Selective N-alkylation of primary amines with R-NH2·HBr and alkyl bromides using a competitive deprotonation/protonation strategy

Article abstract of DOI:10.1039/c4ra01915f

Monoalkylation of primary amines using amine hydrobromides and alkyl bromides has been carried out. Under controlled reaction conditions the reactant primary amine was selectively deprotonated and made available for reaction, while the newly generated secondary amine remained protonated, and did not participate in alkylation further. Reaction was carried out under mild reaction conditions and was applicable to a wide range of primary amines and alkyl bromides.

Full text of DOI:10.1039/c4ra01915f

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Selective N-alkylation of primary amines with
R–NH2$HBr and alkyl bromides using a competitive
deprotonation/protonation strategy†
Cite this: RSC Adv., 2014, 4, 18229
a
a
Shubhankar Bhattacharyya, Uma Pathak, Sweta Mathur,a Subodh Vishnoia
Received 5th March 2014
Accepted 7th April 2014
*
and Rajeev Jainb
DOI: 10.1039/c4ra01915f
www.rsc.org/advances
Monoalkylation of primary amines using amine hydrobromides and in view of the great scope of this reaction, efforts are being
alkyl bromides has been carried out. Under controlled reaction applied to make the reaction practically useful. Salvatore et al.
conditions the reactant primary amine was selectively deprotonated have reported a procedure for monoalkylation of primary amine
and made available for reaction, while the newly generated secondary using cesium bases.11 The selectivity was attributed to ‘cesium
amine remained protonated, and did not participate in alkylation effect’ induced by cesium since exclusively; it was effective in
further. Reaction was carried out under mild reaction conditions and comparison to other similar bases.
was applicable to a wide range of primary amines and alkyl bromides.
We wished to explore the potential of halide–amine reaction
further with an aim to develop a milder, simpler, cost effective
and general protocol for monoalkylation of primary amines. We
reasoned that problem of over alkylation of amines may be
resolved by exploiting the difference in basicity/nucleophilicity
of primary/secondary amines. We hinged our approach on
exploiting greater intrinsic basicity of secondary amine and
thereby greater proton affinity in comparison to primary
amines. Surprisingly, this simple approach has yet not been
explored.
To accomplish this, we proposed to recruit halide salt of the
amine and alkyl halide. We rationalized that under properly
tuned reaction conditions, the reactant amine could be made
available for reaction with the help of a suitable base, which
preferentially deprotonates primary amine in the presence of
secondary amine due to their difference in basicity. The halo
acid formed during the reaction should remain bound to the
newly generated secondary amine, driving it to its thermody-
namic sink, RNH–R1$HX and thereby preventing the secondary
amine to participate in the reaction further.
Amines are important because of their widespread application
as synthetic intermediates1 pharmaceuticals,1 agrochemicals,2
paints,3 dyes,4 drugs,5 polymers,6 etc. Development of synthetic
approaches for selective mono-N-alkylation has been the focus
of research for decades and it continues to be an active area of
research, today also. Methods available for monoalkylation of
amines includes reductive alkylation using aldehydes,7 alkyl-
ation by alkyl halides8 or their equivalents such as dialkyl
sulfates or sulfonates9 and alkylation by alcohols.9,10
Preparation of monoalkyl amines by amine–halide reaction
is conceptually straightforward, reaction occurs under mild
condition and numerous amines and halides are commercially
available. But, in spite of its great potential it is rarely used for
selective monoalkylation of amines. The limited synthetic
applicability of this reaction stems from the fact that once
alkylation of primary amine occurs, a secondary amine is
generated which is more basic than primary amine. Now, the
secondary amine also competes with primary amine for alkyl-
ation, and leads to formation of tertiary amine. Further alkyl-
ation of tertiary amine results in quaternisation of amine.
