
initially acyl azide is converted to an isocyanate molecule
Recently, various fascinating protocols were developed for
the sustainable transformation organic functional groups such
as amine, nitro, nitrile, azide etc. to the corresponding N-
methylated amines by utilizing methanol as a methylating
agent.18-34 Notably, all these functional groups are considered
as surrogate of amines hence, converting them to the
a. K. Chakrabarti, K. Dutta, Dr. S. Kundu
Department of Chemistry; Indian Institute of Technology Kanpur, Kanpur 208016,
India. Email: sabuj@iitk.ac.in.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
10
11
12
13
14
15
16
17
18
19b
20
21
22
23
RuCl2(PPh3)3
KOtBu (1.0)
KOtBu (1.0)
KOH (1.0)
23
73
under mild reaction conditions. Subsequently, by using
appropriate nucleophiles such as water, alcohols or amines,
isocyanate can be transformed to versatile range of
functionalized amines, urethanes and ureas.43, 44 Thus, for the
synthesis of N-methylated amines from carboxylic acids via
utilization of acyl azides as amine surrogate and methanol as
C1 source is fascinating which motivated us to explore this
strategy (Fig. 1).
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DOI: 10.1039/D0OB01303J
RuHCl(CO)(PPh3)3
26
68
17
82
16
77
30
25
88
45
72
85
86
71
30
78
12
81
13
66
74
9
3
3
3
3
3
3
3
3
3
3
3
3
NaOH (1.0)
K2CO3 (1.0)
Na2CO3 (1.0)
Cs2CO3 (1.0)
NaOMe (1.0)
NaOtBu (1.0)
K2CO3 (1.0)
K2CO3 (0.5)
K2CO3 (0.75)
K2CO3 (1.25)
K2CO3 (1. 5)
Results and discussion
53
16
13
8
Initially, using thionyl chloride and sodium azide, 4-
methylbenzoic acid was converted to 4-methylbenzoylazide45
and it was selected as a model substrate. At first this acyl
azides was heated in methanol in presence of phen-py based
ruthenium complex 146 and KOtBu (1 equiv.). However, in
presence of strong base and nucleophilic solvent methanol, it
furnished only methyl 4-methylbenzoate (Scheme 1).
aReaction conditions: 4-methylbenzoylazide (0.372 mmol), Ru(II) Cat. (2
mol%), base (X equiv.), methanol (1.5 mL), 15 h, 140 °C (oil bath
temperature). 1H NMR yield (1,3,5-trimethoxybenzene was used as internal
standard). b18 h heating.
Initial Study
PF6
O
PPh3
N
O
NHMe
t
Next, in the same pot Ru-catalyst and base were added and
heated for the N-methylation reaction. Following this one-pot
two step methodology, various Ru-complexes20,
1
MeOH
Cat. , KO Bu,
N
OMe
Me
N3
N
24 h, 125 °C
Ru
Me
Me
OMe
100%
H
0%
Ph3P
Cl
21, 47
were
1
Modified Strategy
O
screened using KOtBu as a base and methanol as a methylating
agent (Table 1, entries 1-9). Ru(II) precursors like RuCl2(PPh3)3
and Ru(H)(Cl)(CO)(PPh3)3 were also tested, which showed less
reactivity compared to the complex 3 (Table 1, entries 10-11).
Among all the Ru(II) complexes screened in this reaction,
complex 3 delivered the highest yield of N,4-dimethylaniline
(Table 1, entry 3). After screening the catalysts, different bases
were tested in presence of complex 3 in which K2CO3 (1.0
equiv.) presented the best yield (82%) of N, 4-dimethylaniline
within 15 h (Table 1, entries 12-23). Finally, complex 3 with 1.0
equiv. K2CO3 within 18 h furnished 88% yield of the desired
Curtius
Rearrangement
Me
H
N
[Ru]
N
OMe
or
N
R

MeOH
R
Me
R
N3
R
Me
Base
O
Scheme 1 Modification of the strategy.
To avoid the formation of methyl 4-methylbenzoate from 4-
methylbenzoylazide, this strategy was modified. Firstly, the
Curtius rearrangement was carried out by heating 4-
methylbenzoylazide at 70 °C for 3 h in methanol in absence of
base and Ru-catalyst, which produced methyl p-tolylcarbamate
(a1') quantitatively (Scheme 1).
