Selective N-alkylation of arylamines with alkyl chloride in ionic liquids: Scope and applications

Article abstract of DOI:10.1002/ejoc.201200202

An efficient N-selective alkylation of primary aromatic amines in molten quaternary ammonium salts, as the solvent, under relatively mild and base-free conditions is presented. On the basis of the Kamlet-Taft parameters and the nucleophilicity of the IL (ionic liquid) anions, the influence of the ionic liquid was evaluated. This protocol was validated on a larger multigram scale and with the syntheses of bioactive heterocycles (e.g., 1,4-benzothiazine and quinoxalines) and new efficient MALDI matrixes. Copyright

Full text of DOI:10.1002/ejoc.201200202

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201200202
Selective N-Alkylation of Arylamines with Alkyl Chloride in Ionic Liquids:
Scope and Applications
Antonio Monopoli,*[a] Pietro Cotugno,[a] Marina Cortese,[a] Cosima Damiana Calvano,[a]
Francesco Ciminale,[a] and Angelo Nacci*[a,b]
Keywords: Synthetic methods / Ionic liquids / Alkylation / Amines / Heterocycles
An efficient N-selective alkylation of primary aromatic
amines in molten quaternary ammonium salts, as the solvent,
under relatively mild and base-free conditions is presented.
On the basis of the Kamlet–Taft parameters and the nucleo-
philicity of the IL (ionic liquid) anions, the influence of the
ionic liquid was evaluated. This protocol was validated on a
larger multigram scale and with the syntheses of bioactive
heterocycles (e.g., 1,4-benzothiazine and quinoxalines) and
new efficient MALDI matrixes.
low turnover numbers and frequencies (TON and TOF),
prolonged reaction times, and the use of excess amounts of
alcohols and amines to achieve high yields. As a conse-
quence, the direct monoalkylation of anilines is still consid-
ered a competitive method for the selective synthesis of sec-
ondary aromatic amines. In this context, efforts have been
made to prevent overalkylation problems, and for this pur-
pose, additives such as surfactants,[10] halides salts,[11] metal
oxides,[9g] zeolites,[12a] cesium bases,[12b] and Celite[12c] have
been successful employed.
Introduction
N-Alkylated aromatic amines and their derivatives pos-
sess useful biological activities and exhibit extensive appli-
cations in the pharmaceutical, agrochemical, and optoelec-
tronic fields.[1] Secondary aromatic amines play a key role
as antioxidants in petrochemicals and as intermediates in
the manufacturing of dyes, rubbers, and polymers.[2] Re-
cently, it was found that many aromatic amines have impor-
tant applications in analytical chemistry as matrixes in
MALDI-TOF mass spectrometry.[3]
Despite these numerous and well-established methods,
anilines possessing strong electron-withdrawing groups
(e.g., p-NO2) are often reluctant to undergo alkylation, even
in the presence of strong bases (e.g., KOH).[10b] In addition,
the alkyl bromides and alkyl iodides are largely used as alk-
ylating agents, whereas the less expensive and more com-
mercially available alkyl chlorides are generally unreactive,
with the exception of a few activated (benzyl and allyl) sub-
strates. As a consequence, no examples of successful meth-
ods involving electron-poor aniline (e.g., p-NO2) and alkyl
chloride (e.g., n-butyl chloride) have been reported until
now.
Traditional environmentally unfriendly reaction media
(VOC = volatile organic compounds) are commonly used
in these processes, but in some cases, both greener solvents
and more eco-compatible conditions, such as water [under
PTC (phase-transfer catalytic) conditions],[10c,13] lipase/eth-
anol medium, and deep eutectic solvents,[14] have been used
in experiments. In this context, little attention has been paid
to ionic liquids (IL).[15]
Traditionally, these compounds can be prepared in liquid
phase by the nucleophilic displacement between anilines
and alkyl halides[4] or tosylates in the presence of stoichio-
metric amounts of carbonates or hydroxides as bases.[5]
However, this procedure is limited by its poor selectivity
due to the formation of N,N-dialkylated products and qua-
ternary ammonium salts, even with limited amounts of the
alkylating agent. Catalytic methods have also been pro-
posed on the basis of several processes like reductive amin-
ation,[6] alcohol condensation,[7] and transalkylations of ter-
tiary amines.[8] Most of these involve supported catalysts,[9]
but some procedures operate under homogeneous condi-
tions. Although these methods are quite feasible, many of
them suffer from a number of restrictions like the need for
expensive metals,[7c,9c] toxic ligands, and microwave irradia-
tion.[9a] Further drawbacks are a limited substrate scope,
[a] Department of Chemistry, University of Bari “Aldo Moro”,
Via Orabona, 4, 70126 Bari, Italy
Fax: +39-080-5442129
E-mail: antomono@libero.it
IL are often suggested as ideal substitutes for VOCs in
several organic transformations.[16] In this context, through-
out our efforts in developing clean organic syntheses, we
were already drawn to the enhanced reactivity exhibited by
certain anionic nucleophiles in tetraalkylammonium- and
nacci@chimica.uniba.it
[b] CNR – ICCOM, Department of Chemistry, University of Bari
Aldo Moro,
Via Orabona, 4, 70126 Bari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200202.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
