Triton B-mediated mild, convenient, and efficient method for the selective alkylation of cyclic secondary amines and thiols

Article abstract of DOI:10.1080/00397910802654740

Alkylation of cyclic secondary amines, thiols, and pyridazinones has been demonstrated with alkyl halides using Triton B as base and reaction medium.

Full text of DOI:10.1080/00397910802654740

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Triton B–Mediated Mild,
Convenient, and Efficient
Method for the Selective
Alkylation of Cyclic Secondary
Amines and Thiols
H. M. Meshram a , B. Chennakesava Reddy a & P.
Ramesh Goud a
a Organic Chemistry Division I, Indian Institute of
Chemical Technology, Hyderabad, India
Version of record first published: 01 Jun 2009.
To cite this article: H. M. Meshram , B. Chennakesava Reddy & P. Ramesh Goud
(2009): Triton B–Mediated Mild, Convenient, and Efficient Method for the Selective
Alkylation of Cyclic Secondary Amines and Thiols, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:13,
2297-2303
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Synthetic Communications1, 39: 2297–2303, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802654740
Triton B–Mediated Mild, Convenient, and
Efficient Method for the Selective Alkylation of
Cyclic Secondary Amines and Thiols
H. M. Meshram, B. Chennakesava Reddy, and P. Ramesh Goud
Organic Chemistry Division I, Indian Institute of Chemical Technology,
Hyderabad, India
Abstract: Alkylation of cyclic secondary amines, thiols, and pyridazinones has
been demonstrated with alkyl halides using Triton B as base and reaction medium.
Keywords: Alkyl halides, amines, thiols, Triton B
There are numerous methods for the N-alkylation of cyclic secondary
amines. Traditionally, alkylation has been performed using alkyl halides
in an organic solvent in the presence of a base. Metal amides have also
been used as base for the alkylation in the presence of an excess of
triethylamine.[1] Sodium hydride[2] has been reported to catalyze the
alkylation of pyridazinone and pyrrolidinone under forcible conditions,
which leads to a mixture of products.[2] A rapid method using potas-
sium hydroxide (KOH)[3] and a phase-transfer catalyst under microwave
irradiation[4] has been reported for exclusive N-alkylation in dry media.
Alkylation of thiols has been demonstrated using alkyl halides and
potassium carbonate with heating.[5] However, a method with a nonme-
tallic reagent using Huenig’s base[6] has been reported for benzylation
and butylation in an inert atmosphere. Recently, an indirect method
for benzylation[7] has been published using a high-load-soluble oligo-
meric sulfonate ester as a benzyl equivalent under anhydrous condition.
Received August 21, 2008.
Address correspondence to H. M. Meshram, Organic Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: hmmeshram@
yahoo.com
2297

2298
H. M. Meshram, B. C. Reddy, and P. R. Goud
Based on the dry-media concept, the reagent concentration method for
the synthesis of tertiary amines[8] either with or without a small amount
of cosolvent has been reported to increase the yield and shorten
the reaction time. However, the reported methods have the drawbacks
of using strong metallic bases, which causes hydrolysis of ester and
generates metal-ion-containing waste. Some of the methods use dime-
thylformamide (DMF) as a solvent, which requires absolutely dry
conditions, tedious workup, and difficult recovery of the product.
Recently, dry-media[9] reactions are an area of growing interest because
of distinct advantages, such as replacement of hazardous solvent,
enhanced reaction rate, easy recovery of products, and simple opera-
tion. Thus, there is a need to develop an operationally simple, safe,
and widely usable method using a nonmetallic base in solvent-free
conditions.
In recent years, there has been growing interest in the use of alkyl
ammonium ions as phase-transfer catalysts.[10] Herein, we report the
results of Triton B–mediated alkylation of secondary amines, imides,
thiols, and pyridazinones.
EXPERIMENTAL
To optimize the effective conditions, the reaction of N-Boc piperazine
and benzyl bromide was carried out using different ratios (1, 2, and 3
equiv.) of Triton B. With 1 equiv. of Triton B, the reaction proceeded
sluggishly and took longer (12 h) for the completion of reaction. How-
ever, the efficiency of the reaction was enhanced, and reaction time was
shortened (3 h) by employing 3 equiv. of Triton B. Further, keeping
the advantages of dry media in mind, the reaction was performed in
solvent-free conditions (by removing solvent from Triton B). To our
delight, the reaction proceeded well in solvent-free condition and after
extraction with ether gave only alkylated product in excellent yield.
Because this solvent-free protocol is advantageous environmentally
friendly, we examined a variety of substrates in solvent-free conditions.
During the investigation, it was observed that 3 equiv. of Triton B was
not completely utilized in reaction. This fact was further supported by
the reuse of unused Triton B. The remainder of the unused Triton B
along with ammonium bromide was vacuum dried and used for next
reaction cycle. This exercise was repeated for three cycles, and the
products were isolated with gradual decrease in the yield (96, 89, and
82%). The presence of formed ammonium bromide during reaction
has the additional advantage that it may act as a ‘‘salt out’’ reagent,
which facilitates the reaction.[11]

