Selective N-alkylation of primary amines with chloroacetamides under pH-controlled aqueous conditions

Article abstract of DOI:10.1081/SCC-120002124

A practical method for selective alkylation of primary amines with chloroacetamides under modified Finkelstein conditions using stoichiometric amounts of sodium iodide in acetonitrile/water is described. An interesting finding in this study was that α-alkylaminoacetamides are less basic than the corresponding primary alkylamines by about 2pKa units; this necessitated a pH of 12 during alkylation to optimize the monoalkylation selectivity. Depending on the amount of primary amine used, mono:dialkylation selectivities ranged from 2.7 to 10.

Full text of DOI:10.1081/SCC-120002124

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SELECTIVE N-ALKYLATION OF PRIMARY AMINES
WITH CHLOROACETAMIDES UNDER pH-CONTROLLED
AQUEOUS CONDITIONS
Eric Loeser a , Kapa Prasad a & Oljan Repic a
a Process R&D, Chemical and Analytical Development, Novartis Pharmaceuticals
Corporation, 59 Route 10, East Hanover, NJ, 07936, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: Eric Loeser, Kapa Prasad & Oljan Repic (2002): SELECTIVE N-ALKYLATION OF PRIMARY AMINES WITH
CHLOROACETAMIDES UNDER pH-CONTROLLED AQUEOUS CONDITIONS, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 32:3, 403-409
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SYNTHETIC COMMUNICATIONS, 32(3), 403–409 (2002)
SELECTIVE N-ALKYLATION OF
PRIMARY AMINES WITH
CHLOROACETAMIDES
UNDER pH-CONTROLLED
AQUEOUS CONDITIONS
Eric Loeser,* Kapa Prasad, and Oljan Repic
Process R&D, Chemical and Analytical Development,
Novartis Pharmaceuticals Corporation, 59 Route 10,
East Hanover, NJ 07936, USA
ABSTRACT
A practical method for selective alkylation of primary amines
with chloroacetamides under modified Finkelstein conditions
using stoichiometric amounts of sodium iodide in acetonitrile/
water is described. An interesting finding in this study was
that a-alkylaminoacetamides are less basic than the corre-
sponding primary alkylamines by about 2 pKa units; this
necessitated a pHof 12 during alkylation to optimize the
monoalkylation selectivity. Depending on the amount of pri-
mary amine used, mono : dialkylation selectivities ranged
from 2.7 to 10.
*Corresponding author.
403
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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LOESER, PRASAD, AND REPIC
The reaction of primary amines with alkyl halides is a well-studied
area and an attractive method for the preparation of higher alkylated
amines.1 However, when the secondary amines are the desired products
overalkylation is often a problem. This is commonly overcome by using
the amine component in suitable excess. Other methods that are employed
to obviate this problem are the use of protecting groups, reductive amina-
tion methodology, alkylation on solid supports, etc. A more recent method
for supressing overalkylation has been reported by Jung and co-workers.
These investigators showed that the use of cesium hydroxide in anhydrous
DMF allowed a wide variety of primary amines to be alkylated, with
selectivities nearing 10 : 1 in favor of monoalkylation (Scheme 1).2
Scheme 1.
We recently required a simple method for the alkylation of primary
amines with a-chloroacetamides. We applied Jung’s CsOH/DMF conditions
to our system with disappointing selectivity (ratio ꢀ 1.3). Although these
conditions are effective for simple aliphatic alkyl bromides, we were
unable to obtain satisfactory results with our chloroacetamido electrophiles.
This prompted us to undertake a detailed study of alkylation reactions using
amines 1–4 and chloroacetamido electrophiles 5–7 (Table 1). The results of
this study led to the pH-controlled aqueous conditions discussed in the
present communication.
To establish suitable reaction conditions, the model system shown in
Scheme 2 was studied using 1 eq each of amine 1 and chloroacetamide 5.
The amounts of monoalkylated product 8 and dialkylated product 9 were
Table 1. Primary Amines and Chloroacetamido Electrophiles

