E. V. Koroleva et al. / Tetrahedron Letters 53 (2012) 5056–5058
5057
N
AcO
O
O
O
+
N
in situ NaBH(OAc) ,
3
N
+
NH
O
O
H
100
2
O, H ,
C
0
-5 C, CHCl3
O
0
N
+
N
4a
N
O
O
N
O
O
R
OH
1
R
x2HCl
3
a,b
N
2
a R=Me
b R=H
N
4b x2HCl
2
4
b
OH
Scheme 1. Reductive alkylation of N-methylpiperazine with aryl aldehydes.
Table 1
1
-methylpiperazine in the presence of triacetoxy sodium borohy-
Preparation of 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid by reductive amina-
tion in the presence of NaBH –AcOH as the reducing system
dride. This synthesis has several advantages, including a simple
experimental procedure, use of commercially available starting
materials, mild reaction conditions, and high yields of the reaction
products. The procedure allows rapid scale-up for the large-scale
synthesis of 4-[(4-methylpiperazin-1-yl)-methyl]benzoic acid. It
is also suitable for the preparation of other benzyl derivatives of
heterocyclic amines.
4
Entry Substrate Temp (°C), solvent Time (h) Productb
Yieldc (%)
1
2
3
2aa
2b
4a
0–5, CHCl
0–5, CHCl
100, H
3
3
12
12
3
4a5
4b
4b  2HCl
99
90
a
6
7
d
2
O
97
a
b
c
Commercially available.
Products 4 were obtained and characterized as described.
Isolated yield.
Total yield of two stages: 2a?4a?4b  2HCl.
5–7
d
References and notes
1.
(a) Szakacs, Z.; Beni, S.; Vagra, Z.; Orfi, L.; Keri, G.; Noszal, B. J. Med. Chem. 2005,
4
7
8, 249; (b) Koroleva, E. V.; Gusak, K. N.; Ignatovich, Zh. V. Russ. Chem. Rev. 2010,
9, 655; (c) Zimmermann, J. EP 0564409 B1, 1992; Chem. Abstr. 1994, 120,
The benzyl amines were isolated by treatment of the reaction
solution with base followed by extraction; no further purification
was required.
107056.
2
.
(a) Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H.; Meisenbach M.; Schmitz, B.;
Sedelmeier G. EP 1474408, 2003; Chem. Abstr. 2004, 139, 180080w.; (b) Sairam,
P.; Puranic, R.; Kelkar, A. S.; Sasikiran, S.; Veender, M.; Parvathi, A. Synth.
Commun. 2003, 33, 3597; (c) Ivanov, A. S.; Shishkov, S. V. Monatsh. Chem. 2009,
The H NMR, 13C NMR, IR, MS, and elemental analyses were in
1
complete agreement with structures 4a,b. The highest yield of 4-
1
40, 619; (d) Liu, H.; Xia, W.; Luo, Yu. Monatsh. Chem. 2010, 141, 907.
[
(4-methylpiperazin-1-yl)methyl]benzoic acid (4b) was achieved
3
.
.
(a) Ignatovich, J.; Gusak, K.; Chernikhova, T.; Kozlov, N.; Koroleva, E. Chem.
Heterocycl. Comp. 1820, 2007; (b) Ignatovich, Zh. V.; Gusak, K. N.; Kozlov, N. G.;
Koroleva, E. V. Russ. J. Org. Chem. 2007, 43, 1573; (c) Ignatovich, J.; Gusak, K.;
Kozlov, N.; Kovalev, V.; Koroleva, E. Arkivoc 2008, ix, 51.
when it was isolated as the dihydrochloride 4b  2HCl by treating
the benzylation product with hydrochloric acid or by acid hydroly-
5
–7
sis of methyl 4-[(4-methylpiperazin-1-yl)methyl]benzoate (4a).
4
(a) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725; (b) Gutierrez, C. D.;
Bavetsias, V.; McDonald, E. Tetrahedron Lett. 2005, 46, 3595; (c) Tarasevich, V. A.;
Kozlov, N. G. Russ. Chem. Rev. 1999, 68, 55; (d) Hutchins, R. O.; Kandasamy, D. J.
Org. Chem. 1981, 46, 3571; (e) Heydari, A.; Khaksar, S.; Akbari, J.; Esfandyari, M.;
Pourayoubi, M.; Tajbakhsh, M. Tetrahedron Lett. 2007, 48, 1135; (f) Abdel-Magid,
A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996,
61, 3849; (g) Basu, B.; Jha, S.; Bhuiyan, M. H.; Das, P. Synlett 2003, 555; (h) Lane,
C. F. Synthesis 1975, 135; (i) Brusses, J.; van Benthe, R. A. T. M.; Kruse, C. G.; Van
der Gen, A. Tetrahedron: Asymmetry 1990, 1, 163; (j) Bhattacharyya, S. J. Org.
Chem. 1995, 60, 4928; (k) Bhattacharyya, S.; Chatterjee, S.; Williamson, J. S.
