Electroorganic synthesis of benzathine

Article abstract of DOI:10.1016/j.tetlet.2006.11.008

Benzathine is prepared in good yields from cyanobenzene by a combination of electrochemical hydrogenation and Kolbe electrolysis using nickel and platinum electrodes in the presence of methanolic sodium methoxide in an undivided cell.

Full text of DOI:10.1016/j.tetlet.2006.11.008

Tetrahedron Letters 48 (2007) 77–80
Electroorganic synthesis of benzathine
a
b
Shaik Lateef, Srinivasulu Reddy Krishna Mohan and
a,
*
Srinivasulu Reddy Jayarama Reddy
a
Electrochemical Research Laboratory, Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
b
Defence Research and Development Laboratory, Ministry of Defence, Kanchanbagh, Hyderabad 500 058, India
Received 28 August 2006; revised 27 October 2006; accepted 1 November 2006
Available online 21 November 2006
Abstract—Benzathine is prepared in good yields from cyanobenzene by a combination of electrochemical hydrogenation and Kolbe
electrolysis using nickel and platinum electrodes in the presence of methanolic sodium methoxide in an undivided cell.
ꢀ
2006 Elsevier Ltd. All rights reserved.
A benzathine salt of penicillin is used in the treatment of
is low, scale-up is comparatively easy, which also makes
the reaction attractive for technical use and the starting
compounds, carboxylic acids, are readily available in a
wide structural variety.
1
–3
viral diseases like syphilis and rheumatic fever. In the
literature, chemists have synthesized benzathine by a
1
catalytic hydrogenation of N,N -dibenzylethylene dia-
mine, by reaction of a benzyl halide and ethylene dia-
mine in the presence of an aqueous solution of caustic
soda and also by reacting benzylamine with 1,2-dichlo-
Here, we report a new method for the synthesis of
benzathine from the simple molecule cyanobenzene,
which involves the combination of electrochemical hydro-
genation and Kolbe electrolysis.
4
–8
roethane.
These reactions mostly involve the use of
an external supply of hydrogen gas at very high pressure
and are thus not recommended because of the possibili-
ties of explosion and fire. The use of noble metal cata-
lysts and the formation of undesirable by-products
such as mono-, tri- and tetra-benzylethylenediamines
were also major disadvantages of these methods. In view
of green chemistry and the developing interest of chem-
ists in electroorganic chemistry, we attempted the syn-
thesis of benzathine by electrochemical methods.
Electrochemical hydrogenation and Kolbe electrolysis
are used for the synthesis of many organic com-
Earlier, our group reported the synthesis of amino sul-
fonamides from cyano sulfonamides by electrochemical
hydrogenation involving a nickel cathode and a plati-
num anode in methanol–sodium methoxide with freshly
2
0
prepared Raney nickel as catalyst in an undivided cell.
Thus benzylamine 2 could be prepared by electrochem-
ical hydrogenation of cyanobenzene 1 in good yield
2
1
(Scheme 1). The benzylamine was treated with a bro-
mo-ester at room temperature to afford ethyl (benzyl-
amine)acetate 3, which was refluxed in benzene with
benzoyl chloride for 30 min to afford benzoyl protected
ethyl-N-[benzoyl(benzyl)amino]acetate 4. Hydrolysis of
4 with 4 N sodium hydroxide yielded the protected acid
5. Compound 5 on Kolbe electrolysis in an undivided
cell, equipped with platinum electrodes in methanol–
9
–14
pounds.
Schafer and co-workers have published sev-
1
5–18
eral reviews and papers on Kolbe electrolysis.
The advantages of Kolbe electrolysis compared with
1
9
non-electrochemical radical reactions are the use of
simple reaction conditions: a simple undivided cell can
be used, methanolic sodium methoxide serves in most
cases as the solvent/supporting electrolyte, electrode po-
tential need not be controlled, the cost of the electricity
2
sodium methoxide by passing 250 mA/cm of electricity
until the pH of electrolyte changed to 8, afforded
0
0
N,N -dibenzoyl-N,N -dibenzylethylene diamine 6 along
with 9% of the disproportionation product 7. Finally,
6
on acid hydrolysis afforded benzathine 8 in good
yield.
Keywords: Electrochemical hydrogenation; Kolbe electrolysis; Un-
divided cell; Benzathine.
