2,4,6-Trichloro-1,3,5-triazine/dimethylformamide as an efficient reagent for one-pot conversion of alcohols into N-alkylphthalimides

Article abstract of DOI:10.1016/j.cclet.2009.10.006

An efficient and mild method for the direct conversion of alcohols into N-alkylphthalimides using 2,4,6-trichloro-1,3,5-triazine and dimethylformamide was described. The reaction was preceded via (alcoxymethylene) dimethylammonium chloride intermediate an

Full text of DOI:10.1016/j.cclet.2009.10.006

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Chinese Chemical Letters 21 (2010) 171–174
www.elsevier.com/locate/cclet
2,4,6-Trichloro-1,3,5-triazine/dimethylformamide
as an efficient reagent for one-pot conversion of
alcohols into N-alkylphthalimides
*
Babak Mokhtari , Roya Azadi, Aseieh Azhdari
Department of Chemistry, College of Science, Shahid Chamran University, Ahvaz 61357-43337, Iran
Received 29 June 2009
Abstract
An efficient and mild method for the direct conversion of alcohols into N-alkylphthalimides using 2,4,6-trichloro-1,3,5-triazine
and dimethylformamide was described. The reaction was preceded via (alcoxymethylene) dimethylammonium chloride inter-
mediate and produced corresponding N-alkylphthalimides in good-to-excellent yields.
# 2009 Babak Mokhtari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Alcohol; Potassium phthalimide; 2,4,6-Trichloro-1,3,5-triazine; Dimethylformamide; N-alkylphthalimide
The development of new and more efficient synthetic procedure for widely used organic compounds is an important
challenge for synthetic organic chemists. In connection with this, introducing new chemical reagents or finding new
applications for well-known reagents is one of the prime interests. 2,4,6-Trichloro-1,3,5-triazine (TCT) or cyanuric
chloride is a versatile reagent in organic synthesis [1]. The use of TCT has been previously reported for wide variety of
reactions including conversion of carboxylic acids into its functional derivatives [2,3], reduction of carboxylic acids
[4], formylation of alcohols [5], conversion of alcohols into alkyl halides [6], deoxygenation of sulfoxides [7],
synthesis of a-diazoketones [8], b-lactams [9], Swern oxidation of alcohols [10], oxidative coupling of thiols to
disulfides [11], and ring enlargement of cyclic thioacetals [12].
N-Alkylphthalimides are important class of compounds which have been widely used as starting material in
synthetic [13], medicinal [14] and polymer chemistry [15]. Three general strategies have been developed for the
preparation of these compounds. At first, N-alkylphthalimides are prepared by the reaction of phthalimide or more
commonly its anion with alkyl halides or tosylates in the polar aprotic solvents such as DMF [16]. Based on this
general reaction, numerous modified procedures have been developed to prepare the N-alkylphthalimides, including
the use of phase-transfer catalysts [17], microwave irradiations [18] and ionic liquids [19]. In the second approach, the
reaction of primary amines with phthalic acid or phthalic anhydride is used for the synthesis of these alkylimides [20].
In the third synthetic route N-alkylphthalimides are prepared directly from alcohols using Mitsunobu reagent
* Corresponding author.
E-mail address: bmokhtari@scu.ac.ir (B. Mokhtari).
1001-8417/$ – see front matter # 2009 Babak Mokhtari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.10.006

