J. L. Romera et al. / Tetrahedron Letters 45 (2004) 8797–8800
8799
Table 3. Potassium iodide catalysed microwave assisted N-alkylation
of N-alkylaniline derivatives 5a
N-Alkylation of substituted anilines was also examined.
N-(2-Chloroethyl)morpholine (2a) was chosen as the
model alkylating agent. The results are summarised in
Table 4. Electron rich anilines (Table 4, entries 1–3)
were easily alkylated under our standard reaction
conditions (lW, 110°C, 10min). The reaction with
para-hydroxyaniline was chemoselective leading to the
corresponding N-alkyl derivative in good yield (Table 4,
entry 3). The N-alkylation of electron poor anilines
required higher temperatures (170°C) to achieve high
yields (Table 4, entries 4–9). When the reaction was
performed with ortho-nitroaniline (7g) the reaction
mixture needed to be heated at 190°C, probably due
to the steric hindrance caused by the ortho-substituent.
R
N
H
N
R
KI (0.1 eq.), CH3CN
N
+
2a
O
110ºC, 10 min, µW
5a-c
6a-c
Entry
5
6, Yieldb (%)
H
N
R
H
N
1
5a
95
H
N
2
3
5b
5c
90
92
In summary, we have developed a general and efficient
metal-free method for the N-alkylation of anilines under
microwave irradiation.21,22 Studies on the scope and
limitations of this methodology are undergoing and will
be reported in due course.
H
N
a The reactions were done on a 1mmol scale.
b Yield of isolated products 6 based on the alkylating agent 2a.
Supplementary data
ternisation by-products.16 The first results obtained are
shown in Table 3.
Supplementary data associated with this article can be
Table 4. N-Alkylation of substituted anilines (7) with N-(2-chloro-
ethyl)morpholine (2a) under microwave conditionsa
References and notes
H
NH2
N
1. Suwanprasop, S.; Nhujak, T.; Roengsumran, S.; Petsom,
A. Ind. Eng. Chem. Res. 2004, 43, 4973.
2. (a) Stauffer, S. R.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
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K.; Yoon, J. J. Org. Chem. 2002, 67, 2348.
KI (0.1 eq.), CH3CN
N
2a
+
O
T , 10 min, µW
R
R
8a-i
7a-i (3 eq.)
8, Yieldb (%)
NH2
Entry
7
T (°C)
3. Montgomery, J. H. Agrochemicals Desk Reference: Envi-
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R
4. Negwer, M. Organic-chemical drugs and their synonyms
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A.; Hamelin, J.; Texier-Boullet, F.; Jacquault, P.; Mathe,
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14. Jiang, Y.-L.; Hu, Y.-Q.; Feng, S.-Q.; Wu, J.-S.; Wu,
Z.-W.; Yuan, Y.-C. Synth. Commun. 1996, 26, 161.
NH2
1
2
7a
7b
110
110
92
70
MeO
NH2
Me2N
NH2
3
7c
110
90
HO
NH2
4
5
6
7d
7e
7f
170
170
170
95
67
98
F
NH2
O2N
NH2
MeO2C
NH2
7
7g
190
84
NO2
F3C
NH2
8
9
7h
7i
170
170
89
90
NH2
N
a The reactions were done on a 1mmol scale.
b Yield of isolated products 8 based on the alkylating agent 2a.