*
Corresponding author. Tel.: +91 877 2249962; fax: +91 877
249611; e-mail: profjreddy_s@yahoo.co.in
The mechanism of nitrile electroreduction as outlined
in Scheme 2 involves in situ electrochemical generation
2
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.008

78
S. Lateef et al. / Tetrahedron Letters 48 (2007) 77–80
N
_
+
C
Ni
Pt
NH2 Br
CO Et
2
N
H
CO2Et
MeOH-MeONa
84%
Et N, DCM, 92%
3
1
2
3
C H COCl
6
5
reflux
9%
benzene,
pyridine
8
_
N
COOH
N
CO Et
2
+
Pt
Pt
4N NaOH
O
O
o
MeOH-MeONa
0 C, 95%
8
6%
5
4
O
reflux
C H OH, HCl
H
N
N
N
N
H
2
5
O
9
4%
8
6
+
N
OMe
O
7
Scheme 1.
MeOH + e-
.
MeO-
+
Compounds having electron-donating groups such as
H
ads
NH a to the carboxylic acid cannot be subjected to rad-
2
4
H.
+
R
C
N
R CH NH2
2
ads
ical coupling by Kolbe electrolysis as further oxidation
of the intermediate radical predominates due to carbo-
cation stabilization by the amino group. Compounds
with remote amino groups (b or x-position) can be cou-
pled, however, it is appropriate to protect the amino
Scheme 2.
of hydrogen. The hydrogen ion formed from metha-
nol takes one electron resulting in atomic hydrogen
H ) which is adsorbed on the Raney nickel catalyst,
thus no evolution of hydrogen was observed. Finally,
2
2
group.
Å
(
For Kolbe electrolysis, high current densities are needed
for the generation of high radical concentrations, which
Å
the addition of adsorbed atomic hydrogen ðH Þ to
ads
the nitrile group results in formation of the desired
amine.
a
Table 1. Electrochemical synthesis of benzylamine
Entry
Temperature (ꢁC)
Isolated yield (%) of 2
Tables 1 and 2 show the variation of product yields due
to the changes in the reaction temperature and current
densities. The conditions which favour the formation
of good yields of the product were high temperature
and low current density. The reactions at the cathode
mainly include hydrogenation and hydrogen evolution,
which alters the product yield. The results suggest that
elevated temperatures accelerate the reaction of ad-
sorbed hydrogen with the substrate to a greater extent
than the adsorbed atomic hydrogen to hydrogen gas
reaction. Since the increase of current density increases
hydrogen evolution, low current densities are favourable
for electrochemical hydrogenation. The improved prod-
uct yield is again the result of competition between the
two reactions.
1
2
3
4
5
5
15
25
35
45
2
61
70
77
84
87
a
Current density is 10 mA/cm .
a
Table 2. Effect of current density on the synthesis of benzylamine
2
Entry
Current density (mA/cm )
Isolated yield (%) of 2
1
2
3
10
25
50
77
73
66
a
Temperature is 25 ꢁC.

S. Lateef et al. / Tetrahedron Letters 48 (2007) 77–80
79
favour radical coupling. This also leads to fast conver-
sion and a very positive anode potential that promote
oxidation of the negatively charged carboxylate and dis-
favours oxidation of the neutral solvent methanol. Oxi-
dation of carboxylic anion, formation of an alkyl radical
and coupling of the two radicals results in the formation
of Kolbe dimer 6 from benzoyl-protected adduct [ben-
zoyl(benzyl)amino]acetic acid 5 and in addition to 6,
the disproportionation product N-benzyl-N-(meth-
oxymethyl)benzamide 7 was formed in 9% by the oxida-
tion of the radical to a carbocation.
19. Giese, B. Radicals in Organic Synthesis: Formation of
Carbon–Carbon Bonds; Pergamon: Oxford, 1986; pp 36–
1
40.
2
0. Lateef, S. K.; Krishnamohan, S.; Rameshraju, R.; Jaya-
ramareddy, S. Helv. Chim. Acta 2006, 89, 1254–1257.
1. Electrochemical hydrogenation of cyanobenzene: Electro-
chemical hydrogenation was carried out in an undivided
2
2
cell containing a Ni cathode (2 · 2 cm ) and a Pt anode
2
(
2 · 2 cm ) by dissolving 1.03 g (0.01 mol) cyanobenzene 1
in 40 ml of methanol and 0.1 mol of sodium methoxide.