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SELECTIVE N-ALKYLATION OF PRIMARY AMINES
405
Scheme 2. Reaction of 2-Chloro-N,N-diethylacetamide with phenethylamine.
1
measured by HPLC and H-NMR. Switching to K2CO3/DMF with a cat-
alytic amount of NaI gave even worse mono : dialkylation selectivity (0.8)
than the CsOH/DMF system. We suspected this may be due to the amine 1
forming the HCl salt and precipitating out, leaving only the product 8 to
react again with 5 thus leading to extensive dialkylation product 9. When
5% water was added to the DMF solvent to partially solubilize the K2CO3,
the mono : dialkylation ratio improved to 1.6 : 1. Switching to a completely
soluble base (Et3N) gave an even bigger improvement (ratio 3 : 1).
In an attempt to simplify the workup, we ran the reaction in 1 : 1
MeCN/H2O using NaOHas the base. Initial experiments resulted in slow
reaction times, even with stoichiometric amounts of NaI catalyst. Under
these conditions, the driving force for halide exchange present in classical
Finkelstein conditions was now absent due to the high solubility of NaCl in
1 : 1 MeCN/H2O. However, when water content was decreased to about
20%, we observed NaCl precipitation from the mixture during the reaction,
thus driving the conversion of the chloroacetamide to the more reactive
iodoacetamide, thereby increasing the reaction rate. This led to reaction
conditions consisting of 4 : 1 MeCN/H2O with concentrations of 1 M each
in amine, chloroacetamide, and NaI.
To prevent substantial hydrolytic decomposition of the chloroaceta-
mide, simultaneous addition of the NaOHwas necessary. The addition of
base was best controlled by monitoring the pH. We found that a pH as high as
12.5 gave negligible hydrolysis of the chloroacetamide. However, at pH’s
lower than 11 the mono : dialkylation ratio declined substantially (Table 2).
These results can be rationalized by the pKa values of amine 1 and product 8,
which we measured experimentally to be 9.4 and 7.6, respectively. Thus, at
high pH, both amine 1 and product 8 are unprotonated, but at pH9.5
the amine 1 is preferentially protonated and becomes less reactive toward
the electrophile. This offers an explanation for the poor selectivity observed
at pH9.5.
The optimized pH12 conditions were then tested by reaction of
amine 1 with chloroacetamides 6–7 and reactions of amines 2–4 with

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LOESER, PRASAD, AND REPIC
Table 2. Reaction of Amines with Chloroacetamido Electrophiles
chloroacetamide 5.4 The results (Table 2) showed very similar selectivities to
the model reaction. In the case of aniline 4, we ran the reaction at pH7 as we
were concerned about phenolic group alkylation and wanted to ensure the
phenolic group remained protonated. Under these conditions no phenolic
alkylation was observed.
To improve the mono : dialkylation ratio, an excess of amine can be
used as practiced in the literature. However, a simple and efficient method
for recovering unreacted amine from the reaction mixture is still necessary
for this approach to be practical. This was tested on the phenethylamine/
diethylchloroacetamide model system. Since phenethylamine is more basic
than the alkylation product according to pKa analysis, the idea of a frac-
tional crystallization and recycling of phenethylamine becomes attractive
(Scheme 3). It was found that using two equivalents of phenethylamine
increased the mono : dialkyl ratio from 3.4 : 1 to 10 : 1, and that adding
1 eq of HCl allowed most of the unreacted phenethylamine to be removed
in about 90% purity from the mixture and could be recycled.5

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SELECTIVE N-ALKYLATION OF PRIMARY AMINES
407
Scheme 3.
From the mother liquors, the desired monoalkylated product was
isolated as the HBr salt in 75% yield based on chloroacetamide with a
purity of >97% by HPLC. This is a significant improvement over the
45% isolated yield obtained when running the reaction with 1 : 1 stoichio-
metry and could be further improved by optimization, if needed.
REFERENCES
1. Mitsunobu, O. In Comprehensive Organic Synthesis, Trost, B.M.;
Fleming, I., Winterfeldt, E., Eds.; Pergamon Press, 1991; Vol. 6,
pp. 65–101.
2. Salvatore, R.N.; Nagle, A.S.; Schmidt, S.E.; Jung, K.W. In Thirty-Sixth
National Organic Chemistry Symposium, Abstract No. 234.
3. Two buffer systems, i.e., potassium carbonate (pKa 10.25) and a mixture
of di- and tri-sodium borate (pKa’s 12.74, 13.80) were also tested to
provide pHcontrol. Of these, the borate buffer worked best and gave
comparable selectivity (3.3) to the NaOH/pH 12.5 result.
4. A typical reaction was carried out as follows: 0.01 mol each of amine
and chloroacetamide were stirred in 8 mL of MeCN and 2 mL of water
at 23ꢁC (for reactions using 2 : 1 stoichiometry, 0.02 mol of amine was
used). NaI was added (0.01 mol) and the reaction was kept at the desired
pHby adding 40% (w/w) aqueous NaOHas needed. The reaction was
judged complete when the pHbecame constant and by disappearance of
chloroacetamide as determined by HPLC. After standard workup, the
1
final composition of the reaction mixture was determined by H-NMR
and HPLC.6 In the case of compound 8, isolation of the product was
carried out as follows: For a 1 : 1 stoichiometry reaction, the oil obtained
after aqueous workup was dissolved in i-PrOHand 1 eq of 48% HBr
was added. The solvent was stripped under vacuum and the residue

