KF/Al2O3-mediated N-alkylation of amines and nitrogen heterocycles and S-alkylation of thiols

Article abstract of DOI:10.1080/00397910600943634

KF/Al₂O₃ efficiently catalyzes N-alkylation of heterocyclic, primary, and secondary amines and S-alkylation of thiols with a variety of alkyl halides. The N-alkylation and S-alkylation adducts were produced in good to excellent yields and in short times. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600943634

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KF/Al O ‐Mediated N‐Alkylation of Amines
2
3
and Nitrogen Heterocycles and S‐Alkylation of
Thiols
a
a
Firouz Matloubi Moghaddam , Seyedeh Maryam DokhtTaimoory , Hossein
a
a
Ismaili & Ghasem Rezanejade Bardajee
a
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Version of record first published: 24 Nov 2006.
To cite this article: Firouz Matloubi Moghaddam, Seyedeh Maryam DokhtTaimoory, Hossein Ismaili & Ghasem
Rezanejade Bardajee (2006): KF/Al O ‐Mediated N‐Alkylation of Amines and Nitrogen Heterocycles and
2
3
S‐Alkylation of Thiols, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:23, 3599-3607
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Synthetic Communications , 36: 3599–3607, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943634
KF/Al O -Mediated N-Alkylation
2
3
of Amines and Nitrogen Heterocycles
and S-Alkylation of Thiols
Firouz Matloubi Moghaddam,
Seyedeh Maryam DokhtTaimoory, Hossein Ismaili,
and Ghasem Rezanejade Bardajee
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Abstract: KF/Al O efficiently catalyzes N-alkylation of heterocyclic, primary, and
2
3
secondary amines and S-alkylation of thiols with a variety of alkyl halides. The N-
alkylation and S-alkylation adducts were produced in good to excellent yields and in
short times.
Keywords: N-alkylation, S-alkylation, alkyl halides, amines, thiols
INTRODUCTION
The application of KF/Al O to organic synthesis has provided new methods
2
3
for a wide array of organic reactions, many of which are staples of synthetic
organic chemistry. Many reports have been published for the application of
KF/Al O , such as ether synthesis, epoxidation, ring closures, carbon–
2
3
[
1]
nitrogen bond formation, carbon–carbon bond formation, and Michael
[
2a,2b]
additions. On the other hand, several methods using alkyl halides have
been developed for the N-alkylation of amines. Various bases such as Et N,
3
[
3]
[4]
[5]
potassium hydride (KH), lithium naphthalenide, CsOH, thallium(I)
[
6]
[7]
ethoxide,
catalysis also has been reported. In many cases, potassium hydroxide
and CsF-Celite
have been used. Use of phase-transfer
Received in the U.K. January 18, 2006
Address correspondence to Firouz Matloubi Moghaddam, Department of
Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran.
E-mail: matloubi@sharif.edu
3
599

3
600
F. M. Moghaddam et al.
(
phase-transfer catalysts (PTC).
KOH) and t-BuOK were employed as bases in the presence of crown ethers as
[
8a,8b]
The N-alkylation of heterocyclic compounds bearing an acidic hydrogen
atom attached to nitrogen is generally accomplished by treatment of these
compounds with an appropriate base (sodium hydroxide or amide, metalo-
organic compounds) followed by treatment of the resulting salts with an alky-
[
9]
lating agent. An alternative is to perform the reaction of such heterocyclic
compounds under PTC conditions, in which alkyl halides react directly with
heterocyclic compounds without converting them to salts in preliminary
[
10a–c]
steps.
Organosulfur compounds are valued not only for their rich and varied
[
11]
chemistry but also for many important biological properties.
methods have been reported for the synthesis of sulfides, such as alkylation
Plenty of
[12a–c]
of thiols with an alkyl halide in the presence of a strong base,
synthesis of sulfides from thiols and
[13]
reduction of sulfoxides with TiCl2,
alkyl halides using hydrotalcite clays,
[
14]
and reduction of disulfide with
In continuation of our research
on the application of KF/Al O as an efficient and mild base for the
[15]
copper in the presence of alkyl halides.
2
3
promotion of organic reactions, we report herein an efficient N- and S-
alkylation of amines and thiols in the presence of KF/Al O (Scheme 1).
2
3
RESULTS AND DISCUSSION
Our investigations showed that different types of amines (heterocyclic amines,
primary and secondary amines) and thiols (aliphatic and aromatic) react
smoothly with various alkyl halides in the presence of KF/Al O . To obtain
2
3
the optimized reaction conditions, different types of solvents were
examined. The results are summarized in Table 1. Because of the higher solu-
bility of the substrates and higher relative rates of the reaction, acetonitrile was
chosen as the suitable solvent. In a typical procedure, a mixture of indole
(
presence of KF/Al O (1 g) at refluxing temperature in acetonitrile, after con-
2 mmol) and/or thiophenol (2 mmol) with benzylbromide (2 mmol) in the
2
3
ventional workup, afforded the desired adduct in 86 and 91% yields, respect-
ively (Entries 1 and 4, Table 1). The results of optimized conditions are shown
in Tables 2 and 3. Most of these reactions proceeded in relatively short times,
and pure products were obtained by recrystallization or PTLC. The N-
Scheme 1.