To this, 1.0 g of freshly prepared Raney nickel was
added and dissolved oxygen was removed by passing N
2
3
2
gas through the solution for about 10–15 min. Then, the
solution was subjected to electrolysis at a constant current
density of 10 mA/cm and at 35 ꢁC temperature until 4 F/
In conclusion, benzathine can be prepared via a combi-
nation of electrochemical hydrogenation and Kolbe
electrolysis in good yields. Electrochemical hydrogena-
tion involves in situ generation of hydrogen, which does
not involve high pressure generating equipments. Com-
pounds having electron-donating groups b to a carbox-
ylic group can be successively subjected to Kolbe
electrolysis by protection with benzoyl chloride. This
electrolysis procedure is an alternative route for the syn-
thesis of benzathine from the simple molecule cyano-
benzene and has great potential in green chemistry.
2
mol of electricity had been passed. Next, the solution was
transferred to a round-bottomed flask and the solvent was
evaporated. The residue was treated with 10% HCl and the
aqueous layer was washed with ether. The aqueous
solution was made strongly alkaline with sodium hydrox-
ide, extracted with ether (25 ml · 3), dried over Na SO
2
4
and evaporated under reduced pressure to give benzyl-
amine 2 (yield 84%) as a colourless liquid, bp 186–187 ꢁC
2
4
(
lit. 185 ꢁC).
Synthesis of ethyl(benzylamino)acetate (3) from benzyl
amine (2): 1.07 g (0.01 mol) of 2 was taken in a round-
bottomed flask along with 5 ml of DCM and 2.81 ml of
triethylamine. To this mixture, ethyl bromoacetate (1.67 g,
0
.01 mol) was added dropwise at room temperature with
constant stirring for about 2 h. The solvent was evapo-
rated under vacuum and to this 25 ml of water was added
and the aqueous layer was extracted with ether, and the
combined organics were dried over sodium sulfate, evap-
orated and purified by column chromatography (silica gel
References and notes
1
2
3
. Fletcher, A. P.; Knappett, C. R. Br. Med. J. 1953, 1, 188–
89.
. Saxena, A. Curr. Treat. Options Cardiovasc. Med. 2002, 4,
09–319.
. Rieder, G.; Rusizoka, M.; Todd, J.; Maboko, L.; Hoel-
scher, M.; Mmkando, D.; Samky, E.; Lyamuya, E.;
Makey, D.; Grosskurth, H.; Hoyes, R. N. Engl. J. Med.
005, 353, 1236–1244.
. Rebenstorf, M. A.; Mich, K. US Patent 2,773,098, 1956;
Chem. Abstr. 51, P14802d.
1
6
0–120 mesh, hexane:ethyl acetate 3:1) to afford com-
3
pound 3 (yield 92%) as a yellowish liquid, bp 142–143 ꢁC
2
5
(
10 mm Hg) (lit. 140–142 ꢁC at 10 mm Hg).
Synthesis of [benzoyl(benzyl)amino]acetic acid (5): To a
solution of 1.93 g (0.01 mol) of 3 in 10 ml of dry pyridine
and 20 ml of dry benzene (CAUTION: The reaction must
be carried out in a well-ventilated fume cupboard and
protective gloves should be worn), 1.4 g (0.01 mol) of
benzoyl chloride was added dropwise. The mixture was
refluxed at 60–70 ꢁC for about 30 min and then poured
into 100 ml of water. The benzene layer was separated and
the aqueous layer was extracted with benzene (3 · 10 ml).
The combined benzene layers were washed with 5%
sodium carbonate solution (15 ml) followed by 10 ml of
2
4
5
6
7
8
. Jones, W. G. M. GB Patent 762,992, 1956; Chem. Abstr.
5
1, 16534g.
. Lehmann, B. DE Patent 19,604,102, 1997; Chem. Abstr.
27, 135631t.
. Jones, W. G. M. GB Patent 762,991, 1956, Chem. Abstr.
1, 17991d.
. Ivanovna, A. T.; Nikokevich, D. E.; Evgenevich, D. D.;
Evgenevich, E. N. RU Patent 2,237,653, 2004; Chem.
Abstr. 141, 333941w.
. Chiba, T.; Okimoto, M.; Nagai, H.; Takuta, T. Bull.
