Mechanochemical N-alkylation of imides

Article abstract of DOI:10.3762/bjoc.13.169

The mechanochemical N-alkylation of imide derivatives was studied. Reactions under solvent-free conditions in a ball mill gave good yields and could be put in place of the classical solution conditions. The method is general and can be applied to various imides and alkyl halides. Phthalimides prepared under ball milling conditions were used in a mechanochemical Gabriel synthesis of amines by their reaction with 1,2-diaminoethane.

Full text of DOI:10.3762/bjoc.13.169

Mechanochemical N-alkylation of imides
Anamarija Briš, Mateja Đud and Davor Margetić*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Laboratory for Physical-organic Chemistry, Division of Organic
Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička c.
54, 10000 Zagreb, Croatia
doi:10.3762/bjoc.13.169
Received: 03 May 2017
Accepted: 04 August 2017
Published: 22 August 2017
Email:
Davor Margetić* - margetid@irb.hr
This article is part of the Thematic Series "Mechanochemistry".
Guest Editor: J. G. Hernández
* Corresponding author
§ Fax: +385-1-456-1008
Keywords:
© 2017 Briš et al.; licensee Beilstein-Institut.
License and terms: see end of document.
ball milling; Gabriel reaction; imides; mechanochemistry; N-alkylation
Abstract
The mechanochemical N-alkylation of imide derivatives was studied. Reactions under solvent-free conditions in a ball mill gave
good yields and could be put in place of the classical solution conditions. The method is general and can be applied to various
imides and alkyl halides. Phthalimides prepared under ball milling conditions were used in a mechanochemical Gabriel synthesis of
amines by their reaction with 1,2-diaminoethane.
Introduction
The development of environmentally friendly organic reactions alkylation reactions [23] were reported in the literature. The aim
is a growing area of interest [1]. The reduction of the impact of of this study was to establish simple and effective imide alkyl-
chemical reactions on the environment could be achieved by the ation mechanochemical protocols. Imides are usually alkylated
minimization of waste produced in the process, the employ- with alkyl halides in solution (DMF, acetone, DMSO) and the
ment of the more efficient reagents and catalysts and by the ap- reactions were heated for several hours in the presence of a base
plication of microwave [2], photochemical [3] or high pressure [24].
conditions [4], thus reducing reaction time and energy
consumption. In recent time, important progress was made in Results and Discussion
the development of various solvent-free organic reactions [5], The reaction of the norbornene endo-succinimide 1 [25] with
especially by the use of the ball milling technique [6-8]. In 1,3-dibromopropane (2) was used as a model system for the op-
continuation of our interest in eco-friendly organic syntheses timization of the reaction conditions [26]. Here, imide 1 is a
[9-14], we studied mechanochemical N-alkylation reactions of solid, while dibromopropane is a liquid reagent. It was found
imides with alkyl halogenides, and the results are presented in that during the ball-milling process (Retsch MM400 mill at
this paper. Until now, ball milling N-alkylations of ureas [15], 30 Hz, stainless steel 10 mL vial, one 12 mm steel ball) of this
hydrazones [16], imines [17,18], pyridines [19], pyrimidines solid/liquid system, mono-alkylation and formation of imide 3
[20], imidazoles [21], secondary amines [22], as well as allylic was accompanied by the bisalkylated product 4 (Scheme 1).
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Scheme 1: N-Alkylation of imide 1 with 1,3-dibromopropane (2) in a ball mill.