Ultimately, a mixture of amines is obtained which renders the
reaction of little synthetic importance (Scheme 1). Nevertheless,
Important considerations which could inuence the fate of
reaction to a great extent were; selection of suitable base and
solvent for the reaction. For imparting selectivity, a non nucle-
ophilic base with optimum basicity was essential: under the
employed reaction condition it should deprotonate primary
amine in preference to newly generated secondary amine
(Scheme 2).
aSynthetic Chemistry Division, Defence
R & D Establishment, Jhansi Road,
Gwalior-474002, India. E-mail: sc_drde@rediffmail.com; Fax: +91-0751-2341148;
Tel: +91-0751-2390189
bSchool of Studies in Chemistry, Jiwaji University, Gwalior-474002, India
† Electronic supplementary information (ESI) available: General synthetic
procedure, characterization data, 1H and 13C NMR spectra. See DOI:
10.1039/c4ra01915f
Scheme 1 Alkylation of amine with alkyl halide.
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these modications, gratifying results were obtained entry 1
Table 1.
Next, various solvents were screened for their applicability in
this reaction. Both protic and aprotic solvents such as ethanol,
THF, DMF, toluene, DMSO, acetonitrile, etc. were investigated.
In THF, acetonitrile and toluene reaction did not occur satis-
factorily mainly due to the insolubility of the amine salt. In
ethanol the progress of the reaction was very slow. Reaction in
DMSO also showed good selectivity but satisfactory yield was
not found. In DMF the reaction was progressed well but,
simultaneous formylation of amine was also observed. To
Scheme 2 Preferential deprotonation of primary amine.
Solvent oen modulate basicity of amines: in aprotic
solvents the basicity is governed by electronic factor of the
amines and in protic solvent it is inuenced by electronic
factors as well as by degree of solvation.
To see the feasibility of the concept, alkylation of benzyla-
mine$HCl with butylbromide was attempted. Butylbromide and
ꢀ
reduce formylation, reaction was carried out at 20–25 C.
ꢀ
benzylamine$HCl were taken in nitromethane at 70–75 C and
We were pleased to notice that lowering temperature pre-
vented the side reaction without retarding the rate of desired
reaction considerably. Inclusion of drying agent like molecular
one mole of triethylamine was added drop wise. Initially, good
selectivity was obtained (5 h, 44% monoalkylation, 1% dia-
lkylation, 55% unreacted primary amine) but, the reaction
failed to progress further in the desired direction. Aer 14 h,
65% monoalkylated product was formed along with 11% dia-
lkylated product, and 24% starting material remained unreac-
ted. Formation of butylchloride retarded the reaction, and
dialkylation was also observed (Scheme 3).
To explain this we presumed that since, primary require-
ment for selective monoalkylation was to prevent the reaction
generated secondary amine from participating in the reaction
by maintaining it in protonated form, hence, dialkylation may
be due to incomplete protonation of secondary amine, and it
may require some additional time to attain equilibrium
between primary and secondary amine according to Scheme 4.
To evade formation of chlorobutane; hydrochloride salt of
the amine was replaced by hydrobromide salt and triethylamine
was added in portions at regular intervals to avoid over-
alkylation. Aer each addition (triethylamine), reaction was
allowed to undergo complete reaction in terms of alkylation of
the available free primary amine, and establishment of equi-
librium in the reaction mixture according to Scheme 5. With
˚
sieve 4 A enhanced both the rate of N-alkylation and selectivity.
Conducting the reaction in DMSO also produced good results,
but considerable loss in the yield during work up was observed,
hence DMF was nally selected (Table 1).
Aer solvent screening, we directed our attention towards
optimization of the base. Various candidate amine such as
pyridine, diisopropylethylamine (DIPEA), N,N-dimethyl-4-
aminopyridine (DMAP), 1,8-diazabicycloundec-7-ene (DBU),
dicyclohexylamine (DCHA), collidine were studied (Table 2).
DIPEA and DMAP produced slightly better results in terms of
selectivity but their removal from the reaction mixture was
found to be difficult in comparison to triethylamine. Weaker
Table 1 N-Alkylation of benzylamine$HBr with n-butylbromide in
different solventsa
Solvent
Temperature (ꢀC)
Selectivity
Time (h)
Yield
Nitromethane
Ethanol
DMF
DMSO
THF
70–75
Reux
20–25
20–25
20–25
20–25
20–25
80 : 20
4 : 0
87 : 9
90 : 7
—
10
10
9
70
—
76
65
—
—
—
9
—
—
—
Toluene
Acetonitrile
—
—
Scheme
3 Alkylation of benzylamine hydrochloride with
a
Reactions were carried out with benzylamine$HBr (1 eq.),
n-butylbromide (1.1 eq.) and triethylamine (1 eq.).
butylbromide.