KF/Al O -Mediated N-Alkylation of Amines
2
3601
3
Table 1. Effect of solvent on N-alkylation and S-alkylation
b
Alkyl
halide
Time
(min)
Yield
(%)
a
Entry
1
Substrate
Solvent
A
Acetonitrile
120
120
120
86
2
3
A
A
Diethylether
37
62
Dichloromethane
4
5
A
A
A
Acetonitrile
90
90
90
91
56
75
Diethylether
6
Dichloromethane
a
A: PhCH Br.
2
b
Isolated yields of pure products.
alkylation adducts are produced in good to excellent yields, except amides,
which gave low yields (Entries 12 and 13, Table 2). For the primary amides
and amines, only bis-N-alkylated products were obtained (Entries 8, 9, and
13, Table 2). In the case of S-alkylation, aliphatic thiols reacted faster than
thiophenol (Entries 1 and 9, Table 3).
In conclusion, KF/Al O has been shown to be an efficient and mild
2
3
catalyst for the N-alkylation and S-alkylation reactions. The support is
prepared conveniently compared to other reported reagents. Also, this
support is nonvolatile, nonflammable, ecofriendly, inexpensive, safe,
and clean.

3
602
F. M. Moghaddam et al.
Table 2. Alkylation of amines and nitrogen heterocycles with alkyl halides using
KF/Al O
2
3
c
Alkyl
halide
Time Yield
(min)
a
b
Entry
1
Substrate
Product
(%)
A
120
86
2
B
120
89
3
4
C
A
100
120
74
79
5
6
D
A
120
120
68
77
(
continued)

KF/Al O -Mediated N-Alkylation of Amines
2
3603
3
Table 2. Continued
c
Alkyl
halide
Time Yield
(min)
a
b
Entry
7
Substrate
Product
(%)
A
120
65
8
A
90
93
9
C
A
90
60
85
95
1
0
1
1
2
C
120
150
92
54
1
A
(
continued)

3
604
F. M. Moghaddam et al.
Table 2. Continued
c
Alkyl
Time Yield
(%)
a
b
Entry
Substrate
halide
Product
(min)
1
3
A
150
61
a
b
A: benzyl bromide, B: benzyl chloride, C: ethyl bromide, D: iso-butyl bromide.
1
All products were characterized by mp, IR, and H NMR, and their physical data
[
7]
were similar to those reported in the literature.
c
Isolated yields of pure products.
EXPERIMENTAL
The compounds all gave satisfactory spectroscopic data. IR spectra were taken
as thin films for liquid compounds and as KBr pellets for solids on a Nicolet
spectrometer (Magna 550). A Bruker (DRX 500 Avance) NMR was used to
1
13
record the H NMR and C NMR spectra. All NMR spectra were determined
in CDCl at ambient temperature. Melting points were determined on a Buchi
B540 apparatus.
3
Procedure for the Preparation of KF/Al O Support
2
3
The KF/Al O support was prepared according to a previously reported
3
2
16]
[
procedure
(
with some modifications. A mixture of potassium fluoride
45 g) and basic alumina (55 g, type T, Merck) in water (100 mL) was
stirred at room temperature for 10 min. The resulting suspension was
concentrated in vacuum and dried in a vacuum oven at 1208C for 15 h. Use
of basic alumina in the solid support gave better results relative to the
neutral one.
General Experimental Procedure for N-Alkylation
and S-Alkylation
The KF/basic Al O (1 g) was added to a solution of indole for N-alkylation
2
3
and thiophenol for S-alkylation (2.1 mmol) in acetonitrile (10 ml) and stirred
at refluxing temperature for 20 min. Then benzylbromide (2 mmol) was added
to the mixture at room temperature and further stirred at refluxing temperature
for the given time (see Tables 2 and 3) and monitored by thin-layer

KF/Al O -Mediated N-Alkylation of Amines
2
3605
3
2 3
Table 3. Alkylation of thiols with alkyl halides using KF/Al O
c
Alkyl
halide
Time Yield
(%)
a
b
Entry
1
Substrate
Product
(min)
A
90
91
2
B
90
93
3
4
C
D
90
90
84
76
5
6
E
F
90
90
87
82
7
8
A
C
90
90
89
85
9
A
70
83
(
continued)

3
606
F. M. Moghaddam et al.
Table 3. Continued
c
Alkyl
halide
Time Yield
(min)
a
b
Entry
Substrate
Product
(%)
1
0
B
70
87
1
1
1
2
C
F
75
75
78
73
a
A: benzyl bromide, B: benzyl chloride, C: n-butyl bromide, D: iso-propyl bromide,
E: allyl bromide, and F: n-propyl bromide.
b
1
All products were characterized by mp, IR, and H NMR, and their physical data
[
14,17]
were similar to those reported in the literature.
c
Isolated yields of pure products.
chromatography (TLC) (ethyl acetate/petroleum ether 1 : 4). After filtration of
the catalyst, the filtrate was washed with aqueous NaOH (10%) and the
organic phase was evaporated under reduced pressure to furnish the desired
l
product. The crude product was sufficiently pure (TLC and H NMR), and
further purification was performed by preparative thin layer chromatography
l
PTLC). All products were characterized by H NMR and IR. The residual
(
KF/Al O support was dried under vacuum at 1208C for 10 h and reused
2
3
for subsequent reactions. No loss of efficiency with regard to reaction time
and yield was observed after three times.
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