To optimize the reaction conditions, the molar ratio of reagents, trolled by variation of molar ratios of reagents. When 0.3 equiv-
the reaction time and bases were varied. The addition of a small alents of dibromide 2 were used, bisalkylation was the sole
amount of solvent for LAG (liquid-assisted grinding) [27] was reaction and imide 4 was isolated in 52% yield (Table 1,
tested as well. The results are collected in Table 1. The best entry 5). Other inorganic and organic bases employed were less
results were achieved by the use of K2CO3 as base, with large reactive than K2CO3, whereas Cs2CO3 showed a higher reactiv-
excess of dibromide and carbonate. Within one hour of milling, ity, which, due to the inevitable formation of 4, prevented clean
1 was quantitatively converted to the mono-alkylated product 3 mono-alkylation.
which was and isolated in 88% yield by simple work-up
consisting of dissolving the reaction mixture in dichloro- The optimized reaction conditions were used to establish the
methane and washing with water (Table 1, entry 8). Under these scope of this reaction. Firstly, other alkyl halides were em-
milling conditions, an excess of inorganic base may have helped ployed (Scheme 2). These experiments revealed that the sol-
by acting as a grinding auxiliary. A comparison with the synthe- vent-free N-alkylation could be effectively carried out with dif-
sis carried out in solution (acetone, 60 °C) showed a significant ferent alkyl halides, however, the conditions had to be opti-
reduction in time (Table 1, entry 11). Also less efficient was the mized for each substrate. In particular, reactions carried out by a
use of acetone under LAG conditions (Table 1, entry 9). It was one-pot, two-step process [28] of 1 with K2CO3 (producing in
found that the outcome of the reaction could be efficiently con- situ the potassium imide salt), followed by the addition of the
Table 1: N-Alkylation of imide 1 with 2.a
Entry
Base
Ratio 1:2:base
Time [h]
Ratio 1:3:4
Yield [%]b
1
2
K2CO3
1:1:5
0.5
1
68:28:4
0:82:18
0:80:20
0:45:55
43:0:57
0:93:7
1:1:5
3
1:1:5
2
4
1:0.5:5
1:0.3:5
1:3:5
2
5
2
4; 52
3; 88
6
1
7
1:3:5
1c
1
14:83:3
0:100:0
16:65:19
0:0:100
0:100:0
8
1:12:5
1:3:5
9
1d
24d
24e
1 + 1f
2
10
11
12
13
14
15
16
17
18
1:3:5
4; >95
3; >95
1:20:5
1:2:2
3; 54, 4; 6
Na2CO3
Cs2CO3
Cs2CO3
NaHCO3
DBU
1:12:5
1:12:5
1:12:3
1:1:5
89:11:0
0:97:3
2
1
0:97:3
1
48:38:12
24:58:18
35:61:14
1:1:5
1
DMAP
1:1:5
1
aRetsch MM400 ball mill, 10 mL stainless steel vial, 1 × 12 mm stainless steel ball, 30 Hz; bisolated yields, ratio determined by 1H NMR spectroscopy;
c2 × 6 mm balls; dLAG acetone (η = 0.25 μL mg−1); eacetone, 60 °C; fmilling of 1 with K2CO3 for 1 h, followed by the addition of 2 and LAG DMF
(η = 2 μL mg−1) and ball milling for another 1 h.
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Scheme 2: Mechanochemical N-alkylation of imide 1.
halide and further milling in conjunction with LAG (DMF) vent, either by shorter reaction time, less vigorous conditions or
proved useful. Ball milling of 1 with alkyl halides afforded after better yields. Another advantage of solvent-free conditions is
2 h the corresponding N-alkylated products in high yields, with the circumvention of the problematic low solubility of some of
exception of butyl chloride (Table 2, entry 4). The sequential the substrates employed. By conducting the reaction in a ball
milling procedure is advantageous in terms of the use of smaller mill, solubility problems and the issues associated with the
amounts of reagents and a significant reduction of the reaction selection of the most suitable solvent could be avoided. In addi-
time was achieved in comparison with the reaction in DMF. In tion, solid-state reaction diminishes the heterogeneous char-
contrast to the milling of imide 1 with 1,3-dibromopropane (2), acter of alkylation, since inorganic bases in general are not
the reaction with 1,2-dichloroethane gave products 9 and 10, soluble in organic solvents.