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LOESER, PRASAD, AND REPIC
was distilled again with i-PrOAc to remove traces of water during which
white solids precipitated. The solids were slurried in 4 : 1 (v/v) i-PrOAc/
ꢁ
i-PrOHat 50 C, then cooled slowly to room temperature, filtered, and
washed with i-PrOAc to obtain the HBr salt of 8 in 45% yield and
>96% purity. For a 2 : 1 stoichiometry reaction, after aqueous workup
the resulting oil was dissolved in i-PrOHand 1 eq HCl was added. The
solvent was stripped under vacuum during which white solids precipi-
tated. i-PrOAc was added and the mixture distilled again to remove
traces of water, then the solids were slurried in i-PrOAc at 50ꢁC. The
mixture was cooled slowly to room temperature, and the solids (a mix-
ture containing about 90% of the HCl salt of 1 and 10% of the HCl salt
of 8) were filtered off. To the mother liquor containing most of the
product 8 was added i-PrOHand 1 eq of 48% HBr, then the solvents
are stripped under vacuum to obtain white solids. After distilling again
with i-PrOAc to remove traces of water, the solids were slurried in 4 : 1
(v/v) i-PrOAc/i-PrOHat 50 ꢁC, slowly cooled to room temperature,
filtered, and washed with i-PrOAc to obtain the HBr salt of 8 in
>97% purity and 75% yield.
5. The recovered HCl salt of amine 1 could be used for additional reactions
with chloroacetamide 6 by stirring in the MeCN/H2O solvent mixture
and adding 1 eq NaOHto regenerate the free base of 1 prior to adding 6
and the NaI catalyst.
6. For reactions with electrophile 5, the 1H-NMR signals from the
N-CH2-CO group (singlets) were used for determining the ratio of prod-
ucts.7 For reactions with electrophiles 6 and 7, the ratio of products was
determined by HPLC analysis. [Column, Waters Symmetry C-18,
4.6 ꢂ 150 mm; eluent, initial 95 : 5 (v/v) 0.5% H3PO4/MeCN to 95 : 5
(v/v) MeCN/water over 13 min; flow rate, 1.6 mL/min; detection, UV
254 nm]. In all cases the retention time was greater for the dialkyl prod-
uct relative to the corresponding monoalkyl product.
7. Analytical data: HBr salt of 8: Mp 178–185ꢁC (dec). 1HNMR (300 MHz,
D2O) d 7.46–7.55 (5H, m), 4.16 (2H, s), 3.51 (2H, t, J ¼ 7.4 Hz), 3.49 (2H,
q, J ¼ 7.2 Hz), 3.39 (2H, q, J ¼ 7.2 Hz), 3.20 (2H, t, J ¼ 7.4 Hz), 1.27 (3H, t,
J ¼ 7.2 Hz), 1.22 (3H, t, J ¼ 7.2 Hz); 13C NMR (75.5 MHz, D2O) d 164.8,
136.7, 129.5, 129.2, 127.8, 49.0, 47.9, 42.0, 41.3, 32.1, 13.1, 12.2. Anal.
Calcd for C14H23N2OBr: C, 53.33; H, 7.35; N, 8.89; Br, 25.35. Found: C,
53.41; H, 7.22; N, 8.91; Br, 25.74. HBr salt of 9: Mp 187–189ꢁC (dec).
1HNMR (300 MHz, D O) d 7.43–7.58 (5H, m), 4.44 (4H, s), 3.77 (2H, t,
2
J ¼ 7.3 Hz), 3.50 (4H, q, J ¼ 7.3 Hz), 3.37 (4H, q, J ¼ 7.3 Hz), 3.26 (2H, t,
J ¼ 7.3 Hz), 1.27 (6H, t, J ¼ 7.3 Hz), 1.24 (6H, t, J ¼ 7.3 Hz); 13C NMR
(75.5 MHz, D2O) d 163.8, 135.7, 129.6, 129.2, 128.1, 58.0, 56.4, 42.1, 41.6,
31.0, 13.2, 12.2. Anal. Calcd for C20H34N3O2Br: C, 56.07; H, 8.00; N,

