Chloroformate free, scalable approach for the synthesis of organic carbamates and their alkylation

Article abstract of DOI:10.2174/157017813805077280

A convenient method for the synthesis of organic carbamates of 2-aminopyridine without using hazardous chloroformate reagent is developed. This alternate approach for the synthesis of organic carbamates and their alkylation to 2-alkylaminopyridines is more practical and economical to be used on large scale. The amazing behavior of 2- aminopyridine helps in forming organic carbamates unlike 3-aminopyridine and 4-aminopyridine.

Full text of DOI:10.2174/157017813805077280

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60
Letters in Organic Chemistry, 2013, 10, 60-64
Chloroformate Free, Scalable Approach for the Synthesis of Organic
Carbamates and Their Alkylation
Mukesh P. Shewalkar,*a Ramakrishna R. Rao,a Veerbhadra Reddy,a Sunil N. Darandale,b and Deva-
nand B. Shinde b
aAVRA Laboratories Pvt Ltd, Hyderabad, India. 500076
bDepartment of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University Aurangabad, India. 431004
Received September 20, 2012: Revised November 21, 2012: Accepted December 06, 2012
Abstract: A convenient method for the synthesis of organic carbamates of 2-aminopyridine without using hazardous
chloroformate reagent is developed. This alternate approach for the synthesis of organic carbamates and their alkylation to
2-alkylaminopyridines is more practical and economical to be used on large scale. The amazing behavior of 2-
aminopyridine helps in forming organic carbamates unlike 3-aminopyridine and 4-aminopyridine.
Keywords: Alkylation, alkyl aminopyridine, 2-aminopyridine, Boc anhydride, carbamates.
INTRODUCTION
RESULT AND DISCUSSION
Organic carbamates are an important class of compounds
having wide applications in pharmaceuticals and agro-
chemical industry. They are generally used for the protection
of amino groups to form structurally diverse intermediates of
biological importance. The recent past of carbamates has
seen keen interest from pharmaceutical industry for the de-
velopment of drugs and prodrugs. This interest regarding
carbamates has led to the development of recent molecules
like discodermolide [1], geldanamycin [2], cephalosporins
[3], phytostigmine [4], novobiocin [5], sphingomyelin [6],
vancomycin [7], rifampicin [8], rhazinilam [9], maytansine
[10], calcheamycin [11], cyclosporine [12], linezolid [13],
telithromycin [14] etc. Besides the above mentioned mole-
cules, carbamates have also been reported in improving the
activity profile of the parent molecules making them more
potent.
The past decade has seen use of 2-alkylamino pyridines
in a wide class of biologically active compounds. The alkyl
amino pyridines are used for treating diseases and pathologi-
cal conditions involving inflammation [16]. The alkyl amino
pyridines are involved in the reduction of prochiral ketones
[17, 18]. The literature reveals a number of methods for al-
kylation of amine [19-22], using different methods like by
direct alkylation, or by protection of amine followed by alky-
lation and hydrolysis or by amination of cuprates with N-
alkyl hydroxyl amine [23]. All of them could synthesize the
alkyl amino pyridines, but they are associated with difficulty
of handling of reagents, unwanted side reactions and tedious
purification procedures hampering its use for large scale syn-
thesis. The direct alkylation is mostly associated with addi-
tional alkylation as the secondary amine formed by first al-
kylation is more reactive than the primary amine, reducing
the yield of mono alkylated product. Unreacted starting ma-
terial and dialkylated amine as side product are the major
impurities of such process which are always difficult to re-
move. The other method for alkylation is the protection and
de-protection; it is time consuming requiring use of hazard-
ous reagents and extra procedure for purification.
The classical methods for the preparation of carbamates
include the Hoffmann rearrangement, Curtius rearrangement
and Lossen rearrangement reactions. There are several other
methods to synthesize carbamates like with the help of phos-
gene, by reductive carbonylation of aromatic nitro com-
pounds, by the oxidative carbonylation of amines, by using
metal/non-metal carbonates/bicarbonates and by using car-
bon dioxide [15]. Although, there are several reported meth-
ods for the synthesis of the carbamates, still there is scope to
improve the existing procedures. The existing procedures are
hindered due to limitations like long duration of reaction,
insignificant yield, and handling of toxic and hazardous
chemicals, requirement of special type of reactors and skilled
persons to handle these reactions. Due to our interest and in
house use to develop efficient, safe and economical method
on commercial scale we herein report the synthesis of 2-
alkylamino pyridines from the carbamates.
Synthesis of carbamates and carbonates is well reported
in the literature [15-25]. Although synthesis of carbamates is
listed widely in the literature, an organic chemist always gets
attracted to invent more and more convenient method for the
synthesis. For this various catalysts, solvents, bases were
successfully tested. In the recent past, Lowary T. L. and
group [24] reported the most convenient synthesis of alky-
laminopyridines. It involved alkylation of N-formyl 2-
aminopyridine followed by hydrolysis, but it required a dif-
ficult distillation of N-formyl derivative. Alternative method
involved the protection of the amine with Boc anhydride in
tert-butanol [25], then alkylating it in the presence of sodium
hydride followed by deprotection of Boc group. According
to the reported method, the method was claimed as conven-
*Address correspondence to this author at the AVRA Laboratories Pvt Ltd,
Hyderabad, India. 50007; Tel: +91 40 27178566-68;
E-mail: mukeshps21@yahoo.co.in
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