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B. Mokhtari et al. / Chinese Chemical Letters 21 (2010) 171–174
Scheme 1.
(diethylazodicarboxylate/triphenylphosphine) [21] or (chloromethylene) dimethylammonium chloride (which in situ
generates by reaction of DMF with oxalyl chloride) [22].
Unlike the two former approaches, the third ones (direct preparation from alcohols) are scarce in the literature. In
addition, the reported methods suffer from use of the more expensive and explosive reagent such as
diethylazodicarboxylate (DEAD) or more toxic reagent such as oxalyl chloride. Therefore, introducing new method
to promote the conversion of alcohols into N-alkylphthalimides using inexpensive and safer reagent is desired.
In continuation of our previous studies on alkylation of heterocycles [23] and application of TCT in organic
transformation [24] we report here the successful use of TCT/DMF mixed reagent for one-pot conversion of alcohols
into corresponding N-alkylphthalimides (Scheme 1).
For achieving optimal reaction conditions, the reaction of benzyl alcohol with potassium phthalimide in the
presence of TCT/DMF was selected as a model reaction and the effects of the reaction parameters such as amount of
the nucleophile and temperature were studied in detail. In the first step, the effect of the nucleophile amount was
studied and the results showed for giving the best yields of N-benzylphthalimide the 5 equivalent of nucleophile
respect to alcohol are required. In addition, the effect of the temperature was also investigated. The results revealed
that the conversion of benzyl alcohol into N-benzylphthalimide was easily performed at 65 8C and this temperature
was applied for subsequent reactions.
It should be noted, thin layer chromatography of the model reaction showed that benzyl chloride was formed during
reaction course. Since this side product can be easily converted into N-benzylphthalimide under reaction condition, it
has no effect on the outcome of the reaction. Furthermore, the formation of the benzyl chloride can be prevented using
lithium fluoride.
Having optimized conditions in hand, we began to assess the scope and limitations of the reaction. As can be seen in
Table 1, potassium phthalimide was alkylated with a wide variety of primary and secondary alcohols.
As clear from Table 1, the primary and primary benzylic alcohols (entries 1–5, 7, and 8) were effectively converted
into corresponding alkylphthalimides in excellent yields. On the other hand, the yields of the N-alkylphthalimides
from the secondary alcohols (entries 6 and 9) were lower than primary ones.
In another attempt, this method was examined for the large scale preparation of N-alkylphthalimides. The results
for the preparation of N-benzylphthalimide from benzyl alcohol (20 mmol) as a model compound showed that this
method can be easily applied for the large scale synthesis of this compound.
Based on the previous report [6] and our finding, the following mechanism can be suggested for this conversion
(Scheme 2). At first, positively charged adduct (I) is formed from the reaction of TCT with DMF. This positively
charged adduct (I) interacts with alcohol and produces (III). This intermediate has two possible fates: it can combine
with a phthalimide anion nucleophile to produce corresponding N-alkylphthalimide. In addition, the chloride ion could
be attacked on the intermediate (III) to produce alkyl chloride. Under reaction conditions, the chloride can be
substituted by phthalimide ion. In the cases of tertiary alcohol, alkyl chloride was formed in the reaction mixture as a
major product that cannot be easily converted into alkylphthalimide under this reaction condition.
In summary, the present investigation has demonstrated that the use of TCT/DMF system offers an efficient and
mild method for the one-pot conversion of primary and secondary alcohols into N-alkylphthalimides.
1. General procedure for the synthesis of N-alkylphthalimide
Trichloro-1,3,5-triazine (0.183 g, 1.0 mmol) was added to DMF (0.2 mL), maintained at 25 8C. After the formation
of a white solid, the reaction was monitored by thin layer chromatography (TLC) until the complete disappearance of
TCT, and CH2Cl2 (10 mL) was added, followed by the alcohol (0.95 mmol) and potassium phthalimide (0.927,

B. Mokhtari et al. / Chinese Chemical Letters 21 (2010) 171–174
173
Table 1
Conversion of alcohols into N-alkylphthalimides with TCT/DMF at 65 8C.
Entry
1
Product
Time (h)
3
Yielda (%)
93
m.p.
Ref.b
[19]
114–116
2
2.5
96
102–103
[25]
3
4
5
6
5
87
91
83
69c
74–75
180–181
127–128
Oil
[25]
[25]
[20]
[26]
4
3.5
5
7
8
9
5
76
31–32
47–49
Oil
[19]
[27]
[27]
5.5
5.5
72
61c
a
Isolated pure products.
b
c
All the products are known compounds and were identified by comparison of their physical and spectral data with those of authentic samples.
Alkyl chloride was formed as a side product.
Scheme 2.
5 mmol in 10 mL DMF). Then, the mixture was stirred at 65 8C and monitored (TLC) until completion of the reaction
(2.5–5.5 h). The organic layer was washed with water (3Â 10 mL), and dried over anhydrous Na2SO4. After
evaporation of the solvent the product was further purified by flash column chromatography using ethyl acetate/n-
hexane (1/10) as the eluent.
Acknowledgment
We thank Shahid Chamran University Research Council, Ahvaz, for financial support of this investigation (No. 87).

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B. Mokhtari et al. / Chinese Chemical Letters 21 (2010) 171–174
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