Table 1. Optimization for the transformation of 4-methylbenzoylazide to N, product (Table 1, entry 19).
4-dimethylanilinea
Table 2. Scope of N-methylation of aryl acyl azidesa
O
H
N
HMe
N
OMe
O
MeOH
, 70 °C, 3 h
i)
N3
MeOH
, 70 °C, 3 h
i)
+
NHCH3
O
N3
ii) Ru(II) Cat., Base, 15 h, 140 °C
Me
PF6
Me
Me
3
ii) Cat. , K2CO3,18 h,140 °C
a1'
a1
X
X
PF6
PF6
X = C, N
X = C, N
PPh
3 R2
PPh3
NCCH3
N
NHCH3
NHCH3
N
NHCH3
N
N
N
N
N
N
N
N
Ru
Ru
Ru
H3CO
a3
R2
H3C
R1
Ph3P
Cl
Me
Ph3P
Cl
H3CCN
Cl
a2
83%
NHCH3
78%
NHCH3
a1
80%
6
7
8
9
R2 = Me
R2
tBu
R2 = Ph
R2 = H
Cat.
Cat.
Cat.
Cat.
1
2
3
4
R1 = OMe Cat.
5
Cat.
=
R1 = OH
R1 = Me
R1 = H
Cat.
Cat.
Cat.
NHCH3
Cl
F
Me
a6
a4
93%
NHCH3
a5
77%
92%
Entry
Catalyst (2 mol%)
Base (equiv.)
Yield of a1
(%)
Yield of
a1' (%)
NHCH3
NHCH3
MeO
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
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)
46
27
52
28
26
47
38
30
36
50
68
46
70
73
50
59
68
61
OMe
47%
MeO
a9
Cl
76%
N
a8
a7
84%
NHCH3
NHCH3
NHCH3
NHCH3
O
O
N
a13
63%
a11
a10
84%
a12
55%
79%
aReaction conditions: azide (1 mmol), Cat. 3 (2 mol%), K2CO3 (1 mmol),
methanol (3.0 mL), 18 h, 140 °C (oil bath temperature). Isolated yields.
2 | J. Name., 2012, 00, 1-3
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After optimization of the reaction conditions, this protocol this reaction, concentration of methyl p-tolylcarbamate was
View Article Online
DOI: 10.1039/D0OB01303J
was applied on variety of acyl azides which was synthesized decreased gradually and concentration of N, 4-dimethylaniline
from corresponding acids to evaluate the scope of this increased steadily. Notably, during the whole course of the
methodology. Different ortho, para- and meta- substituted aryl reaction concentration of 4-methylaniline was remained very
acyl azides bearing both electron donating and electron low (Fig. 2). This suggested that the probably the rate of
withdrawing substituents furnished the final methylated conversion of methyl p-tolylcarbamate to 4-methylaniline was
amines with good to excellent isolated yields (Table 2, entries relatively slower than the conversion of 4-methylaniline to N,
a1-a9). Then, the scope of the reaction was further expanded 4-dimethylaniline.
by converting naphthyl and benzodioxole acyl azides to N-
As time course analysis of the reaction suggested that the
methylated amines successfully (Table 2, entries a10-a11). conversion of methyl p-tolylcarbamate to 4-methylaniline was
Interestingly, heteroatom containing 2-pyridyl and 3-pyridyl slower than the methylation of 4-methylaniline; thus, further
acyl azides were selectively furnished the corresponding N- mechanistic studies were carried to investigate the conversion
methylated amines (Table 2, entries a12-a13).
of methyl p-tolylcarbamate to 4-methylaniline (Fig. 3A). For
Afterward, the reactivity of benzyl and alkyl acyl azides were this purpose, two parallel control experiments were conducted
tested which provided the dimethylated product in presence for the conversion of methyl p-tolylcarbamate to 4-
of 3 mol% cat. 3 after 36 h (Table 3, entries a14-a17). Notably, methylaniline, one in presence of only K2CO3 and other with
with these substrates 20 h heating at 100 °C was required for catalyst 3 and K2CO3. Notably, rate of conversion of methyl p-
the Curtius rearrangement step. Additionally, in this reaction tolylcarbamate was similar under both these conditions. This
conditions, 2-phenylacetyl azide, 2-(naphthalen-1-yl)acetyl experiment suggested that the Ru complex had no role in the
azide and 3-phenylpropanoyl azide provided the N,N- transformation of methyl p-tolylcarbamate to 4-methylaniline
dimethylated amines in good to moderate yields (Table 3, (Fig. 3A).
entries a18-a20).