Table 2 N-Alkylation benzylamine$HBr with butylbromide utilizing
different basesa
Scheme 4 Equilibrium between protonated primary and secondary
amine.
Base
Selectivity
Time
Yield
Pyridine
Triethylamine
DIPEA
DMAP
DBU
—
—
9
8
8
6
—
76
77
79
73
74
—
87 : 9
89 : 8
93 : 4
81 : 16
83 : 13
37 : 0
DCHA
Collidine
6
6
a
Reactions were carried out with benzylamine$HBr (1 eq.),
n-butylbromide (1 eq.) in DMF at 20–25 ꢀC.
Scheme 5 Selective mono alkylation of amines.
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Table 3 Chemoselective formation of secondary amines from primary amines and alkyl halides
Entry no.
Primary amine$HBr
Alkyl halide
Product
Et3N eq.
Time (h)
Selectivityb
Yieldc
76
1
2
1
1
9
9
87 : 9
n-C8H17-Br
81 : 15
73
3
4
5
1
1
1
10
10
16
86 : 10
87 : 6
78
79
77
85 : 12
6a
3
12
100 : 0
82
7a
8a
9
3
3
1
1
11
11
12
10
100 : 0
100 : 0
92 : 0.2
96 : 0.5
87
86
84
83
10
11
12
1.2
1.2
22
18
73 : 0.3
77 : 1
62
64
13
14
1
16
15
93 : 3
76
63
Ph-NH2
1.5
70 : 10
15
CH3-(CH2)4-Br
1.5
10
71 : 8
66
a
b
Free amine was used. Selectivity – monoalkylation : dialkylation, reaction was monitored by GC-MS, rest of the primary amine remained
unreacted. c Isolated yield.
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base like pyridine as expected were found ineffective, collidine such as a-halo ester with free benzylamine failed to produce
also did not produce satisfactory conversion. Application of selectivity. But, useful outcome of the reaction was restored by
inorganic bases was also not found effective. Keeping in view employing of hydrobromide salt of benzylamine (entry 9).
the practical applicability, triethylamine remained the base of Similarly, good selectivity was observed in case of alkylation of
choice.
phenylethylamine hydrobromide with 2-bromopropionate
An optimized procedure utilizing hydrobromide salt of (entry 10). Reaction of cyclohexylamine with alkyl bromides and
benzylamine, butylbromide, triethylamine and DMF follows as: a-halo ester also exhibited excellent selectivity (entry 11, 12 and
1 mmol of amine hydrobromide salt, 1.1 mmol of butylbromide 13) but longer reaction time (22 h) was required. To investigate
˚
and 0.25 g of 4 A molecular sieves were taken in 1 ml dry DMF at the scope the reaction further, aromatic amine was investigated
20–25 ꢀC. Triethylamine 1 mol, was mixed with 1 ml of DMF and (entry no. 14 and 15) and by employing a slightly higher amount
added to the reaction mixture portionwise (1/40th) over a period of base, they were also found to be suitable partners in this
of 8 h with continuous stirring. Progress of the reaction was reaction.
monitored by TLC and GC-MS. On completion of the reaction
monoalkylated product was isolated by usual work up approach for monoalkylation of primary amines. Due to easy
procedure. availability of a broad range of substrates, convenience and
In conclusion, we have demonstrated a simple and efficient
With the optimized reaction conditions in hand, scope of practicability of the method, this may nd wide application in
this strategy was probed with a variety of amines and alkyl synthetic and medicinal chemistry.
bromides. N-Alkylation of all the primary amine with primary
halide investigated in this work progressed smoothly (Table 3,
entry 1–4). Next, the protocol was attempted for secondary
Notes and references
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