A. Monopoli, A. Nacci et al.
FULL PAPER
alkylpyridinium-based ionic liquids, in which very weak Table 1. Solvent optimization in the selective N-alkylation of 1.[a]
electrostatic interactions with the bulky cation moiety
would conceivably make an anion behave as a “naked nu-
cleophile”. Exploiting this effect, we could develop in these
neoteric solvents a series of cascade reactions capable of
creating complex structures like spirocyclopropanes[17a] and
Run Solvent
T [°C] Conv. [%][b]
Product ratio [%][c]
dihydrofurans[17b] or lead to cyclic carbonates through an
easy epoxide ring opening followed by carbonation of the
resulting alkoxide anions.[17c]
2
3
1
2
CH3CN
DMA
90
90
90
90
90
90
90
60
60
60
60
60
60
90
90
90
90
90
90
90
–
7
22
10
–
–
100
100
100
–
–
–
–
–
–
As a result of our success with these IL, we are interested
in exploiting their promoting effects on the nucleophilic dis-
placements involving aromatic amines. Stimulated by the
improvement in the eco-compatibility of this reaction and
by the activation of unreactive electron-poor anilines and
chlorides, that are still challenging topics for this process,
we report here the first example of a base-free direct N-
selective alkylation of aromatic amines in molten tetraalk-
ylammonium salts (IL) as the reaction medium.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
DMSO
[Bupy]PF6
[Bmim]BF4
[Bmim]PF6
TBABF4
[Bupy]Br
[Bmim]Cl
[Bmim]Br
[Bmim]I
TBACl
–
–
–
16
50
59
59
60
48
72
99
70
97
62
80
95
60
100
94
98
94
80
99
91
64
88
78
71
88
79
87
–
6
2
6
20
1
9
36
12
22
29
12
21
13
TBABr
[Bupy]Br
[Bmim]Cl
[Bmim]Br
[Bmim]I
TBACl
Results and Discussion
First, we focused our attention on the choice of the ionic
liquid. To this end, we investigated some representative ex-
TBABr
amples among the main classes of IL, namely tetrabutylam- 20
monium- (TBA), butylpyridinium- [Bupy], and butylmeth-
ylimidazolium- [Bmim] based IL, and evaluated their ability
to promote the model selective N-alkylation of aniline with
butyl chloride.
TBAI
[a] General conditions: IL (0.5 g), aniline (1, 0.5 mmol), BuCl
(0.5 mmol), stirred at 60–90 °C, 3 h. [b] Conversions of aniline into
both 2 and 3 were evaluated by GLC and H NMR spectroscopy.
[c] Ratios evaluated on the basis of the GLC peak areas of all the
products detected.
1
Preliminary calibration experiments were conducted on
0.5 mmol of aniline, which was added to a solution of an
equimolar amount of BuCl in 0.5 g of IL without the base.
The reaction mixture was stirred and heated at 60–90 °C
for 3 h. The progress of this reaction was typically revealed
by an increase in the turbidity due to the formation of N-
substituted anilinium salts, which are partially insoluble in
ried out at 90 °C, the data reveal that the type of IL anion
affects, in some way, the coupling efficiency in the following
–
–
order: Br– Ͼ Cl– Ͼ I– ϾϾ BF4 ≈ PF6 . Indeed, ionic li-
–
–
quids containing the ions BF4 or PF6 were inefficient in
promoting the alkylation with chlorobutane (Table 1,
Runs 4–7),[15b] whereas those containing halides ions gave
moderate to good results, with bromides resulting in a more
effective conversion than the corresponding chloride and,
in sequence, iodide ionic liquid (Table 1, Runs 15–20).
The better performance of IL containing a halide as the
anion seems roughly in line with the Hughes–Ingold
rules.[18] These were extensively applied in a recent review
by Welton[16a] in a discussion about the solvent effect of
ionic solvents on a variety of reactions, including the N-
alkylation of aliphatic amines in IL that do not contain
halides.[19] In this connection, ionic solvent anions (Y– in
Figure 1) would contribute to the stabilization of the acti-
vated complex by virtue of their ability to accept a hydrogen
bond from the incipient anilinium ion. Thus, the observed
1
the IL. The reactions were monitored by H NMR spec-
troscopy and GC–MS by the addition of an aqueous solu-
tion of NaHCO3 to the reaction mixtures and then the ex-
traction of the N-alkylation products with ethyl ether. The
analyses of the reaction mixture after prolonged times (after
3 h) did not show any appreciable variations in the product
distributions.
The representative results of our preliminary screening
are reported in Table 1. This shows that reactions carried
out in polar molecular solvents, commonly used in nucleo-
philic substitutions, were unproductive (Table 1, Runs 1–3).
On the contrary, most of the investigated ionic liquids pro-
moted the N-alkylation with conversions and selectivities
depending on the reaction conditions and the specific IL
(Table 1, Runs 4–20).
The reaction temperature affected the coupling in a pre-
dictable manner, that is, reactions at a lower temperature
(60 °C) were less productive but more selective in all the IL
investigated (Table 1, Runs 8–13 and 14–20). It is note-
worthy that heating above 90 °C did not result in a further
increase in conversions.