where bis-product 10 was the major, despite of large excess of
reagent (Table 2, entry 9). The physical state of the halide Ex situ IR spectroscopy (ATR) of milling of imides 11–17 with
reagents (either liquid or solid alkyl halides) did not influence K2CO3 was used for monitoring the reaction progress, which
the reaction outcome (see Supporting Information File 1, showed for instance, that potassium phthalimide [29] was
Table S1).
formed after one hour of grinding (Figure 2). This salt was,
without isolation, subjected to further milling with benzyl bro-
Further alkylation experiments were carried out with mide with LAG (DMF) to obtain alkylated products in high
selected imides 11–17 (Figure 1, Table 3). The sequential yields. Formation of potassium salts of other imides listed in
mechanochemical alkylation was found to be often advanta- Table 3 by K2CO3 has been also proven by ex situ IR monitor-
geous over the reaction carried out by standard procedure in sol- ing (see Supporting Information File 1). It indicates that potas-
Table 2: Mechanochemical N-alkylation of imide 1.
Entry
Halide
EtBr
Product
Ratio 1:RX:K2CO3
Time, conditions
Ratio 1:producta
Yield [%]b
1
2
3
4
5
6
7
8
5
5
5
6
7
8
8
1:10:5
1:2:2
1:10:5
1:6:2
1:2:2
1:1:5
1:2:4
2 h
0:100
>95
87
1 + 1 hc
2 h
EtI
10:90
97:3
BuCl
BnBr
1 + 1 hc
1 + 1 hc
2 h
81
65:35
1 + 1 hc
63
59
8
1:1:5
72 hd
2 h
9
ClCH2CH2Cl
9,10
1:12:5
51:6:43
aRatio determined by 1H NMR spectroscopy; bisolated yields; cmilling of 1 with K2CO3 for 1 h, followed by the addition of RX and LAG (DMF,
η = 2 μL mg−1) and ball milling for another 1 h; dDMF, 50 °C, 3d.
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Figure 1: Products of alkylation of imides 11–17.
Table 3: Mechanochemical N-alkylation of imides 11–17.a
Entry
Substrate
Bromide
Ratio imide:RX:K2CO3
Product, yield [%]b
1
2
2
BnBr
1:2:4
1:2:2
18, 73
19, 98
11
12
3
4
EtBr
1:2:2
1:2:2
22, 75
23, 97
BnBr
5
1:2:2
24, 94
6
7
8
9
1:2:2
1:2:2
1:2:2
1:2:2
25, 95
26, 90
27, 98
28, 32; 29, 4
10
BnBr
1:2:2
20, 89
13
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Table 3: Mechanochemical N-alkylation of imides 11–17.a (continued)
11
12
BnBr
BnBr
1:2:2
1:4:4
21, 67
30, 93
14
15
13
BnBr
BnBr
1:4:4
31, 99
16
14
15
1:2:2
1:1:2
32, 98
32, 37; 33, 17
17
aMilling of imides with K2CO3 for 1 h, followed by the addition of RX and LAG (DMF, η = 2 μL mg−1) and ball milling for another 1 h; bisolated yields.
Figure 2: Ex situ IR spectroscopy of the reaction of 12 and benzyl bromide in the ball mill: a) phthalimide 12; b) first step: phthalimide + K2CO3,
1 h milling; c) second step: addition of benzyl bromide, LAG DMF and further 1 h milling.
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
sium carbonate is capable of the deprotonation of the imides azine (36). The required substrate 36 was prepared by
with pKa values at least within the range of 8.3–9.9 units [30] mechanochemical condensation [35] of alloxane (34) and 4,5-
under ball milling conditions.