Chem. Soc. Jpn. 1983, 56, 719–723.
0. Dandge, C. N.; Naik, D. G.; Kapadi, A. H. Ind. J. Chem.
988, 27, 854–855.
1. Kubota, T.; Ishii, T.; Minamikawa, H.; Yamaguhi, S.;
Tanaka, T. Chem. Lett. 1988, 1987–1990.
2. Sugiya, M.; Nohira, H. Chem. Lett. 1998, 479–480.
3. Bonner, W. A.; Mango, F. D. J. Org. Chem. 1964, 29,
30–435.
4. Matzeit, A.; Schafer, H. J.; Amatore, C. Synthesis 1995,
432–1442.
5. Klunenberg, H.; Schafer, H. J. Angew. Chem., Int. Ed.
Engl. 1978, 17, 47–48.
1
5
2 4
water and then dried over Na SO . The benzene layer was
removed under vacuum to give ethyl-N-[benzoyl(benzyl)-
amino]acetate 4 (yield 89%). Compound 4 thus obtained
was dissolved in 5 ml of methanol. To this, 4 ml of 4 N
NaOH was added at 0 ꢁC and the mixture stirred for 1 h.
Methanol was removed under reduced pressure, the
solution was acidified with 1 N HCl and then extracted
with ethyl acetate, which on removal under vacuum gave
compound 5 (yield 95%).
9
1
1
1
1
1
Data for (4): pale yellow powder, mp 172–175 ꢁC. IR
ꢀ
1 1
(
KBr): m = 1679, 1746 cm . H NMR (300 MHz, CDCl )
3
4
d = 1.26 (t, 3H, CH
CH –CO), 4.16 (m, 2H, –CH
Ar–H). C NMR (75 MHz, CDCl ) d = 12.91 (CH –
3
), 3.50 (s, 2H, Ar–CH
2
), 3.84, (s, 2H,
1
1
1
1
1
–
2
2
–CH ), 7.05–7.62 (m, 10H,
3
1
1
3
3
2
CH
26.44, 126.91, 127.87, 128.78, 129.45, 131.24, 138.62
aromatic carbons), 168.36 (Ph–CO), 172.46 (COO). Anal.
3 2 2 2 3
), 51.43 (N–CH ), 57.69 (Ph–CH ), 58.33 (CH –CH ),
1
(
6. Harenbrock, M.; Matzeit, A.; Schafer, H. J. Liebigs Ann.
1
996, 55–62.
Calcd for C H NO (297.34): C, 72.71; H, 6.44. Found:
7. Idelmann, A. W.; Aus dem Kahmen, M.; Schafer, H. J.
Acta Chem. Scand. 1998, 52, 672–682.
8. Goular, M. O. F.; Schafer, H. J. J. Braz. Chem. Soc. 1999,
18 19
3
C, 72.69; H, 6.48.
[
Benzoyl(benzyl)amino]acetic acid (5): colourless powder,
ꢀ
1 1
mp 258–260 ꢁC. IR (KBr): m = 1689, 1746, 3297 cm . H
1
0, 153–162.

80
S. Lateef et al. / Tetrahedron Letters 48 (2007) 77–80
NMR (300 MHz, CDCl
.39 (s, 2H, Ph–CH –N), 7.04–7.88 (m, 10H, Ar–H).
NMR (75 MHz, CDCl ) d = 51.84 (N–CH ), 56.91 (Ph–
3
) d = 4.02 (s, 2H, N–CH
2
–CO),
N-benzyl-N-(methoxymethyl)benzamide (7): colourless
1
1
3
ꢀ1
powder, mp 132–135 ꢁC. IR (KBr): m = 1691 cm . H
4
2
C
NMR (300 MHz, CDCl ) d = 3.58 (s, 3H, CH ), 4.32 (s,
3
2
3
3
CH
37.11 (aromatic carbons), 168.74 (Ph–CO), 174.93
COOH). Anal. Calcd For C16 (269.30): C,
2
), 126.14, 126.72, 127.47, 128.56, 129.71, 130.94,
2H, Ar–CH
2
), 4.96 (s, 2H, CH
2
–O–), 7.08–7.58 (m, 10 H,
1
3
1
(
Ar–H). C NMR (75 MHz, CDCl
52.95 (O–CH ), 81.26 (N–CH ), 126.24, 127.12, 128.94,
129.45, 130.11, 131.36, 137.21 (aromatic carbons), 169.45
(Ph–CO). Anal. Calcd for C16 (255.32) C,75.27;
H, 6.71. Found: C, 75.30; H, 6.65.