Concerning the ionic liquid, we found that the nature of
Figure 1. Hydrogen-bonding stabilization of the activated complex
the anion played the predominant role. For reactions car- by the ionic liquids anions.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
Selective N-Alkylation of Arylamines
order of reactivity based on the solvent anions, Br–, Cl– ϾϾ (times and temperatures) were varied depending on the sub-
–
–
BF4 , PF6 , would simply reflect the higher value of the strate to maximize the monoalkylation process (Table 2).
hydrogen bond basicity (β)[20] of Br– and Cl– with respect
to BF4 and PF6 .
As found previously with aniline and also with other aro-
matic amines, the increase in selectivity observed at lower
–
–
However, a closer inspection of the β values for all the temperatures was generally associated to lower conversions.
employed IL anions would point to an overall reactivity in Nevertheless, aniline and BuCl were coupled in TBABr, re-
–
the order of Cl– (β = 1.00) Ͼ Br– (β = 0.67) ϾϾ BF4 (β = sulting in discrete conversion (72%) and good selectivity
–
0.37) ≈ I– (β = 0.30) Ͼ PF6 (β = 0.21). This appears dif- (91%) at 60 °C (Table 2, Run 2). With activated alkylating
ferent from the observed order of reactivity (Br– Ͼ Cl– Ͼ agents such as benzyl (Bn) and allyl chloride or butyl brom-
–
–
I– ϾϾ BF4 ≈ PF6 ).
ide, milder reaction conditions were successfully applied (T
It is interesting that for all of the alkylations performed = 45 °C, Table 2, Runs 3, 4, and 6). At variance with this,
in IL with the Br– and I– anions, the GC–MS analyses re- the less reactive 2-chloropentane was converted only for
vealed the intermediate formation of bromobutane and 47% even at 90 °C (Table 2, Run 5).
iodobutane. Control reactions carried out under the same
As expected, the presence of electron-withdrawing
N-alkylation conditions, but in the absence of aniline, con- groups on the aromatic ring of the starting material re-
firmed that BuCl in TBABr, [Bmim]Br, and [Bmim]I under- quired harsh conditions or prolonged reaction times. How-
went a reversible nucleophilic exchange of chloride for the ever, with this protocol, we successfully coupled the less re-
halide anion of the ionic solvent, affording BuBr or BuI. active p-nitroaniline with chlorobutane at 110 °C with a
GC–MS revealed the equilibrium conversions for BuBr, conversion of 82% and a selectivity of 98% (Table 2,
33% in TBABr and 25% in [Bmim]Br, and for BuI, 75% in Run 9). Of course, the same electron-poor aniline reacted
[Bmim]I.
smoothly with the more activated alkyl chlorides and BuBr
In view of such halide exchange reactions, it is possible at 90 °C (Table 2, Runs 7–13).
to complement the explanation of solvent performance to
Gradually, milder conditions were applied to the more
resolve the apparent anomaly concerning TBABr, [Bmim]- activated substrates such as 4-fluoro-, 4-bromo-, and 4-
Br, and [Bmim]I. In all of these solvents, our N-alkylations iodoaniline (Table 2, Runs 14–20), and even for 4-bromo-
proceeded better than expectations based on the hydrogen- naphthalen-1-amine (Table 2, Runs 21 and 22). These sub-
bonding basicity, β, of Br– and I–. Indeed, this enhanced strates afforded products with high selectivities and conver-
reactivity reflects the nucleofugality scale of halides in nu- sions that were dependent on the alkylating agents. Interest-
cleophilic substitutions, I– Ͼ Br– Ͼ Cl–. Therefore, one ingly, in the case of the bromonaphthylamine in TBACl at
might conclude that the halide exchange reactions resulted 90 °C, the bromine atom on the ring was replaced by chlo-
in an increase in the N-alkylation rate in these solvents, as a rine, and thus, N-butyl-4-chloronaphthalen-1-amine (2o)
consequence of the increasing nucleofugality of the leaving was the sole product observed (Table 2, Run 22). This reac-
group on the alkylating agent, changing from the poor tion, which looks like a nucleophilic substitution reaction
BuCl to more reactive BuBr or BuI.
on an aromatic substrate bearing a NH2 deactivating group,
IL cations had only a slight influence on the alkylation. finds precedents in some reactions of halonaphthols with
Among them, butylpyridinium IL proved to be less efficient nucleophiles.[21]
in terms of selectivity (Table 1, Run 14) and were excluded
By analogy with those reactions, our result can be de-
from the screening. Of the remaining two cations, the tetra- scribed as a nucleophilic displacement by the IL chloride
butylammonium cation promoted the coupling slightly anion, not on the deactivated 4-bromonaphthalen-1-amine,
better than the imidazolium cation, and this result was but on its imine tautomer (Scheme 1), with which an SN2
more evident with the chloride salts (Table 1, Runs 15 and mechanism might be compatible. According to this hypoth-
18).
esis, we found that 4-bromo-N,N-dibutylnaphthalen-1-
This different behavior can be attributed to the decrease amine, devoid of the hydrogen atoms essential for tauto-
in the reaction rate because of the hydrogen bonding be- merization, did not exchange the bromide for the chloride
tween the solvent and the aniline nucleophile. This stabilizes anion in TBACl under comparable conditions.
it with respect to the activated complex, which is a weaker
hydrogen-bond acceptor than the nucleophile itself.[16b] On
the basis of this, the better hydrogen-bonding donor prop-
erties of the [Bmim] cation compared to the TBA cation,
because of the slight acidity at its C-2 position, can account
for the better promoting ability of the tetrabutylammo-
nium-based IL.
