2566
M. Feroci et al. / Tetrahedron Letters 53 (2012) 2564–2567
Table 1 (continued)
Entry
Substrate
Alkylating reagent
Products (Yields)
NH2
Cl
Cl
SH
Br
NH
Cl
12
3b
SH
8ba (89%)
Cl
Cl
4a
NH2
Cl
Cl
Cl
Cl
NH2
OH
O
Br
4a
NH
Cl
13
3c
OH
8ca (10%)
9ca (88%)
a
The reduction was conducted under galvanostatic conditions (20 mA cmꢀ2), on Pt electrodes in a divided cell at rt, on 20 ml MeCN-0.1 M TEAHFP solution containing
1 mmol of substrate. At the end of the electrolysis, 1 mmol of alkylating agent was added. After 2 h at rt, usual workup gave the products.
b
Cycloserine was added to the catholyte at the end of the electrolysis. At the end of the alkylation reaction, the crude was treated with ethyl chloroformate/NaHCO3.
completely selective for the oxyamide moiety and the yield in
product 5a was quite high (Scheme 3).
hand, the reactivity of aniline nitrogen atom in this reaction is
strongly dependent on the other functional group present on the
aromatic ring.
Unfortunately, in a short period of time the alkylated cycloser-
ine 5a was subjected to degradation, probably to the cycloserine
dimer, piperazinedione; this dimerization is reported to occur even
in the solid state and it requires the free amino group.9 So, in order
to avoid the degradation of the alkylated product, the amino group
was transformed into carbamate by reaction with ethyl chlorofor-
mate after the alkylation reaction (to avoid altering the selectivity
of the electrochemical reaction). In this case, 94% yield in product
5aa was achieved (Table 1, entry 1).
Very good yields in 2-alkylated cycloserine were obtained using
various benzyl or alkyl bromides, with no racemization10 (Table 1,
entries 1–6). With all bromides used, the selectivity is complete
versus the oxyamide nitrogen atom, thus confirming the regiose-
lectivity of this electrochemical methodology.
In fact, if a thiol group is present (substrate 3b, Table 1, entry
12), the selective N-alkylation in good yield (89%) is obtained,
while when a hydroxy group is present (substrate 3c, Table 1, entry
13), the reaction is prevalent on the oxygen atom, probably be-
cause of the higher acidity of the phenol moiety. On the other hand,
selective O-alkylation of aminophenols has been achieved only
protecting the aniline group as imine and then performing the
alkylation.15 These last three results evidence that this reaction is
influenced by both the nucleophilicity and the acidity of the func-
tional groups.
In conclusion, electrogenerated acetonitrile anion has con-
firmed to be a selective reagent in the N-alkylation of bifunctional
substrates (cycloserine, b-amino alcohols,
a-substituted anilines).
Following this information, we have subjected 1,2-amino alco-
hols to an alkylation reaction, induced by acetonitrile anion depro-
tonation, hoping to obtain a nitrogen-selective mono alkylation in
the presence of a hydroxy moiety.
The selective N-monoalkylation of b-amino alcohols is usually
achieved by the reaction with an aldehyde and subsequent reduc-
tion of the corresponding adduct,11 as the direct action of a base
and of an alkylating agent can lead to low yields and low selectivity
and requests long reaction times or/and high temperature.12 Very
good results (in yields and selectivity) have been reached by Kol
and Bar-Haim, using the chelation to 9-BBN prior to deprotonation
and alkylation of amino alcohols.13
As 1,2-amino alcohols 2a–d are neither electroactive nor
degradable, we have added them to the catholyte prior to the
cathodic reduction. 2-(Bromomethyl)-1,3-dichlorobenzene was
used as alkylating agent and the results are reported in Table 1, en-
tries 7–10. The N-monoalkylated amino alcohols 6aa–6ca were
selectively obtained in good yields (Table 1, entries 7–9)14 with
no byproducts due to bis-alkylation or O-alkylation. Only in the
case of 1-amino-2,3-dihydro-1H-inden-2-ol 2d (entry 10) 15% of
N,O-bis-alkylation product 7da has been isolated, indicating that
the first deprotonation/alkylation affects the nitrogen atom and
only in a second time the reaction interests the oxygen.
Then, we have exploited this reaction using different amines.
When the alkylation reaction is carried out on the substrates con-
taining simultaneously a benzylamine and aniline nitrogens (sub-
strate 3a, Table 1, entry 11), the alkylation is much less effective
(42%), but selective on the benzyl nitrogen atom. On the other
The main advantages in the use of this base are the easiness of gen-
eration and the complete absence of metallic cations, which could
inhibit its reactivity.
In no case N,N-bis-alkylation has been obtained, rendering this
methodology really competitive with the current chemical meth-
odologies for the monoalkylation of amines.
Acknowledgments
This work was financially supported by Miur and Cnr, Italy. The
authors thank M. Marco Di Pilato for his support to the experimen-
tal part of the work. Special thanks are due to Dr. Roberto Cirilli
from Dipartimento del Farmaco, Istituto Superiore di Sanità, Roma,
for the chiral HPLC analysis.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. Rossi, L.; Feroci, M.; Inesi, A. Mini-Rev. Org. Chem. 2005, 2, 343–357.
2. (a) Bianchi, G.; Feroci, M.; Rossi, L. Eur. J. Org. Chem. 2009, 3863–3866; (b)
Feroci, M.; Chiarotto, I.; Rossi, L.; Inesi, A. Adv. Synth. Catal. 2008, 350, 2740–
2746.
3. (a) Feroci, M.; Orsini, M.; Sotgiu, G.; Rossi, L.; Inesi, A. J. Org. Chem. 2005, 70,
7795–7798; (b) Feroci, M.; Lessard, J.; Orsini, M.; Inesi, A. Tetrahedron Lett.
2005, 46, 8517–8519; (c) Feroci, M. Adv. Synth. Catal. 2007, 349, 2177–2181;
Feroci, Marta