Chloroformate Free, Scalable Approach
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
61
O
O
a
b
c
N
N
H
O
N
1
NH2
N
N
O
N
NH
2
4a
3
Scheme 1. (a) Boc anhydride, t-butanol (b) MeI, NaH, THF (c) H+.
R2
N
R2
N
ient and most suitable for the synthesis of alkylamino pyri-
dine. The reported method is illustrated in Scheme 1.
R1
R1
O
The literatures [15, 26-28] revealed use of t- butanol and
chloroformate for the synthesis of carbamates and sodium
hydride for their alkylation. In our efforts to develop a safe
and robust method for the synthesis of carbamates on a large
scale, we needed to avoid these reagents as each one of them
has its own limitation. The use of t-butanol as a solvent at
low temperature is always troublesome and has limited ap-
plications as a solvent due to its lower freezing point
(~25oC). The chloroformates are widely used for the protec-
tion of amine in the form of carbamates. But being toxic and
difficult to handle the use of chloroformates always re-
mained the second choice for the organic chemist. Sodium
hydride as we all know requires special techniques to handle,
slightest of mishandling might led to a major accident. These
factors propelled us to synthesize the reaction in other sol-
vent and use of Boc anhydride for protection of amine
Scheme 2.
Alcohol
Boc2O
R3
N
O
NH2
H
2
1
2a R1=R2=H; R3 = Me
2b R1=R2=H; R3 = Et
2c R1=R2=H; R3 = i-Pr
2d R1=R2=H; R3 = n-Bu
2e R1=R2=H; R3 = n-Pr
2f R1=R2=H; R3 = i-Bu
2g R1=Br; R2=H; R3 = Me
2h R1=H; R2=Me; R3 = Me
Scheme 3. Formation of carbamates by using various alcohols.
butyl carbamates rather than methyl carbamates. The possi-
ble reason for the formation of such product could be attrib-
uted to the position of the amine group. In the case of 2-
aminopyridine the position of amino group in 2nd place plays
a key role, the formation of an intermediate 5 (Fig. 1) is eas-
ily possible which could open with the abundantly available
solvents to form corresponding carbamate.
O
a
N
NH2
N
N
H
O
2a
1
(a) Boc anhydride, MeOH, 99%
N+
Scheme 2. Formation of carbamates using methanol as solvent.
NH
The reaction was first carried out using 2-aminopyridine,
Boc anhydride and methanol as a solvent and corresponding
Boc derivative was being expecting. But to our surprise we
obtained methyl carbamate (Scheme 2, comp 2a) in 99%
yield which was quite high as compared to Boc derivatives
reported in literature [15] (70% yield). The formation of
methyl carbamate is obviously because of transesterification.
As we confirmed the formation of methyl carbamate using
methanol and Boc anhydride, we assumed this to be more
convenient and high yield approach to make such carbamates
without need to handle toxic reagents. To evaluate the ro-
bustness of this method we employed solvents like methanol,
ethanol and propanol, butanol (Scheme 3) results of which
confirmed the formation of corresponding carbamates in
very good yield. The process was found to be operationally
very simple as with only partial concentration of the solvent,
product precipitated out which was collected by simple fil-
tration in high yield and purity.
O
5
Fig. (1). Cyclic intermediate of 2-aminopyridine.
This indicates the importance of position of amino group
while forming trans esterification products (2a-2h). The po-
sition of amino group in 4-amino pyridine and 3-amino-
pyridine is far away for the formation of this cyclic interme-
diate, hence they tend to form the normal Boc derivatives.
The last aim of our synthesis was to develop an alterna-
tive to sodium hydride which has handling issues. For this
purpose we firstly investigated the use of potassium carbon-
ate as a base for alkylation, the isolated product was found to
be of moderate yield (50%). Alternatively we used potas-
sium tert-butoxide as base for alkylation of 2a in tetrahydro-
furan. The potassium tert-butoxide was found to be effective
as product was obtained in more than 97% yield. The ob-
tained product was then hydrolyzed in 10% NaOH and the
crude was purified either by distillation or recrystallization.
Scheme 4.
Similarly to prepare more organic carbamates we decided
to use 4-aminopyridine and 3-aminopyridine instead of using
2-aminopyridine as starting material. The isolated products
from the reaction of 4-aminopyridine and 3-aminopyridine
with Boc anhydride in methanol were corresponding tert-