Scheme 1. Tautomeric equilibrium generating the imine species of
4-bromonaphthalen-1-amine.
With these considerations in mind, choosing either
TBABr or TBACl as the reaction medium, we decided to
With this protocol, even sterically demanding substrates
explore the scope and limitations of this method extending provided moderate to good couplings (Table 2, Runs 26–
it to a plethora of anilines and alkyl chlorides. On the basis 32), with the exception of o-bromoaniline which gave poor
of the preliminary results (Table 1), and giving advantage results when treated with chlorobutane (Table 2, Runs 23–
to the selectivities over the yields, the reaction conditions 25).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
A. Monopoli, A. Nacci et al.
FULL PAPER
Table 2. N-alkylation of anilines in tetraalkylammonium-based ionic liquids.[a]
[a] General conditions: alkylating chloride (0.5 mmol), aromatic amine (0.5 mmol), TBABr (0.5 g) or TBACl (0.5 g). [b] Conversion deter-
mined by 1H NMR and GLC. The remaining product was identified as unreacted aromatic amine. [c] Percentage of monoalkylated amine
2a–u with respect to the dialkylated one as determined by 1H NMR and GLC. [d] N-butyl-4-chloronaphthalen-1-amine was the sole
isolated product.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
Selective N-Alkylation of Arylamines
To validate this method, we performed a multigram-scale had recently been used as a matrix in MALDI mass spec-
experiment. To this end, aniline (3.72 g, 40 mmol) was trometry for the detection of lipids.[3a] A severe limitation
treated with an equimolar amount of chlorobutane in in the use of 9-AA is its high polarity, which imposes the
molten TBACl (20 g). We were favorably surprised to find need for alcoholic co-solvents to dissolve the matrix and
that the reaction occurred at a milder temperature on a allow for a good co-crystallization with the analyte (usually
larger scale. Indeed, after 3 h at 60 °C, aniline afforded the a mixture of methanol/2-propanol is required). This causes
N-butyl derivative in a 60% isolated yield and a selectivity the formation of nonhomogeneous spots and then irreprod-
of 98% (Scheme 2).
ucible analyses, thus limiting the application of such a ma-
trix in the quantitative analysis of nonpolar compounds. A
more intimate contact between the matrix and analyte
could be achieved by using alternative preparation methods
to the classic dried droplet, but this is usually longer, more
complicated, and less reproducible.
To solve this problem, we increased the solubility of the
matrix in low polar solvents by introducing a benzyl group
on the nitrogen atom (Scheme 4). In addition, the selective
monoalkylation would assure the presence on the matrix of
a NH proton, suitable for the protonation of the analyte
which would be revealed as the ion [M + H]+ in the positive
mode.
Scheme 2. Multigram-scale N-selective alkylation of aniline with n-
butyl chloride in TBACl.
Next, to widen the scope of this protocol, we investigated
the synthesis of bioactive N-substituted anilines, focusing
on the two condensed heterocycles benzothiazine and quin-
oxaline. Indeed, 1,4-benzothiazine ring 4 is of significant
interest as it constitutes the skeleton of many synthetic
drugs and bioactive compounds.[22] This has led to the de-
velopment of several synthetic methods, with some repre-
sentative examples provided by the condensation between
anilines and dicarbonyls or esters,[23] between 2-aminobenz-
enethiol and enoates,[24] alkynes,[25] or α-halogenated carb-
onyl compounds,[26] and moreover by the annulation of
benzyl arylimines.[27] Similarly, 1,2,3,4-tetrahydroquinoxal-
ine (5) and its derivatives are useful organic intermediates
for pharmaceutical[28] and many other applications. Very re-
cently, some 1,2,3,4-tetrahydroquinoxalines were found to
be promising dyes and cell adhesion agents.[29] An abun-
dance of synthetic methods have been developed for the
construction of these useful heterocycles.[30] Among them,
the selective reduction of quinoxaline derivatives is still the
most employed approach, but requires toxic or expensive
reducing reagents, such as lithium aluminium hydride,[31]
sodium borohydride,[32] titanium chloride,[33] indium pow-
der,[34] and borane.[35]
Scheme 4. Monobenzylation of 9-AA in TBACl.
The LDI (laser desorption/ionization) spectrum of
monobenzylated matrix 7 shows an intense signal at m/z
285.15, corresponding to the protonated ion [M + H]+ and
a small contribution of the radical cation [M]+· observed
at m/z 284.13 (see Supporting Information). In the mass
spectrum, no interfering signals were observed in the region
investigated (up to 1000 m/z), suggesting 7 as a potential
matrix for the analysis of low molecular weight compounds.