Hydrolysis of 6, for the synthesis of benzathine (8):
Compound 6 (2.24 g (0.005 mol)) was dissolved in 12 ml
of ethanol in a 50 ml round-bottomed flask. To this, 4 ml
of concentrated HCl was added dropwise and the mixture
refluxed for about 40 min and then diluted with 30 ml of
water. The reaction mixture was poured into 50 ml of ice
water, to this 5% aqueous sodium hydroxide solution was
added with vigorous stirring until the solution became
slightly alkaline. The mixture was extracted with ether and
3 3
) d = 52.66 (Ph–CH ),
H
15NO
3
3
2
71.36; H, 5.61. Found: C, 71.40; H, 5.69.
Kolbe electrolysis: Compound 5 (1.35 g (0.005 mol)) was
H17NO
2
added to an undivided electrolytic cell containing 40 ml
2
methanol equipped with platinum electrodes (2 · 2 cm ).
The pH was adjusted to slightly alkaline with sodium
methoxide and dissolved oxygen was removed by passing
2
N gas through the solution for 10–15 min. The solution
was then subjected to electrolysis at 35–40 ꢁC at a constant
2
current density of 250 mA/cm until the pH of the
electrolyte had changed to 8. The solution was transferred
to a round-bottomed flask and the solvent was evaporated
in vacuo. The residue was dissolved in ethyl acetate and
transferred to a separating funnel. The organic phase was
washed with 10% HCl solution, then saturated sodium
bicarbonate (2 · 25 ml) and brine (2 · 25 ml). The organic
phase was dried over sodium sulfate and filtered. The
2 4
the organics were dried over Na SO and purified by
column chromatography (hexane:ethyl acetate 3:1) (yield
94%) pale yellow oily liquid, bp 214–215 ꢁC (12 mm Hg)
2
6
ꢀ1
.
(lit. 212–213 ꢁC at 12 mm Hg). IR (KBr): m = 3345 cm
0
1
filtrate was concentrated to give a mixture of N,N -
H NMR (300 MHz, CDCl
3.75 (s, 4H, Ph–CH –N), 4.65 (br s, 2H, NH), 7.18–7.57
(m, 10H, Ar–H). Anal. Calcd for C H N (240.34) C,
3 2
) d = 2.62 (s, 4H, N–CH –),
0
dibenzoyl-N,N -dibenzylethylenediamine (6) (yield 86%)
2
and N-benzyl-N-(methoxymethyl)benzamide (7) (yield
1
6
20
2
9
(
%), which was purified by column chromatography
silica gel 60–120 mesh, hexane:ethyl acetate 9:1).
Data for (6): colourless powder, mp 313–315 ꢁC. IR (KBr):
79.96; H, 8.39. Found: C, 79.99; H, 8.36.
22. Haufe, J.; Beck, F. Chem. Ing. Technol. 1970, 42, 170–
172.
23. Mozingo, R. Org. Synth. Coll. 1955, III, 181–183.
24. Egli, R. A. Helv. Chim. Acta 1970, 53, 47–53.
25. Page, B. C. P.; Leach, C. D.; Hayman, M. C.; Hamzah,
S. A.; Allin, M. S.; Mckee, V. Synlett 2003, 7, 1025–
1027.
ꢀ
1 1
m = 1695 cm . H NMR (300 MHz, CDCl ) d = 3.62 (s,
3
4H, N–CH
2
–), 4.39 (s, 4H, Ph–CH
2
–N), 7.01–7.82 (m,
13
20H, Ar–H). C NMR (75 MHz, CDCl
3
) d = 44.44 (N–
CH ), 51.92 (Ph–CH ), 126.35, 126.64, 127.41, 128.39,
2
2
1
29.73, 130.71, 131.46, 136.55 (aromatic carbons), 165.79
Ph–CO). Anal. Calcd for C30 (448.56) C, 80.33;
H, 6.29. Found: C, 80.30; H, 6.33.
(
H
28
2
N O
2
26. Foster, A. E.; Chaberek, S.; Martell, A. E. J. Am. Chem.
Soc. 1949, 71, 3842–3843.