62
Letters in Organic Chemistry, 2013, Vol. 10, No. 1
Shewalkar et al.
O
O
b
a
N
NH
R1
N
N
O
N
N
H
O
R1
3a
4a
2a
4a; R1= CH3
4b; R1= Et
4c; R1= Bn
3a; R1= CH3
3b; R1= Et
3c; R1= Bn
(a) Alkyl halides, Potassium-.tert-butoxide, THF (b) 10% NaOH, MeOH.
Scheme 4. Alkylation of carbamates.
CONCLUSION
6.99-7.01 (m, 1 H), 7.67-7.72 (m, 1 H,), 7.99-8.02 (d, 1 H, J
= 8.43 Hz), 8.29-8.31 (d, 1 H, J = 3.96 Hz), 8.87 (br, s, 1H);
13C NMR (CDCl3) 52.18, 112.53, 118.31, 138.58, 147.45,
152.68, 154.23.
To summarize we hereby report the astonishing behavior
of 2-aminopyridine unlike 3-aminopyridine and 4-
aminopyridine. Taking this advantage we developed an effi-
cient, economical and scalable route for the synthesis of 2-
alkylamino pyridines (4) through carbamates (2) without
using chloroformates, t-butanol and sodium hydride. The
process is scalable, operationally simple; the use of hazard-
ous reagents is avoided. Water workup and further purifica-
tion of carbamates are not required making it ideal to explore
it on large scale as well as environment friendly by reducing
the effluent.
Ethyl pyridin-2-ylcarbamate (2b). white solid, mp 101-
1
103oC, 99% yield, H NMR (CDCl3) ꢀ= 1.32-1.37 (t, 3 H, J
=7.08), 4.23-4.20 ( q, 2 H, J =7.08), 6.99-7.01 (m, 1 H),
7.67-7.72 (m, 1 H,), 7.99-8.02 (d, 1 H, J = 8.43 Hz), 8.29-
8.31 (d, 1 H, J = 3.96 Hz ), 9 (br, s, 1H); 13C NMR (CDCl3)
14.62, 61.20, 112.65, 118.29, 138.41, 138.52, 147.49,
152.75, 153.85.
Isopropyl pyridin-2-ylcarbamate (2c). white solid, mp
75-77oC, 99% yield, 1H NMR (CDCl3) ꢀ= 1.32-1.34 (d, 6 H,
J = 6.24 Hz), 5.01-5.09 (m, 1 H), 6.95-6.99 (m, 1 H), 7.65-
7.77 (m, 1 H,), 8.00-8.02 (d, 1 H, J = 8.46 Hz), 8.31-8.8.33
(d, 1 H, J = 5.96 Hz), 8.95 (br, s, 1H); 13C NMR (CDCl3)
22.15, 68.85, 112.52, 118.34, 138.39, 147.63, 152.49,
154.27.
EXPERIMENTAL SECTION
General: Tetrahydrofuran used for alkylation was dried
over sodium and the reactions were carried out under nitro-
gen. For rest of the reactions, commercial grade solvents
were used. All reactions were monitored by TLC (silica-
coated plates) and visualized under UV light. TLC was per-
formed on Merck 60 F-254 silica gel plates. Yields refer to
isolated yields. High-resolution mass spectra were obtained
by using QTOF mass spectrometer (QTOF Premier, Waters,
USA), using ESI method. 1H NMR spectra were recorded on
a 300 MHz Bruker spectrometer and are 13C NMR spectra
were recorded on a 50 MHz Bruker spectrometer are re-
ported as parts per million (ppm) downfield from a
tetramethylsilane as internal standard. Chemical shifts are
reported relative to TMS as an internal standard.
n-butyl pyridin-2-ylcarbamate (2d). white solid, mp
60-63oC, 99% yield, 1H NMR (CDCl3) ꢀ= 0.93-0.98 (t, 3 H,
J = 7.35 Hz), 1.37-1.49 (m, 2 H), 1.65-1.75 (m, 2 H), 4.19-
4.23 (m, 2 H), 6.95-6.98 (m, 1 H), 7.66-7.72 (m, 1 H,), 8.01-
8.04 (d, 1 H, J = 8.43 Hz), 8.32-8.8.34 (d, 1 H, J = 4.08 Hz),
9.4 (br, s, 1H); 13C NMR (CDCl3) 13.67, 19.07, 30.79, 65.01,
112.64, 118.11, 138.46, 147.14, 152.88, 153.95.
n-propyl pyridin-2-ylcarbamate (2e). white solid, mp
72-74oC, 99% yield, 1H NMR (CDCl3) ꢀ= 0.96-1.01 (t, 3 H,
J = 7.38 Hz), 1.55-1.80 ( m, 2 H), 4.15-4.19 (t, 3 H, J = 6.79
Hz), 6.96-6.99 (m, 1 H), 7.66-7.72 (m, 1 H,), 8.01-8.04 (d, 1
H, J = 8.46 Hz), 8.33-8.8.34 (dd, 1 H, J = 4.98 Hz, 1.02 Hz),
9.48 (br, s, 1H); 13C NMR (CDCl3) 10.39, 22.39, 66.83,
112.72, 118.19, 138.53, 147.45, 125.99, 154.03.
Materials. 2-aminopyridine, Methyl iodide, Ethyl iodide,
Benzyl bromide, Boc anhydride, potassium tert-butoxide,
were commercially available and used without any further
purification.
i-butyl pyridin-2-ylcarbamate (2f). white solid, mp 67-
69oC, 98% yield, 1H NMR (CDCl3) ꢀ= 0.96-0.98 (d, 6 H, J =
6.72 Hz), 1.97-2.06 (m, 1 H), 3.98-4.00 (d, 2 H, J = 6.72
Hz), 6.96-6.99 (m, 1 H), 7.66-7.72 (m, 1 H,), 8.00-8.03 (d, 1
H, J = 8.46 Hz), 8.32-8.8.34 (dd, 1 H, J = 4.98 Hz, 1.02 Hz),
9.28 (br, s, 1H); 13C NMR (CDCl3) 19.06, 27.99, 71.30,
112.71, 118.10, 138.44, 147.38, 152.90, 153.96.
General Procedure for Preparation of Carbamates
(2): All the reactions were carried out on 10mmol scale. 2-
Aminopyridine was dissolved in appropriate alcohol (3
times) and cooled to 0oC. To this solution Boc anhydride
(1.2Eq) was added and reaction mixture was allowed to cool
to room temperature. Reaction mixture was stirred at the
same temperature for 4hr. Half volume of the alcohol was
removed on rotavapor. Solid separated was collected by fil-
tration.
Methyl 5-bromopyridin-2-ylcarbamate (2g). white
solid, mp 188-191oC, 97% yield, 1H NMR (DMSO-d6) 3.34
(s, 3 H), 7.80-7.83 (d, 1 H, J = 8.94 Hz), 7.96-8.00 (dd, 1 H,
J = 2.43, 2.47 Hz), 8.37-8.38 (d, 1 H, J = 2.16 Hz); 13C
Methyl pyridin-2-ylcarbamate (2a). white solid, mp
1
129-131oC, 98% yield, H NMR (CDCl3) ꢀ= 3.82 (s, 3 H),