Next, compound 7 was tested as a MALDI matrix in
two separate experiments carried out with two standards of
differing polarities, the diglyceride and triglyceride of stear-
in. Encouraging results were obtained with significant im-
provements in the signal/noise ratio (S/N) for both the
analytes distearin and tristearin (detected as sodium
[M + Na]+ and potassium [M + K]+ ion adducts) with re-
spect to unmodified matrix 6 (see Supporting Information).
As expected, the higher enhancement of the S/N (more than
three times with respect to the unmodified matrix, Figure 2)
was observed in the case of the triglyceride, as there were
problems encountered in solubilizing the unmodified matrix
in the low polar solvents (CHCl3) required to dissolve that
analyte.
With this in mind, we verified whether our protocol
could be a simple and green method for access to these
valuable heterocycles. Indeed, by treating 1,2-dichloro-
ethane with 2-aminobenzenthiol and benzene-1,2-diamine
in TBACl at 60 °C, we obtained in moderate to good yields
3,4-dihydro-2H-benzo[b][1,4]thiazine (4) and 1,2,3,4-tetra-
hydroquinoxaline (5), respectively (Scheme 3).
Additional studies are currently underway to expand the
scope of this methodology. As an extension to the heterocy-
Scheme 3. Synthesis of bioactive N-substituted anilines in TBACl.
As a further application of this protocol, we examined cles synthesis depicted in Scheme 3, the preparation of
the synthesis of N-alkyl-substituted aromatic amines, useful benzodiazepine derivatives by reacting benzene-1,2-diamine
in MALDI mass spectrometry. To this end, we carried out with an array of dihalides such as 1,3-dichloropropane (for
the monoalkylation of a polycyclic aromatic amine such as the ring expansion), α-dihaloketones, halogenated acid
9-aminoacridine (6, 9-AA) with benzyl chloride. This amine chlorides, and esters is under investigation.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
A. Monopoli, A. Nacci et al.
FULL PAPER
(1 mL)], aromatic amine (0.5 mmol), and alkyl halide (0.5 mmol)
were added, and the mixture was stirred and heated for the proper
reaction times (see Tables 1 and 2). The reaction mixture was then
diluted with aqueous NaHCO3 and extracted with Et2O
(5ϫ1 mL). The combined organic layers were dried with anhy-
drous MgSO4, and the solvent was removed in vacuo. The crude
mixture was analyzed by GC–MS and NMR spectroscopy. The
products were identified on the basis of their spectroscopic data
with those reported in the literature or by comparison of the data
obtained from authentic commercial samples.
Multigram-Scale Synthesis of N-Butylaniline: To TBACl (20 g) were
added aniline (3.72 g, 40 mmol) and an equimolar amount of butyl
chloride (3.70 g). The mixture was stirred at 60 °C for 3 h. The
reaction mixture was then diluted with aqueous NaHCO3 and ex-
tracted with ethyl acetate (5ϫ10 mL). The combined organic layers
were dried with anhydrous MgSO4, and the solvent was removed
in vacuo. The crude mixture was chromatographed on silica gel
(petroleum ether/ethyl acetate, 15:1) to afford N-butylaniline
(3.58 g, 60%).
Figure 2. MALDI spectrum of tristearin carried out with the fol-
lowing as matrixes: (a) 9-aminoacridine (6) and (b) N-benzylacrid-
ine (7).
3,4-Dihydro-2H-benzo[b][1,4]thiazine (4): 2-Aminobenzenthiol
(0.5 mmol) and an equimolar amount of 1,2-dichloroethane were
stirred at 60 °C for 1 h. After extraction, 4 was obtained in 89%
yield. The product was identified by comparison of its spectro-
scopic data with those reported in literature.
Conclusions
In summary, we developed a method for the N-selective
alkylation of primary aromatic amines with a chloroalkane
in tetraalkylammonium ionic liquids. A preliminary screen-
ing highlighted the crucial role of the IL anions on the effi-
ciency of the coupling, interpretable on the basis of both
Kamlet–Taft β parameters and nucleophilicity. At the same
time, the slight influence of the IL cations was also shown,
explained by the known hydrogen-bonding donor proper-
ties of these ionic media. Generally, reactions carried out in
tetrabutylammonium chloride proved to be more selective
towards monoalkylation. All the analogous processes per-
formed in molecular solvents gave unsatisfactory results.
The practical benefits of this protocol include the readily
available and inexpensive starting materials, the versatility
of the substrate, the experimentally straightforward pro-
cedures, and the moderate to good product yields. In ad-
dition, this method is highly sustainable because of the em-
ployment of green solvents (ionic liquids) and base-free and
relatively mild conditions.
1,2,3,4-Tetrahydroquinoxaline (5): Following the procedure re-
ported above, 5 was obtained in 56% yield. The product was iden-
tified by comparison of its spectroscopic data with those reported
in literature.
Synthesis of N-Benzyl-9-aminoacridine (7): To TBACl (5 g) were
added 9-aminoacridine (6, 0.97 g, 5 mmol) and an equimolar
amount of benzyl chloride (0.63 g), and the mixture was stirred at
60 °C for 4 h. The reaction mixture was then diluted with aqueous
NaHCO3 and extracted with ethyl acetate (5ϫ2 mL). The com-
bined organic layers were dried with anhydrous MgSO4, and the
solvent was removed in vacuo. The crude solid was recrystallized
from ethyl acetate/hexane to give 7 in high purity (68% yield). The
MALDI spectrum of this matrix is reported in the Supporting In-
formation
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra and MALDI spectra for the un-
known products and matrixes.
