Efficient and scalable method for the selective alkylation and acylation of secondary amines in the presence of primary amines

Article abstract of DOI:10.1021/op049812w

Selective substitution of secondary amines in the presence of primary amines is performed by using the reaction solvent, methyl isobutylketone (MIBK), as a temporary protecting group for the primary amine. After acylation or alkylation of the secondary amine, the resulting imine intermediate is smoothly hydrolysed, leading to the free primary amine in high yield and purity. This procedure represents a cheap and scalable alternative to multistep methods requiring several protections and deprotections.

Full text of DOI:10.1021/op049812w

Organic Process Research & Development 2005, 9, 102−104
Efficient and Scalable Method for the Selective Alkylation and Acylation of
Secondary Amines in the Presence of Primary Amines
Fr e´ d e´ ric Laduron,* Vanessa Tamborowski, Luc Moens, Andr a´ s Horv a´ th, Dirk De Smaele, and Stef Leurs
Chemical DeVelopment - Process Research, Johnson & Johnson Pharmaceutical Research & DeVelopment, Belgium
Abstract:
Scheme 1
Selective substitution of secondary amines in the presence of
primary amines is performed by using the reaction solvent,
methyl isobutylketone (MIBK), as a temporary protecting group
for the primary amine. After acylation or alkylation of the
secondary amine, the resulting imine intermediate is smoothly
hydrolysed, leading to the free primary amine in high yield and
purity. This procedure represents a cheap and scalable alterna-
tive to multistep methods requiring several protections and
deprotections.
Despite many amino protecting groups being available,1
efficient and cost-effective differentiation between NH and
NH sites of diamino compounds is a major challenge in
2
organic synthesis. Some methods allowing the selective
protection of a primary amine in the presence of a secondary
amine are described in the literature. However, they all
require the use of an additional reagent such as ethyl
trifluoroacetate, trityl chloride, or benzaldehyde that have
to be removed after deprotection, making the process more
expensive. Procedures avoiding these drawbacks are therefore
highly desired for large-scale synthesis.
Basically, the diamino compound is condensed with
MIBK to form an imine leaving the secondary amine
available to react with an alkylating or acylating agent. The
imine is finally hydrolyzed under neutral conditions provid-
ing the free primary amine.
This method was generalised to some representative
commercially available diamino compounds and actually
allowed the chemoselective acylation and alkylation of
secondary amines.
2
3
4
During our work necessitating a selective alkylation of a
secondary amine in the presence of a primary amine, we
developed a short procedure in which 4-methyl-2-pentanone
4
-Methyl-2-pentanone (MIBK) boils at 116 °C and
provides an efficient azeotrope with water boiling at 88 °C.
On the basis of this property, three different processes for
the imine formation were developed. First, we found that
high boiling free diamines could be quantitatively trans-
formed to the imine by removal of water by azeotropic
distillation (Table 1, Method A). Low boiling free diamines
were converted to the Schiff base by heating them in the
presence of a dehydrating agent such as magnesium or
sodium sulphate (Table 1, Method B). Finally, hydrochloride
(MIBK), an inexpensive solvent, was used not only as the
reaction medium but also as a temporary protecting group
for the primary amine (Scheme 1). We found that heating 1
in MIBK with sodium carbonate in the presence of 1-chloro-
3-methoxypropane led selectively to the alkylated imine 2.
Hydrolysis of 2 provided the free primary amine 3 in good
yield and high purity. Alkylation of 1 carried out in other
solvents gave 3 with large amounts of polyalkylated products.
It is known that imines of some closely related 1,3-amino
alcohols exist as mixtures with the corresponding 1,3-
Table 1. Selective Boc-protection of secondary N in the
presence of primary N
5
oxazine; however, this tautomer (possibly leading to bis-
alkylation) was not observed in the case of 2.
*
To whom correspondence should be addressed. E-mail: frederic.laduron@
mil.be.
(1) (a) Theodoridis, G. Tetrahedron 2000, 56, 2339. (b) Green, T. W.; Wuts,
P. G. M. ProtectiVe Groups in Organic Synthesis, 3rd ed.; Wiley: New
York, 1999.
(
(
2) O’Sullivan, M. C.; Dalrymple, D. M. Tetrahedron Lett. 1995, 36, 3451
3) (a) Krakowiak, K. E.; Bradshaw, J. S. Synth. Commun. 1998, 28, 3451. (b)
Xu, D.; Mattner, P. G.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron
Lett. 1996, 37, 5301.
(
4) Prugh, J. D.; Birchenough, L. A.; Eghertson, M. S. Synth. Commun. 1992,
a
2
2, 2357.
(1) (A) azeotropic distillation in MIBK; (B) reflux in MIBK with Na
; (C) azeotropic distillation in MIBK with 2.5 equiv of Na CO
O. All products and imine
2
SO
4
or MgSO
2 2
Boc) O, 0 °C, 30 min. (3) H O or IPA/H
intermediates were characterised by GC-MS and/or NMR spectra.
4
2
3
. (2)
(
5) (a) Pedrosa, R.; Andr e´ s, C.; Duque-Soladana, J. P.; Ros o´ n, C. D.
Tetrahedron: Asymmetry 2000, 11, 2809. (b) F u¨ l o¨ p, F.; L a´ z a´ r, L.; Pelczer,
I.; Bern a´ th, G. Tetrahedron 1988, 44, 2993.
b
(
2
1
02
•
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10.1021/op049812w CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/21/2004