Triton B–Mediated Alkylation
General Procedure
2299
A mixture of Triton B (3 mmol) and amine=thiol (1 mmol) was stirred at
rt for 15 min. Then alkyl halide (1.2 mmol) was added dropwise, and the
resulting mixture was stirred at rt for the time given in (Table 1). After
completion of the reaction, as indicated by thin-layer chromatography
(TLC), the mixture was extracted with ether (3 ꢀ 15 ml). The combined
organic layer washed with water and dried over Na2SO4, and the solvent
was evaporated under reduced pressure. The crude product was purified
by passing it through a small silica-gel bed to give the pure product.
Benzylation of N-Boc piperazine and homopiperazine (entries 1 and
3) proceeded expediously and delivered the N-alkylated product in excel-
lent yield, whereas the benzylation of N-methyl piperazine (entry 2) was
relatively slow. Next, we examined the 4-hydroxy-substituted piperazine
(entry 5), which also showed the enhanced rate of reaction. To further
determine the scope of this method, a range of secondary amines and
thiols were examined (see Table 1). Nitrogen selectivity over oxygen[12]
is further shown by examining the substrates with cyclic imide system.
For example, alkylation of pyrrolidinone (entry 6) and 5-phenyl pyridiza-
none (entry 7) gives a selectively N-alkylated product. Encouraged by
these results, we extended this protocol for the alkylation of thiols
(entries 9 and 10) and 2-mercapto benzothiazole (entry 11) with alkyl
halides, and S-alkylated products were obtained in excellent yield. The
present reaction conditions for the N-alkylation is compatible with Boc
and ester groups. As can be seen from Table 1, the method is applicable
for a variety of secondary amines and thiols and gives the desired
alkylated product in excellent yield.
Spectral Data for Selected Products
Compound 1a
1
Yellow solid; mp 62–63ꢁC; H NMR (300MHz, CDCl3) d (ppm) 1.45
(s, 9H), 2.36 (t, 4H, J ¼ 4.532 Hz); 3.3 (t, 4H, J ¼ 4.532 Hz) 3.47 (s, 2H),
7.2 (m, 5H); EIMS m=z 299 (M þ Na)þ, 185, 91, 77; IR (KBr) n ¼ 2972,
2942, 1685, 1427 cmꢂ1
.
Compound 5a
1
Liquid; H NMR (300 MHz, CDCl3) d (ppm) 2.4 (m, 4H), 2.85 (m, 4H),
3.55 (s, 2H), 7.2 (m, 9H); EIMS m=z 303 (M þ 1), 302 (Mþ), 224, 191,
175, 91, 77. IR (KBr) n ¼ 3382, 3030, 2927, 2817, 1486 cmꢂ1
.