It is noteworthy that this protocol complements existing
strategies,[15] broadening their scope with more challenging
substrates. To the best of our knowledge for the first time
in the literature, the direct N-alkylation strategy was applied
to alkyl chlorides and simultaneously to a wide range of
anilines, including deactivated ones such as p-nitroaniline.
The protocol was validated by the alkylation of aniline on
a larger multigram scale and by the synthesis of bioactive
heterocycles (e.g., benzothiazine and quinoxalines), and fi-
nally it was applied to the preparation of a new and promis-
ing MALDI matrix.
Acknowledgments
Partial financial support for this work by the Italian Ministry of
University and Scientific Research (MIUR) and by the University
of Bari is gratefully acknowledged.
[1] L. Hayden, G. Sauter, F. Ore, P. Pasillas, J. Hoover, G. Lindsay,
R. Henry, J. Appl. Phys. 1990, 68, 456.
[2] a) C. Brielles, J. J. Harnett, E. Doris, Tetrahedron Lett. 2001,
42, 8301; b) D. H. R. Barton, E. Doris, Tetrahedron Lett. 1996,
37, 3295; c) S. Yuvaraj, V. V. Balasubramanian, M. Palanich-
amy, Appl. Catal. A 1999, 176, 111; d) Y. Yoshida, Y. Tanabe,
Synthesis 1999, 10, 1739; e) S. Narayanan, K. Deshpande,
Appl. Catal. A 1996, 135, 125; f) P. S. Singh, R. Brandy-
opadhyay, B. S. Rao, Appl. Catal. A 1996, 136, 177; g) M. A.
Aramendia, V. Boru, C. Jimenez, J. M. Marinas, F. J. Romero,
Appl. Catal. A 1999, 183, 73; h) B. L. Su, D. Barthbomeuf,
Appl. Catal. A 1995, 124, 73; i) I. I. Ivanova, E. B. Pomakhina,
A. I. Rebrov, M. Hunger, Y. G. Kolyagin, J. Weitkamp, J. Catal.
2001, 203, 375; j) K. Nishamol, K. S. Rahna, S. Sungunan, J.
Experimental Section
General Procedure for the N-Alkylation of Primary Aromatic
Amines in Ionic Liquids: Into a 10-mL gastight vial, equipped with
a screw cap and a magnetic bar, IL [0.5 g, or molecular solvent
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
Selective N-Alkylation of Arylamines
Mol. Catal. A: Chem. 2004, 209, 89; k) K. Okano, H. Tokuy-
ama, T. Fukuyama, Org. Lett. 2003, 5, 4987.
a) R. Shroff, A. Muck, A. Svatos, Rapid Commun. Mass Spec-
trom. 2007, 21, 3295; b) C. D. Calvano, C. G. Zambonin, F.
Palmisano, Rapid Commun. Mass Spectrom. 2011, 25, 1757.
M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed.,
Wiley, New York, 2001, p. 499.
a) E. M. Beccalli, G. Broggini, S. Sottocornola, M. Martinelli,
Chem. Rev. 2007, 107, 5318–5365; b) M. Taillefer, N. Xia, N.
Ouali, Angew. Chem. 2008, 120, 3140; Angew. Chem. Int. Ed.
2008, 47, 3096–3099.
a) K. Shimizu, M. Nihimura, A. Satsuma, ChemCatChem
2009, 1, 497; b) K. Yamaguchi, J. L. He, T. Oishi, N. Mizuno,
Chem. Eur. J. 2010, 16, 7199; c) P. R. Likhar, R. Arundhathi,
M. L. Kantam, P. S. Prathima, Eur. J. Org. Chem. 2009, 5383;
d) J. W. Kim, K. Yamaguchi, N. Mizuno, J. Catal. 2009, 263,
205; e) J. L. He, K. Shimizu, N. Mizuno, Chem. Lett. 2010, 39,
1182; f) X. J. Cui, Y. Zhang, F. Shi, Y. Q. Deng, Chem. Eur. J.
2011, 17, 1021; g) F. Shi, M. K. Tse, M. Beller, J. Am. Chem.
Soc. 2009, 131, 1175; h) L. L. Santos, P. Serna, A. Corma,
Chem. Eur. J. 2009, 15, 8196; i) A. Corma, T. Rodenas, M. J.
Sabater, Chem. Eur. J. 2010, 16, 254.
a) A. K. Szardening, T. S. Burkoth, G. C. Look, D. A.
Campbell, J. Org. Chem. 1996, 61, 6720; b) T. Rische, B.
Kitsos-Rzychon, P. Eibracht, Tetrahedron Lett. 1998, 54, 2723;
c) C. H. Tang, L. He, Y. M. Liu, Y. Cao, H. Y. He, K. N. Fan,
Chem. Eur. J. 2011, 17, 7172; d) M. M. Dell’Anna, P. Mastror-
illi, A. Rizzuti, C. Leonelli, Appl. Catal. A 2011, 401, 134.
