Zinc mediated alkylation of cyclic secondary amines

Article abstract of DOI:10.1081/SCC-120021838

Zinc metal mediated simple and efficient alkylation of cyclic secondary amines e.g., piperazines and morpholine with allyl bromide, chlorobromo propane and p-methoxy benzyl bromide is described in good yields.

Full text of DOI:10.1081/SCC-120021838

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Zinc Mediated Alkylation of Cyclic Secondary Amines
M. S. R. Murty a , B. Jyothirmai a , Palakodety Radha Krishna a & J. S. Yadav a
a D-202, Discovery Laboratory, Organic Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Version of record first published: 20 Aug 2006.
To cite this article: M. S. R. Murty, B. Jyothirmai, Palakodety Radha Krishna & J. S. Yadav (2003): Zinc Mediated Alkylation of
Cyclic Secondary Amines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:14, 2483-2486
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 14, pp. 2483–2486, 2003
Zinc Mediated Alkylation of
Cyclic Secondary Amines#
*
M. S. R. Murty, B. Jyothirmai,
Palakodety Radha Krishna, and J. S. Yadav
D-202, Discovery Laboratory,
OrganicChemistry Division, Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
Zinc metal mediated simple and efficient alkylation of cyclic second-
ary amines e.g., piperazines and morpholine with allyl bromide,
chlorobromo propane and p-methoxy benzyl bromide is described
in good yields.
Key Words: Zinc; Cyclic secondary amines; Alkylation.
#IICT Communication No. 4715.
*Correspondence: M. S. R. Murty, D-202, Discovery Laboratory, Organic
Chemistry Division, Indian Institute of Chemical Technology, Hyderabad
500 007, India; E-mail: madugula51@yahoo.com.
2483
DOI: 10.1081/SCC-120021838
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2484
Murty et al.
The alkylation of amines is accomplished by the reaction of alkylat-
ing reagent and amine in the presence of base like potassium carbonate or
sodium hydride.[1,2] N-alkylation of carbamates was reported using
cesium carbonate in presence of phase transfer catalyst.[3] However,
these procedures involve the reaction at reflux temperature and longer
reaction time. In our recent work we have reported zinc promoted facile
synthesis of carbamates[4] and esterification of acid chlorides with alco-
hols.[5] Herein we wish to report a simple, convenient, and general method
for alkylation of cyclic secondary amines (1–5) using zinc(metal grade) as
an inexpensive catalyst (Eq. (1)).
Zn
(Eq.1)
X
N
R
R-Br
X
NH
+
THF, r.t
ð1Þ
X = O; N-methyl, N-ethyl,N-benzyl,N-(2 pyrimidyl);
R = chloropropyl, allyl, p-methoxy benzyl
Alkylation of compounds 1–5 with chlorobromopropane with the
conventional reported methods did not give satisfactory yields whereas
in the zincmedium the yields of the alkylated products (6–20) were very
good. This is remarkable achievement over the existing conventional
methods. The reaction of alkylating reagent with cyclic amine in the
presence of zinc is remarkably fast and led to good yields of the products.
It was observed that in the absence of zinc no product was formed. It
was also investigated if there was any possibility of using zincin catalyt-
ical or at least in less than stoichiometric quantities. However high yields
of the products with high purity were found with 1 eq. zinc.
In conclusion the present method is simple and convenient for the
preparation of various N-alkyl/aralkyl substituted cyclic amines. The
advantage of the present method over existing methods is the use of
zincas a reusable actalyst. This is remarkable and makes the method
economically valuable.
EXPERIMENTAL
Melting points were determined on a Buchi capillary melting point
apparatus. The 1H NMR spectra were recorded on Varian Gemini
200 MHz spectrometer using TMS as an internal standard. Mass spectra
were recorded on a VG micromass 70-70H mass spectrometer and IR
spectra were recorded on Nicolet FT IR-740.