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SELECTIVE N-ALKYLATION OF PRIMARY AMINES
409
9.80; Br, 18.65. Found: C, 55.83; H, 8.00; N, 9.87; Br, 18.43. Mono-
alkylated product (1 þ 6): 1HNMR (300 MHz, CDCl ) d 7.14–7.32
3
(5H, m), 3.29–3.56 (6H, m), 2.79–2.94 (4H, m), 2.06 (1H, br.s),
1.77–2.00 (4H, m). Dialkylated product (1 þ 6) was not isolated in pure
form. The identity of the compound was confirmed by HPLC-MS;
344(MHþ). Monoalkylated product (1 þ 7): 1HNMR (300 MHz,
CDCl3) d 7.16–7.34 (5H, m), 4.67–4.75 (1H, m), 3.30–3.70 (4H, m),
2.78–2.96 (4H, m), 1.96–2.37 (4H, m), 1.90 (1H, br.s). Dialkylated prod-
uct (1 þ 7); 1HNMR (300 MHz, CDCl ) d 7.13–7.34 (5H, m), 4.63–5.51
3
(2H, m), 3.26–4.05 (8H, m), 2.77–3.22 (4H, m), 1.69–2.43 (8H, m).
d
Monoalkylated product (2 þ 5); 1HNMR (300 MHz, CDCl )
3
7.20–7.38 (5H, m), 3.87 (2H, s), 3.40 (2H, q, J ¼ 7.2 Hz), 3.38 (2H, s),
3.20 (2H, q, J ¼ 7.2 Hz), 2.50 (1H, br.s), 1.13 (6H, t, J ¼ 7.2 Hz).
1
Dialkylated product (2 þ 5); HNMR (300 MHz, CDCl ) d 7.22–7.38
3
(5H, m), 3.89 (2H, s), 3.48 (4H, s), 3.35 (4H, q, J ¼ 7.7 Hz), 3.28 (4H, q,
J ¼ 7.7 Hz), 1.23 (6H, t, J ¼ 7.7 Hz), 1.17 (6H, t, J ¼ 7.7 Hz). Mono-
1
alkylated product (3 þ 5); HNMR (300 MHz, CDCl ) d 7.19 (2H, t,
3
J ¼ 7.7 Hz), 6.72 (1H, t, J ¼ 7.7 Hz), 6.64 (2H, d, J ¼ 7.7 Hz), 4.20 (1H,
br.s), 3.86 (2H, s), 3.45 (2H, q, J ¼ 7.4 Hz), 3.22 (2H, q, J ¼ 7.4 Hz), 1.25
(3H, t, J ¼ 7.4 Hz), 1.17 (3H, t, J ¼ 7.4 Hz). Dialkylated product (3 þ 5);
1HNMR (300 MHz, CDCl ) d 7.16 (2H, t, J ¼ 7.7 Hz), 6.70 (1H, t,
3
J ¼ 7.7 Hz), 6.51 (2H, d, J ¼ 7.7 Hz), 4.24 (4H, s), 3.42 (4H, q,
J ¼ 7.4 Hz), 3.36 (4H, q, J ¼ 7.4 Hz), 1.25 (6H, t, J ¼ 7.4 Hz), 1.17 (6H,
t, J ¼ 7.4 Hz). Monoalkylated product (4 þ 5); 1HNMR (300 MHz,
D2O þ DCl) d 7.27 (2H, d, J ¼ 9.2 Hz), 6.85 (2H, d, J ¼ 9.2 Hz), 4.31
(2H, s), 3.24 (2H, q, J ¼ 7.1 Hz), 3.18 (2H, q, J ¼ 7.1 Hz), 0.99 (3H, t,
J ¼ 7.1 Hz), 0.95 (3H, t, J ¼ 7.1 Hz). Dialkylated product (4 þ 5);
1HNMR (300 MHz, D O þ DCl) d 7.45 (2H, d, J ¼ 9.2 Hz), 6.86 (2H,
2
d, J ¼ 9.2 Hz), 4.68 (4H, s), 3.20 (4H, q, J ¼ 7.1 Hz), 3.17 (4H, q,
J ¼ 7.1 Hz), 0.99 (6H, t, J ¼ 7.1 Hz), 0.92 (6H, t, J ¼ 7.1 Hz).
Received in the USA March 19, 2001

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