L. DЈAccolti, A. Monopoli, J. Org. Chem. 2003, 68, 4406; c)
V. Calò, A. Nacci, A. Monopoli, A. Fanizzi, Org. Lett. 2002,
4, 2561.
[3]
[18] a) C. K. Ingold, Structure and Mechanism in Organic Chemis-
try, 2nd ed., Bell, London, 1969; b) E. D. Hughes, C. K. Ingold,
J. Chem. Soc. 1935, 244; c) C. Reichardt, Solvents and Solvent
Effects in Organic Chemistry, 3rd ed., Wiley-VCH, Weinheim,
Germany, 2003.
[19] L. Crowhurst, N. L. Lancaster, J. M. Pérez-Arlandis, T. Welton,
J. Am. Chem. Soc. 2004, 126, 11549.
[20] For Kamlet–Taft parameters of IL ions, see: L. Crowhurst,
P. R. Mawdsley, J. M. Perez-Arlandis, P. A. Salter, T. Welton,
Phys. Chem. Chem. Phys. 2003, 5, 2790.
[21] a) M. Bosco, V. Calò, F. Ciminale, L. Forlani, L. Lopez, E.
Nonnis, P. E. Todesco, Gazz. Chim. Ital. 1971, 101, 685; b) B.
Bonfiglioli, M. Bosco, L. Forlani, P. E. Todesco, Gazz. Chim.
Ital. 1975, 105, 789; c) P. E. Todesco, M. Bosco, L. Forlani, J.
Chem. Soc. B 1970, 9, 1742.
[22] a) F. Schiaffella, A. Macchiarulo, L. Milanese, A. Vecchiarelli,
R. Fringuelli, Bioorg. Med. Chem. 2006, 14, 5196; b) V. Cecch-
etti, V. Calderone, O. Tabarrini, S. Sabatini, E. Filipponi, L.
Testai, R. Spogli, E. Martinotti, A. Fravolini, J. Med. Chem.
2003, 46, 3670; c) S. Inoue, K. Hasegawa, K. Wakamatsu, S.
Ito, Melanoma Res. 1998, 8, 105.
[23] S. Florio, V. Capriati, G. Colli, Tetrahedron 1997, 53, 5839.
[24] F. K. Kirchner, E. J. Alexander, J. Am. Chem. Soc. 1959, 81,
1721.
[25] V. Balasubramaniyan, P. Balasubramaniyan, A. S. Shaikh, Tet-
rahedron 1986, 42, 2731.
[26] a) O. Unger, Ber. Dtsch. Chem. Ges. 1897, 30, 607; b) O. Unger,
G. Graff, Ber. Dtsch. Chem. Ges. 1897, 30, 2389.
[4]
[5]
[6]
[7]
[8]
[9]
a) K. Fujita, Z. Li, N. Ozeki, R. Yamaguchi, Tetrahedron Lett.
2003, 44, 2687; b) S. Michlik, R. Kempe, Chem. Eur. J. 2010,
16, 13193–13198.
[27] J. D. Charrier, C. Landreau, D. Deniaud, F. Reliquet, A. Re-
liquet, J. C. Meslin, Tetrahedron 2001, 57, 4195.
a) M. C. Lubinu, L. De Luca, G. Giacomelli, A. Porcheddu,
Chem. Eur. J. 2011, 17, 82; b) D. Hollmann, S. Bahn, A. Til-
lack, M. Beller, Angew. Chem. 2007, 119, 8440; Angew. Chem.
Int. Ed. 2007, 46, 8291; c) S. Bahn, D. Hollmann, A. Tillack,
M. Beller, Adv. Synth. Catal. 2008, 350, 2099; d) O. Saidi, A. J.
Blacker, M. M. Farah, S. P. Marsden, J. M. J. Williams, Angew.
Chem. 2009, 121, 7511; Angew. Chem. Int. Ed. 2009, 48, 7375;
see also: e) A. J. Blacker, M. M. Farah, M. I. Hall, S. P.
Marsden, O. Saidi, J. M. J. Williams, Org. Lett. 2009, 11, 2039;
f) S. Bahn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. J.
Williams, M. Beller, Chem. Eur. J. 2010, 16, 3590; g) M. B.
Gawande, S. S. Deshpande, J. R. Satam, R. V. Jayaram, Catal.
Commun. 2007, 8, 576.
[28] a) C. T. Eary, Z. S. Jones, R. D. Groneberg, L. E. Burgess,
D. A. Mareska, M. D. Drew, J. F. Blake, E. R. Laird, D. Bala-
chari, M. O’Sullivan, A. Allen, V. Marsh, Bioorg. Med. Chem.
Lett. 2007, 17, 2608; b) J. A. Sikorski, J. Med. Chem. 2006, 49,
1; c) K. Torisu, K. Kobayashi, M. Iwahashi, Y. Nakai, T. On-
oda, T. Nagase, I. Sugimoto, Y. Okada, R. Matsumoto, F.
Nanbu, S. Ohuchida, H. Nakai, M. Toda, Bioorg. Med. Chem.
2004, 12, 5361.