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Cyclic Secondary Amines
2485
In a typical procedure, activated zinc powder (0.65 g, 10 mmol) is
added to a solution of methyl piperazine 1 (1.0 g, 10 mmol), chlorobromo-
propane (1.5 g, 10 mmol) in THF (10 mL) and stirred at room temperature
for 1h. After completition of the reaction, the mixture is filtered and the
solid is washed with solvent ether (3 Â 10 mL). The combined filtrate was
treated with 10% NaHCO3 (10 mL), water (2 Â 10 mL), dried (Na2SO4)
and evaporated to give the product 6 (1.15 g, 68%). Compounds 7–20 are
prepared as described above and the reaction time is 1h for all the Entries
1–15 (see Table 1). The recovered zinc was activated,[6] reused and found
that there was no substantial loss in the activity.
All the products were characterized by spectral data (1H NMR and
Mass). Spectral Data of selected compounds: 1H NMR (200 MHz,
Table 1. Preparation of alkylated cyclic amines.
Entry
Cyclic amine
Alkylating agent
Product (yield)
Br
Cl
NH
N
X
X
Cl
1
2
3
4
5
1 X¼N-CH3
2 X¼N-C2H5
3 X¼N-benzyl
4 X¼N(2-pyrimidyl)
5 X¼O
6 X¼N-CH3 (68%)
7 X¼N-C2H5 (75%)
8 X¼N-Benzyl (92%)
9 X¼N(2-pyrimidyl) (76%)
10 X¼O (95%)
Br
N
X
6
7
11 X¼N-CH3 (61%)
12 X¼N-C2H5 (63%)
13 X¼N-benzyl (95%)
14 X¼N-(2-pyrimidyl) (88%)
15 X¼O (72%)
8
9
10
Br
N
X
OMe
OMe
11
12
13
14
15
16 X¼N-CH3 (85%)
17 X¼N-C2H5 (71%)
18 X¼N-benzyl (86%)
19 X¼N-(2-pyrimidyl) (72%)
20 X¼O (70%)

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2486
Murty et al.
CDCl3, TMS): Compound 7: ꢀ 1.10 (t, 3H, –CH3, J ¼ 6.8 Hz), 1.90–2.01
(m, 2H, –CH2), 2.20–2.60 (m, 12H), 3.60 (t, 2H, –CH2, J ¼ 7.0 Hz); MS
(m/z) 190 (Mþ) (Found: C, 56.72; H, 10.12; N, 14.75. C9H19N2Cl requires
C, 56.68; H, 10.04; N, 14.69%). 13: ꢀ 2.50–2.60 (m, 8H), 3.50–3.60 (m,
4H), 5.10–5.20 (m, 2H), 5.70–5.90 (m, 1H), 7.30–7.40 (br.s, 5H, Ar-H);
MS (m/z) 216 (Mþ) (Found: C, 77.85; H, 9.46; N, 13.03. C14H20N2
requires C, 77.73; H, 9.32; N, 12.95%). 20: ꢀ 2.35–2.50 (m, 4H), 3.40
(s, 3H, –OCH3), 3.75–3.90 (m, 6H), 6.50–6.80 (m, 2H, Ar-H), 7.15–7.20
(m, 2H, Ar-H); MS (m/z) 207 (Mþ) (Found: C, 69.62; H, 8.38; N, 6.85.
C12H17NO2 requires C, 69.54; H, 8.27; N, 6.76%).
REFERENCES
1. Gupta, P.P.; Sharma, J.N. J. Med. Chem. 1973, 16 (7), 797.
2. Depreux, P.; Aichaoui, H.; Lesienr, I. Heterocycles 1993, 1051.
3. Salvatore, R.N.; Shin, S.I.; Flanders, V.L.; Jung, K.W. Tetrahedron
Lett. 2001, 42 (10), 1799.
4. Yadav, J.S.; Reddy, G.S.; Reddy, M.M.; Meshram, H.M.
Tetrahedron Lett. 1998, 39, 3259.
5. Yadav, J.S.; Reddy, G.S.; Himabindu, K. Synth. Commun. 1998,
28 (13), 2337.
6. Used zincwas treated with 10% HCl, washed with water, acetone
and dried in oven for 10 h at 120–130ꢀC.
Received in the Netherlands October 16, 2002