Table 3. Scope of N-methylation of benzyl and alkyl acyl azidesa
O
MeOH
, 100 °C, 20 h
i)
CH3
N
N3
R
CH3
R
3
ii) Cat. , K2CO3, 36 h,140 °C
Ph
CH3
H3C
CH3
N
CH3
CH3
CH3
Ph
N
N
N
CH3
CH3
CH3
75%b
66%b
a15
77%b
a17
a14
a16
46%b
CH3
Fig. 3 3A) Investigation of the role of K2CO3 and Cat. 3 in the transformation of
carbamate ester to 4-methylaniline; 3B) Effect of counter cation of bases in the
transformation of carbamate ester to 4-methylaniline without Cat. 3.
CH3
CH3
N
N
N
CH3
CH3
86%b
CH3
82%b
57%b
a20
a18
a19
After that, several experiments were conducted to
understand the effect of hydroxide and carbonate bases for
the conversion of methyl p-tolylcarbamate to 4-methylaniline
(Fig. 3B). It was found that for lithium and sodium counter
cation containing hydroxide bases exhibited better
performance than their corresponding carbonate bases.
Whereas, with the bigger potassium and caesium counter
cation, reverse trend was observed (Fig. 3B). The reactivity
difference of carbonate and hydroxide bases in this
transformation is not clear to us at this moment.
aReaction conditions: acyl azide (1 mmol), Cat. 3 (3 mol%), K2CO3 (1 mmol),
methanol (3.0 mL), 36 h, 140 °C (oil bath temperature). Isolated yields.
Fig. 2 Time dependent product distribution studies of methyl p-tolylcarbamate
to N, 4-dimethylaniline.
To get insight of the reaction mechanism, time dependent
product distribution was monitored during the transformation
of methyl p-tolylcarbamate to N-methylated amines (Fig. 2). In
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J. Name., 2013, 00, 1-3 | 3
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Fig. 4 4A) Effect of counter cation of bases in N-methylation of 4-methylaniline;
4B) KIE in N-methylation of 4-methylaniline catalysed by complex 3.
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DOI: 10.1039/D0OB01303J
Base played a key role in metal catalyzed N-methylation
21, 48
reactions using methanol.20,
Therefore, the effect of
Scheme 3. Experiments with methanol-d4.
different carbonate and hydroxide bases were investigated in
the N-methylation reaction catalyzed by complex 3 (Fig. 4A).
Notably, with these bases, similar trend was observed as
mentioned with transformation of carbamate ester (Fig. 3B)
and among the carbonate and hydroxide bases reactivity
increased in the order of size of the counter cation Li<Na<K~Cs
(Fig. 4A). This study suggested that both in the transformation
of carbamate ester to amine and in N-methylation of amine
step, counter cation of bases have crucial role. Methanol
dehydrogenation is one of the vital step in N-methylation
reaction. To understand the importance of the methanol
dehydrogenation step, KIE study was performed for the N-
methylation of 4-methylaniline using CH3OH and CD3OD in
presence of Cat. 3 which revealed that kH/kD for this reaction is
2.3 (Fig. 4B). These results indicated that the C-H bond
breaking of methanol is kinetically important in this
transformation.
To understand this multistep reaction more clearly, each
crucial steps of the transformation of acyl azide to N-
methylamines was studied more carefully (Scheme 2). These
control experiments as well as time frame analysis of the
reactions clearly suggested that conversion of methyl-p-
tolylcarbamate (B) to 4-methylaniline (C) was much slower
than the Curtius rearrangement and methylation steps
(Scheme 2).