Chloroformate Free, Scalable Approach
Letters in Organic Chemistry, 2013, Vol. 10, No. 1 63
(DMSO-d6) 52.45, 113.15, 114.34, 141.01, 148.82, 151.71,
CONFLICT OF INTEREST
154.43.
The author(s) confirm that this article content has no con-
flicts of interest.
Methyl 4-methylpyridin-2-ylcarbamate (2h). White
1
solid, mp 131-132oC, 99% yield, H NMR (CDCl3) ꢁ= 2.36
(s, 3 H), 3.81 (S, 3 H), 4.76 (br, s, 1 H), 6.81-6.82 (d, 2 H, J
= 5.01 Hz), 7.86 (S, 3 H), 8.15-8.17 (d, 2 H, J = 5.1 Hz), 13C
NMR (CDCl3) 21.24, 52.19, 113.01, 119.68, 147.13, 150.01,
152.65, 154.36.
ACKNOWLEDGEMENTS
Mukesh P. Shewalkar is thankful to Dr. A. V. Ramarao
for his guidance and support.
General Procedure for Alkylation (3). To a suspension
of 2 in THF (10 times) and potassium tert-butoxide (1.2Eq),
alkyl halide was added drop wise at 0oC and reaction mixture
was allowed to cool to room temperature. Reaction mixture
was then stirred at the same temperature for 12hr. It was
cooled to 0oC and quenched by water (5 times). Product was
extracted into ethyl acetate. Concentration of organic layer
offered the crude product which was used directly for next
reaction.
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N-methylpyridin-2-amine (4a). Color less liquid, 97%
1
yield, H NMR (CDCl3) ꢁ= 2.90-2.92 (d, 3 H, J = 5.1 Hz),
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1
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3.25- 3.34 (m, 2 H), 4.45 (br, s, 1H), 6.35-6.37 (m, 1 H),
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Letters in Organic Chemistry, 2013, Vol. 10, No. 1
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