dimethyl-1,2-phenylenediamine (35) in the presence of p-tolu-
enesulfonic acid [36,37] (Scheme 3). The α-dione/α-diamine
Deprotonation of phthalimide in solution is usually carried out reaction proceeds in a similar manner and yield to the condensa-
with the use of bases stronger than K2CO3 [31] and this differ- tion reaction carried out under classical reaction conditions
ence in reactivity in comparison to solvent free conditions has a (1 M HCl, 60 °C, 30 min) [38]. Mechanochemical one-pot, two-
precedence in the application of weaker base in mechanochem- step solid-state N-alkylation of 36 with benzyl bromide yielded
ical synthesis of triphenylphosphoranes [32]. Often DMF is 1,3-dibenzylalloxazine 39 in quantitative yield, whereas the
used as solvent in imide alkylation reactions, which promotes reaction of 36 with less reactive ethyl bromide (four equiva-
SN2 reactions [33] and its low volatility is advantageous over lents) under LAG conditions afforded bis- and mono-alkylated
more environmentally friendly solvents which might be consid- products 37 and 38 (in 62% overall yield), with 1,3-diethyl-
ered for LAG in mechanosynthesis.
alloxazine 37 as the major component (4:1 ratio). A change of
the stoichiometry of reagents by milling with an equimolar
A comparison of results with literature values demonstrates the amount of ethyl bromide resulted in the dominant formation of
benefits of mechanosynthesis. For instance, alkylation of theo- the mono-alkylated 1-ethyl product 38.
bromine (14) [34] in a microwave reactor in solution gives two
side-products, an O-alkylated and a uracil ring-opened product The N-alkylated phthalimides 23 and 24, which were prepared
(induced by base). The reaction selectivity is highly influenced in the previous section were employed in solvent-free Gabriel
by the solvent. The formation of the ring-opened product could synthesis of primary amines (Scheme 4). In these milling reac-
be fully suppressed under mechanochemical conditions, due to tions, the hazardous hydrazine hydrate was replaced by 1,2-
the mild conditions and the absence of solvent. An additional diaminoethane [39] and conversion to the corresponding
advantage of the solvent-free milling procedure is that there is benzylamines was quantitative within 1 h. As a proof of concept
no need for tetrabutylammonium iodide as phase-transfer cata- of reaction, p-methylbenzylamine was isolated in 41% yield in
lyst to increase the limited solubility of 14.
the form of acetamide 42. In this way, a three-step, two-pot
(A and B, Scheme 5) Gabriel synthesis of amines was carried
The selectivity was observed for certain substrates. For out in a ball mill. The synthetically desired development of a
example, the alkylation of phthalimide 12 with 1,4-bis(bromo- three-step, one-pot mechanochemical Gabriel synthesis of
methyl)benzene led to the formation of two products, namely 28 amines could not be accomplished, as the complex reaction
and 29. By keeping the ratio of the alkyl halide reagent at two mixtures containing considerable amounts of various side prod-
equivalents, ball milling afforded mainly the targeted mono- ucts such as bisamide 43.
alkylated product 28 (Table 3, entry 9). The regioselectivity of
substrates with two nitrogen-sites available for alkylation could Computational section
be also controlled by reagent ratio or choice of the alkyl halide. To elucidate reasons for the observed regioselectivities, the
For instance in the reaction of uracil (17) or 7,8-dimethylallox- reactions of uracil and 7,8-dimethylalloxazine with benzyl-
Scheme 3: Mechanosynthesis of 7,8-dimethylalloxazine (36) and its N-alkylation.
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Beilstein J. Org. Chem. 2017, 13, 1745–1752.
Scheme 4: Gabriel synthesis of amines in ball mill.
Scheme 5: Three-step, two-pot Gabriel synthesis of amines in ball mill.
amine and ethyl bromide were studied by DFT calculations Acknowledgements
using the B3LYP/6-311+G**//B3LYP/6-31G*+ZPVE method. This work is financially supported by the Ministry of science,
The transition-state calculations of the SN2 reaction of imides education and sport of the Republic of Croatia (project No. 098-
and bromides were used to determine the activation energies. It 0982933-3218) and the Croatian Science Foundation (grant no.
was found that for benzyl and ethyl bromides the activation 9310). We also thank to Dr. Vjekoslav Štrukil for valuable
energy differences are 2–3 kcal mol−1 in favor of the N1 posi- discussions and suggestions.
tions in uracil and 7,8-dimethylalloxazine. These calculations
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