For further illustration about the mechanism of this study,
kinetic experiments with methanol-d4 were performed
(Scheme 3). 4-Methylbenzoylazide was converted to D4-N, 4-
dimethylaniline (63%) under optimized conditions (Scheme 3).
The other intermediates such as 4-methylphenylisocyanate,
methyl-p-tolylcarbamate, 4-methylaniline and 4-methyl-N-
methyleneaniline were also furnished the corresponding
deuterium incorporated methylamines by using methanol-d4
(Scheme 3). These experiments idicated potential involvement
of these intermediates in this transformation and methanol
acted as the C1 source as well as the hydrogen donor.
To collect more information, we carried out DFT calculation
for the N-methylation of 4-methylaniline catalyzed by the
complex 3 (Fig. 5). This process was divided into three steps:
(a) dehydrogenation of methanol, (b) imine formation and (c)
hydrogenation of the C=N bond. First, base assisted activation
of complex 3 in presence of methanol generated the
intermediate I1. Next, dissociation of PPh3 from I1 produced
the intermediate I2. The intermediate I2 followed a concerted
four-membered cyclic transition state (-hydrogen elimination
step) TS1 (21.61 kcal/mol) to dehydrogenate methanol and
formed Ru-H intermediate I3 (Fig. 5). The formaldehyde
molecule generated in this dehydrogenation step subsequently
reacted with the amine to give the corresponding imine
molecule. Next, hydrogenation of imine occurred by Ru-H
through another transition state TS2 (27.81 kcal/mol) with the
activation barrier of 3.32 kcal/mol (Figure 5). Finally, from the
intermediate I5, I2 and N-methylamine product were formed
through methanolysis. From the DFT calculation, it was
observed that N-methylene imine hydrogenation step (TS2)
required over all higher energy barrier than the β-hydrogen
elimination step (TS1).
O
H
Curtius
N
OMe
Rearrangement
N3
O
MeOH 3 h
-N
2
,
, 70 °C,
Me
Me
Me
100%
B,
A
H
N
NH2
MeOH
, 18 h
OMe
K2CO3
, 140 °C
O
Me
91%
C,
B
H
N
3
MeOH
Cat.
+
Me
Me
NH2
,
K2CO3 - H2O, +H2
Me
Me
Me
5 h
, 140 °C
99%
D,
D,
C
PPh3
Me
H
N
H
N
N
OMe
Ru
N
N
3
MeOH
+
Cat.
N
CH2
H
O
, 18 h
, 140 °C
K2CO3
Gsol
TS2
Me
kcal/mol
- H2O, +H2
88%
B
27.81
PPh3
N
Scheme 2. Control experiments.
TS2
N
Ru
H
O
N
I4
24.49
H
H
TS1
D
O
Me
N
21.61
I3
CD OD
, 70 °C, 3 h
i)
PPh3
3
CD3
I5
20.77
N
21.18
N
N3
Ru
N
TS1
3
CD OD
CH3OH
H3
ii) Cat. , K2CO3,
3
N
CH2
Me
C
H
PPh3
N
Ru
18 h, 140 °C
PPh3
Me
Me
I2
14.55
63%
Me
I5
HN
N
CH3
N
O
D
N
Ru
N
N
14.55
NCO
N
N
H
H
3
CD OD
3
Cat. , K2CO3,
CD3
H
PPh3
PPh3
I6
I2
I3
N
Me
18 h, 140 °C
PPh3
Me
Me
N
Ru
O
CH3
N
I1
0.00
N
N
67%
Ru O
N
N
CH3
N
I2
N
N
D
N
N
H
I2
PPh3
N
N
3
CD OD
3
Cat. , K2CO3,
N
OMe
CD3
N
Ru
O
Me
N
CH3
18 h, 140 °C
O
PPh3
Me
Me
I1
66%
76%
54%
D
N-Methylene imine
hydrogenation
NH2
N
3
CD OD
Methanol dehydrogenation
Cat. , K2CO3,
3
CD3
9 h, 140 °C
Me
D
N
N
3
CD OD
3
Cat. , K2CO3,
CH2D
CH2
6 h, 140 °C
Me
Me
4 | J. Name., 2012, 00, 1-3
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Fig. 5 Calculated Gibbs free energies (kcal/mol) for the formation of N, 4-
dimethylaniline from 4-methylaniline using methanol (Hybrid functional, M06-2X
was used with the LANL2DZ basis set for Ru and 6-31G** basis set for non-metal
elements).