ammonium salts required sodium carbonate to liberate the
free base while azeotropic distillation allowed the water
removal (Table 1, Method C).
After complete imine formation (monitored by GC and
further characterized by GC-MS), 1 equiv of the electrophile
was added to the reaction mixture. We demonstrated that
acylation with Boc anhydride (Scheme 2, Table 1), as well
A short aqueous workup removed the salts, and the MIBK
phase containing the alkylated or acylated imine was
evaporated, and subsequently heated with water until com-
plete hydrolysis. Evaporation of water (and eventual cosol-
vent) provided finally the free secondary amine in good yield
and purity.
Reactions with Boc anhydride were carried out with cyclic
and acyclic diamines and showed high selectivities (Table
Scheme 2
1
). The products were obtained in high yields and with high
purities (GC > 92%). The only encountered byproduct was
the diacylated product formed by substitution of the primary
and the secondary amines with (Boc)
where necessary) lead to the pure compounds in very good
yields.
2
O. Further purification
(
Reactions with alkyl halides are outlined in Table 2. In
this case, one additional equivalent of an inorganic base was
required to trap the liberated acid. Benzylation gave a high
yield of monobenzylated product containing 8% of the
dibenzylated product. However, before hydrolysis of the
Table 2. Selective alkylation of secondary N in the presence
of primary N
as alkylation with alkyl halides (Scheme 1, Table 2), took
place smoothly. The Schiff bases are therefore stable to
substitution conditions as long as water is excluded.
(
6) (Experimental) Method A: In a flask equipped with a Dean-Stark trap
and a condenser, a mixture of the diamine in 2 L/M of MIBK was heated
to reflux under nitrogen. Reaction progress was monitored by recording
the volume of water produced and/or by GC analysis of the reaction mixture.
After no more water was produced, the mixture was cooled to 0 °C. Boc
anhydride (1 equiv) dissolved in a minimum of MIBK was then added
dropwise to the flask. After stirring for 0.5 h at room temperature, water
a
Method C: (1) azeotropic distillation in MIBK with 3.5 equiv of Na
O or IPA/H O.
2 3
CO .
(
2) Electrophile, rt. (3) H
2
2
(
0.2 L/M) was added. The aqueous layer was split off, and MIBK was
evaporated under reduced pressure leading to the imine intermediate. Water
and 2-propanol were then added, and the mixture was heated to 50 °C until
completion of the hydrolysis. Solvents were then distilled off providing the
free primary amine. Method B: A mixture of 4-(aminomethyl)-piperidine
imine, we observed that the reaction with benzyl chloride
had yielded less than 0.5% of the dibenzylated product. This
can be explained by the difference in the response factors in
GC between the imine and the amine. The low yield obtained
for the reaction with allyl bromide is presumably due to loss
of product during workup. No optimization was performed.
Scheme 1 demonstrated that a less activated alkyl chloride
gave also rise to the monoalkylated product in high yield
4
(57 g, 0.5 mol) and anhydrous MgSO (30 g, 0.25 mol) in MIBK (1000
mL, 2 L/M) was heated to reflux under nitrogen. After no more starting
material was observed by GC, the reaction mixture was cooled to 0 °C. To
this mixture, was added dropwise to a solution of BOC anhydride (109 g,
0
.5 mol) dissolved in a minimum of MIBK. After stirring for 0.5 h at room
temperature, water (100 mL, 0.2 L/M) was added to dissolve inorganic salts.
The aqueous layer was split off, and MIBK was evaporated under reduced
pressure leading to the imine intermediate. Water (50 mL) and 2-propanol
7
(500 mL) were then added, and the mixture was heated to 50 °C until
and high purity. This reaction was performed in the presence
of a catalytic amount of potassium iodide. No trace of a
dialkylated byproduct was detected.
completion of the hydrolysis. Solvents were then distilled off providing
tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (98.4 g, 92% yield). MS
+
1
(
CI) m/z 215 (MH ). H NMR (400 MHz, CDCl
3
): 1.08 (2H, m), 1.45
(
2
3
(
10H, m), 1.70 (2H, bd, J ) 13.3 Hz), 1.81 (2H), 2.58 (2H, d, J ) 6.6 Hz),
In conclusion, we demonstrated the efficiency of a method
allowing the selective substitution of secondary amine in the
presence of a primary amine. The latter is temporarily
protected by MIBK, the reaction solvent. The potential of
1
3
.68 (2H, m), 4.10 (2H, m). C NMR (100 MHz, CDCl
3
): 28.31, 29.63,
9.27, 43.68, 47.68, 79.09, 154.71. Method C for Boc protection: MIBK
2 L/M) was added to a flask containing the diamine hydrochloride salt (1
equiv) and sodium carbonate (2.5 equiv). The heterogeneous mixture was
heated to reflux under nitrogen, and water was removed from the reaction
mixture with a Dean-Stark trap. When the imine formation went to
completion, the flask was cooled to 0 °C. Boc anhydride (1 equiv) dissolved
in a minimum of MIBK was then added dropwise to the flask. After stirring
for 0.5 h at room temperature, water (0.5 L/M) was added. The aqueous
layer was split off, and MIBK was evaporated under reduced pressure
leading to the imine intermediate. Water and 2-propanol were then added,
and the mixture was heated to 50 °C until completion of the hydrolysis.
Solvents were then distilled off providing the free primary amine. Method
C for alkylation: MIBK (2 L/M) was added to a flask containing the
diamine hydrochloride salt (1 equiv) and sodium carbonate (3.5 equiv). The
heterogeneous mixture was heated to reflux under nitrogen, and water was
removed from the reaction mixture with a Dean-Stark trap. When the imine
formation went to completion, the flask was cooled to room temperature.
Alkyl halide (1 equiv) was then added to the mixture. After the mixture
stirred overnight at room temperature, water (0.5 L/M) was added. The
aqueous layer was split off, and MIBK was evaporated under reduced
pressure leading to the imine intermediate. Water and 2-propanol were then
added, and the mixture was heated to 50 °C until completion of the
hydrolysis. Solvents were then distilled off providing the free primary amine.
(7) (3S,4S)-4-(aminomethyl)-1-(3-methoxypropyl)piperidin-3-ol (3): MS (CI)
+
1
3
m/z 203 (MH ). H NMR (360 MHz, CDCl ): 1.14-1.27 (m, 1 H), 1.27-
1.39 (m, 1 H), 1.55 (ddd, J ) 12.7, 6.1, 2.7 Hz, 1 H), 1.72-1.83 (m, 3 H),
1.92 (td, J ) 11.5, 2.5 Hz, 1 H), 2.35-2.50 (m, 2 H), 2.69 (dd, J ) 12.2,
10.0 Hz, 1 H), 2.81-2.89 (m, 1 H), 3.02 (t, J ) 3.6 Hz, 1 H), 3.03-3.08
(m, 1 H), 3.32 (s, 3 H), 3.38 (br, 3H), 3.41 (t, J ) 6.4 Hz, 2 H), 3.63 (td,
J ) 9.5, 4.4 Hz, 1 H). Products identified by comparison with authentical
samples made by literature methods: (tert-butyl 4-(aminomethyl)piperidine-
1-carboxylate) Yoneda, Y.; Kawajiri, S.; Hasegawa, A.; Kito, F.; Katano,
S.; Takano, E.; Mimura, T. Bioorg. Med. Chem. Lett. 2001, 11, 1261; (tert-
butyl 4-aminopiperidine-1-carboxylate) Mach, R. H.; Luedtke, R. R.;
Unsworth, C. D. et al. J. Med. Chem. 1993, 36, 3707; (tert-butyl 4-(2-
aminoethyl)piperazine-1-carboxylate) Yang, L.; Patchett, A. A.; Pasternak,
A. et al. WO 9845285; (tert-butyl (2-aminoethyl)benzylcarbamate) Kruijtzer,
J. A. W.; Lefeber, D. J.; Liskamp, R. M. J. Tetrahedron Lett. 1997, 38
(30), 5335; (1-benzylpiperidine-4-amine) Acros no. 18766. Identity of all
products was also confirmed at the level of their crystalline derivatives which
are pharmaceutical intermediates under patenting.
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103

this protocol was illustrated by carrying out acylation
reactions with BOC anhydride as well as alkylation reactions
in MIBK under homogeneous or heterogeneous condition-
s.Moreover, those transformations could be easily performed
in a “one-pot” fashion making this methodology very
attractive for large-scale synthesis.
Acknowledgment
This contribution is dedicated to the memory of Vanessa
Tamborowski.
Received for review October 13, 2004.
OP049812W
104
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