Synth. Commun. 1997, 4265; (l) Sahema, I.; Borah, R.; Sarma, J. C. J. Chem. Soc.,
Perkin Trans. 1 2000, 503.
As far as we know, our protocol constitutes the first report of
the successful use of 4-formylbenzoic acid and its methyl ester in
the non-catalytic direct reductive alkylation to prepare 4-[(4-
methylpiperazin-1-yl)methyl]benzoic acid, and also is the first
example using in situ prepared triacetoxy sodium borohydride.
All the previously reported procedures use more complex reagents
with less effect.
In light of its simplicity, this method is expected to be suitable
for the synthesis of other tertiary amines. Thus we have synthesized
tertiary amines including methyl 4-(morpholino-methyl)benzoate,
methyl 4-(pyrrolidin-1-ylmethyl)benzoate, and 1-methyl-4-(4-
5
.
General procedure for the benzylation of 1-methylpiperazine (1). Synthesis of methyl
4
-[(4-methylpiperazin-1-yl)methyl]benzoate (4a): AcOH (100%) (140 mL, 2.44 mol)
was added over 1 h to a flask containing stirred NaBH (20.0 g, 0.53 mol) and
CHCl (220 mL) at 0–5 °C. The resulting mixture was stirred at 0–5 °C for 1.5 h and
-methylpiperazine (1) (28.0 ml, 0.25 mol) and solution of methyl 4-
formylbenzoate (2a) (43.4 g, 0.26 mol) in CHCl (60 mL) were added. The
resulting mixture was stirred at 0–5 °C for 1 h and then for 12 h at rt. the
mixture was treated with H O (150 mL) and Na CO until pH 8.0–9.0. The aqueous
phase was extracted with EtOAc (2 Â 100 ml) then both organic layers were
combined, washed with H SO
4
5
nitrobenzyl)piperazine. These amines were obtained in 87–90%
3
1
a
yields, while the same reductive alkylation reaction under the pre-
viously described protocol produced these amines in 47–70% yields
3
3
a,c,5
(Scheme 2).
2
2
3
In conclusion, we have described a facile and highly efficient
procedure for the in situ synthesis of 4-[(4-methylpiperazin-1-
yl)methyl]benzoic acid through direct reductive alkylation of
2
O (1 Â 100 ml), and dried over anhydrous Na
2
4
.
Filtration and evaporation of the solvents gave methyl 4-[(4-methylpiperazin-1-
yl)methyl]benzoate (4a): yellowish oil; yield: 61.6 g, 99%. 1H NMR (500 MHz,
CDCl
CH OCO); 7.43 (d, J = 8.0 Hz, 2H, Har), 7.99 (d, J = 8.0 Hz, 2H, Har); C NMR
125 MHz, CDCl
3
): 2.30 (s, 3H, CH –N), 2.48 (m, 8H, CHpip), 3.57 (s, 2H, CH ); 3.92 (s, 3H,
3
2
13
3
(
3
): 45.99, 51.90, 53.06, 55.02, 62.52, 128.81, 128.87, 129.46,
À1
1
43.78, 167.05. IR (film): 3450, 1725, 1275, 755, 620 cm . MS (70 eV): m/z 248
N
+
4 8 3 4 8 3
H NCH ] (100%), 99 [NC H NCH
]+ (80%). Anal. Calcd for
+
X=NMe, n=1, R=p-NO
2
[M] (90%), 149 [M-NC
: C, 67.74; H, 8.06; N, 11.29. Found: C, 67.54; H, 7.98; N, 11.59. Using
N
Me
NO2
14 20 2 2
C H N O
O
this protocol methyl 4-(morpholinomethyl)benzoate was obtained in 90% yield,
methyl 4-pyrrolidin-1-ylmethyl)benzoate in 87% yield and 1-methyl-4-(4-
nitrobenzyl)piperazine in 90% yield; these products had spectral characteristics
9
0%
2
X=O, n=1, R=CO Me
NH
N
+
1
13
3a
O
( H NMR, C NMR, IR, MS) identical with those described earlier.
X
n
R
CO
2
Me
6. Synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoic
acid (4b) and
9
0%
X=CH
2
, n=0, R=CO
2
Me
dihydrochloride (4b  2HCl): According to the general procedure, amine
(28.0 g, 0.28 mol) and 4-formylbenzoic acid (2b) (45.0 g, 0.30 mol) were
reacted for 12 h. The mixture was treated with H O and Na CO until pH 7.0
and extracted with EtOAc. Evaporation of the aqueous residue under vacuum
gave 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid (4b): white powder;
1
N
2
2
3
CO Me
2
8
7%
1
yield: 61.2 g, 90%; mp. 255 °C; H NMR (500 MHz, D
2
O) d: 2.81 (s, 3H, CH
3
-N),
Scheme 2. Reductive alkylation of heterocyclic amines with aryl aldehydes.
2
2.5–3.4 (m, 8H, CHpip), 3.72 (s, 2H, CH ), 7.38 (d, J = 8.0 Hz, 2H, HAr), 7.88 (d,