were added under inert condition and heated for specified
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time at 140 °C (oil bath temperature). ADftOeIr: 1t0h.1a0t3,9t/hDe0OreBa0c13t0io3nJ
mixture was allowed to cool down at room temperature. The
1
solvent was evaporated to dryness and subjected to H NMR
Based on the several control experiments and kinetic studies,
the schematic pathway for the formation of N-methylated
amine from acyl azide using methanol was proposed (Scheme
4). Initially, following the Curtius rearrangement, acyl azide
was converted to carbamate ester. Next, base mediated
transformation generated the amine derivative from
carbamate ester (Scheme 4). Subsequently, methanol
analysis for the calculation of the yield (1,3,5-
trimethoxybenzene was used as internal standard). Finally, the
pure methylated amines were isolated by column
chromatography using silica gel and hexane-ethyl acetate or
ethyl acetate-methanol as eluent.
B) Procedure for Benzyl and Alkyl Acyl Azides
In a screw cap tube, acyl azide (1.0 mmol) and methanol (1.5
mL) were taken under argon atmosphere and heated at 100 °C
in oil bath for 20 h. Then, it was cooled to room temperature
and catalyst 3 (3 mol%), K2CO3 (1.0 mmol), methanol (1.5 mL)
were added under inert condition and heated for specified
time at 140 °C (oil bath temperature). After that, the reaction
mixture was allowed to cool down at room temperature. The
dehydrogenation by the catalyst
3
would generated
formaldehyde and the [Ru-H] species. This formaldehyde
reacted with the amine to give the corresponding imine
(Scheme 4). Finally, the imine was hydrogenated by the [Ru-H]
to form the N-methylated amine product (Scheme 4).
H
N
O
Curtius
MeOH
1
OMe
solvent was evaporated to dryness and subjected to H NMR
R
NCO
R
R
R
N3
Rearrangement
analysis for the calculation of the yield (1,3,5-
trimethoxybenzene was used as internal standard). Finally, the
pure methylated amines were isolated by column
chromatography using silica gel and hexane-ethyl acetate or
ethyl acetate-methanol as eluent.
O
-N2
MeOH K2CO3
[Ru] + MeOH
H
N
[Ru-H]
R
NH2
R
N CH2
Me
MeOH
[Ru-H] + HCHO
- H2O
Scheme 4. Proposed pathway for the N-methylation of acyl azide.
Conflicts of interest
There are no conflicts to declare.
Conclusions
Acknowledgements
In conclusion, transformation of various acyl azides to the
corresponding N-methyl amines was developed by combining
one-pot Curtius rearrangement and BH methodology.
Interestingly, following this protocol varieties of aryl, benzyl
and aliphatic carboxylic acids were successfully converted to
methylated amines via acyl azide intermediate catalyzed by a
simple (NNN)Ru(II) complex. Control experiments suggested
that the Ru(II) complex had no role in transformation of
carbamate ester to amine and this step was slower than the N-
methylation step. Additionally, the counter cation of base has
vital role in both transformation of carbamate ester to amine
and in N-methylation of amine steps. Kinetic isotope effect 1.
We are grateful to the Department of Science and Technology,
International Cooperation (INT/RUS/RFBR/P-326), India and
the Science and Engineering Research Board (CRG/2018/
000214), India for financial support. KC thanks UGC-India for
fellowship. We also thank HPC IIT Kanpur for computational
facilities.
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/D0OB01303J
Table of Content
Curtius
Rearrangement
Borrowing Hydrogen
Methodology
Me
N
O
H
N
or
=
R
R
Me
Aryl
R
N3
R
Me
[Ru] / MeOH
R
Alkyl and Benzyl
=
Broad Substrate Scope
Kinetic and Mechanistic Studies
Methanol as C1 Source
DFT Calculation
Ru(II) complex catalysed direct transformation of acyl azides to N-methylamines was developed for
the first time using methanol via one pot Curtius rearrangement and Borrowing Hydrogen methodology.