[29] a) Y. Chandrasekaran, G. K. Dutta, B. R. Kanth, S. Patil, Dyes
Pigm. 2009, 83, 162; b) V. Satam, R. Rajule, S. Bendre, P. Bi-
neesh, V. Kanetkar, J. Heterocycl. Chem. 2009, 46, 221; c) A.
Wojcik, R. Nicolaescu, P. V. Kamat, Y. Chandrasekaran, S. Pa-
til, J. Phys. Chem. A 2010, 114, 2744.
[10] a) H. Kashiwagi, S. Enomoto, Chem. Soc. Jpn. 1980, 2, 279; b)
E. V. Dehmlow, R. Thieser, H. Zahalka, Y. Sasson, Tetrahedron
Lett. 1985, 26, 297; c) C. Siswanto, J. F. Rathman, J. Colloid
Interface Sci. 1997, 196, 99.
[30] a) D. Cartigny, T. Nagano, T. Ayad, J.-P. Gnent, T. Ohshima,
K. Mashima, V. Ratovelomanana-Vidal, Adv. Synth. Catal.
2010, 352, 1886; b) N. Mrsic, T. Jerphagnon, A. J. Minnaard,
B. L. Feringa, J. G. de Vries, Adv. Synth. Catal. 2009, 351, 2549;
c) L. Qiu, F. Kwong, J. Wu, W. Lam, S. Chan, W. Yu, Y. Li,
R. Guo, Z. Zhou, A. S. C. Chan, J. Am. Chem. Soc. 2006, 128,
5955; d) D. V. La Barbera, E. B. Skibo, Bioorg. Med. Chem.
2005, 13, 387; e) V. Nair, R. Dhanya, C. Rajesh, M. M.
Bhadbhade, K. Manoj, Org. Lett. 2004, 6, 4743; f) J. P.
Henschke, M. J. Burk, C. G. Malan, D. Herzberg, J. A. Pe-
terson, A. J. Wildsmith, C. J. Cobley, G. Casy, Adv. Synth. Ca-
tal. 2003, 345, 300; g) C. Bianchini, P. Barbaro, G. Scapacci, J.
Organomet. Chem. 2001, 621, 26.
[11] J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996,
118, 7215.
[12] a) M. Onaka, K. Ishikawa, Y. Izumi, Chem. Lett. 1982, 1783;
b) M. Onaka, A. Umezono, M. Kawai, Y. Izumi, J. Chem. Soc.,
Chem. Commun. 1985, 1202; c) T. Ando, J. Yamawaki, Chem.
Lett. 1979, 45.
[13] C. B. Singh, V. Kavala, A. K. Samal, B. K. Patel, Eur. J. Org.
Chem. 2007, 1369.
[14] B. Singh, H. Lobo, G. Shankarling, Catal. Lett. 2011, 141, 178.
[15] a) C. Chiappe, D. Pieraccini, Green Chem. 2003, 5, 193; b) C.
Chiappe, P. Piccioli, D. Pieraccini, Green Chem. 2006, 8, 277–
281; c) Y. Gök, I. Özdemir, E. Çetinkaya, Chin. J. Catal. 2007,
28, 489–491.
[16] a) J. P. Hallett, T. Welton, Chem. Rev. 2011, 111, 3508; b) C. D.
Hubbard, P. Illner, R. van Eldik, Chem. Soc. Rev. 2011, 40, 272;
c) F. D’Anna, R. Noto, Tetrahedron 2007, 63, 11681; d) M.
Meciarova, M. Cigan, S. Toma, A. Gaplovsky, Eur. J. Org.
Chem. 2008, 4408.
[31] R. C. DeSelms, H. S. Mosher, J. Am. Chem. Soc. 1960, 82,
3762.
[32] K. V. Rao, D. J. Jackman, J. Heterocycl. Chem. 1973, 10, 213.
[33] J. Armand, K. Chekir, J. Heterocycl. Chem. 1980, 17, 1237.
[34] C. J. Moody, M. R. Pitts, Synlett 1998, 1029.
[35] A. M. McKinney, K. R. Jackson, R. N. Salvatore, E.-M. Sav-
rides, M. J. Edattel, T. Gavin, J. Heterocycl. Chem. 2005, 42,
1031.
[17] a) V. Calò, A. Nacci, L. Lopez, V. L. Lerario, Tetrahedron Lett.
2000, 41, 8977; b) V. Calò, F. Scordari, A. Nacci, E. Schingaro,
Received: February 20, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20202
/KAP1
Date: 16-04-12 10:58:18
Pages: 8
A. Monopoli, A. Nacci et al.
FULL PAPER
N-Selective Alkylation
A. Monopoli,* P. Cotugno, M. Cortese,
C. D. Calvano, F. Ciminale,
A. Nacci* .......................................... 1–8
A protocol for the selective N-alkylation of
primary aromatic amines in tetraalkylam-
monium ionic liquids was developed. This
approach complements existing strategies
by broadening the scope with more chal-
lenging substrates (e.g., p-nitroaniline) and
alkylating agents (chloroalkane).
Selective N-Alkylation of Arylamines with
Alkyl Chloride in Ionic Liquids: Scope and
Applications
Keywords: Synthetic methods
/
Ionic
liquids / Alkylation / Amines / Heterocycles
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0