2300
H. M. Meshram, B. C. Reddy, and P. R. Goud
Table 1. Triton B–mediated alkylationa of cyclic amines and thiols
Entry Amines=thiols
Alkyl halides
Time (h)b Products Yieldc (% )
1
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
3
3.5
3
1a
1b
1c
96
91
94
2
3
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
4
5
4
2a
2b
2c
89
84
85
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
2
2.5
2.5
3a
3b
3c
97
94
95
4
5
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
2
3
2
4a
4b
4c
95
91
93
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
1.5
2
1.5
5a
5b
5c
97
95
96
6
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
3
5
4
6a
6b
6c
92
87
85
7
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
5
5
4
7a
7b
7c
90
88
90
8
a) PhCH2Br
b) ClCH2COOCH3
c) n-Bu-Br
2
3
2.5
8a
8b
8c
93
96
94
9
a) PhCH2Br
b) ClCH2COOCH3
c) n-Bu-Br
1.5
2
2.5
9a
9b
9c
96
97
94
10
11
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
2
2.5
2.5
10a
10b
10c
97
95
94
a) PhCH2Br
b) CICH2COOEt
c) n-Bu-Br
2
2
3
11a
11b
11c
97
94
95
aAll the products exhibited physical and spectral (NMR, mass, IR) properties
in accordance with the assigned structure.
bAll reactions are carried out at rt only.
cIsolated yield.

Triton B–Mediated Alkylation
2301
Compound 5c
1
Yellow solid; mp 95–96ꢁC; H NMR (300 MHz, CDCl3) d (ppm) 0.9
(t, 3H, J ¼ 7.554 Hz), 1.2 (m, 2H), 1.5 (m, 2H), 2.2 (m, 4H), 2.4
(m, 4H), 2.8 (m, 2H), 7.2 (m, 2H), 7.4 (m, 2H); EIMS m=z 291
(M þ Na)þ, 157, 101, 76; IR (KBr) n ¼ 3371, 2960, 1450, 1393 cmꢂ1
.
Compound 7a
Yellow solid; mp 98–99ꢁC; 1HNMR (300 MHz, CDCl3) d (ppm) 5.3
(s, 2H), 7.2–7.5 (m, 11H), 7.85 (s, 1H); EIMS m=z 285 (M þ Na)þ, 185,
171, 91, 77; IR (KBr) n ¼ 2980, 1650, 1580, 1375.
Compound 8b
1
White solid; mp 147–148ꢁC; H NMR (300 MHz, CDCl3) d (ppm) 2.5
(s, 3H), 3.7 (s, 3H), 4.6 (s, 2H), 6.9–7.7 (m, 3H); EIMS m=z 272
(M þ Na)þ, 177, 135, 94; IR (KBr) n ¼ 3080, 2987, 2958, 1772, 1736,
1676, 1454 cmꢂ1
.
Compound 9b
1
Yellow liquid; H NMR (300 MHz, CDCl3) d (ppm) 3.59 (s, 2H), 3.7
(s, 3H), 7.2 (m, 5H); EIMS m=z 221 (M þ K)þ, 151, 109, 77, 59; IR
(KBr) n ¼ 3057, 3000, 2952, 1738, 1438, 1278.
Compound 11a
1
Semisolid; H NMR (300 MHz, CDCl3) d (ppm) 4.65 (s, 2H), 7.2–7.4
(m, 5H), 7.4–7.5 (m, 2H), 7.75 (m, 1H), 7.9 (m, 1H); EIMS m=z 257
(Mþ), 166, 91, 77. IR (KBr) n ¼ 3060, 3028, 1457, 1426 cmꢂ1
.
CONCLUSION
In conclusion, we have demonstrated a mild and efficient protocol for
the alkylation of cyclic secondary amines, imides, pyridazinones, and
thiols using Triton B as a base. The nonmetallic nature of the base and
solvent-free conditions make the procedure safe and green. Moreover,
the present method tolerates the presence of Boc and ester groups.

2302
H. M. Meshram, B. C. Reddy, and P. R. Goud
ACKNOWLEDGMENTS
B. C. K. R. and P. R. G. thank the Council of Scientific and Industrial
Research–University Grants Commission for the award of a fellowship
and Dr. J. S. Yadav, director, Indian Institute of Chemical Technology,
for his support and encouragement.
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