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U. Košak et al. / Tetrahedron Letters 55 (2014) 2037–2039
Table 1
of LiAlH4 in anhydrous THF was used to reduce both amide
bonds:11 the benzoyl amide on the piperidine nitrogen was
reduced to a benzyl amine, and the primary amide on the piperi-
dine side chain was reduced to an aminomethyl group to give
compound 3. Compound 3 was not isolated, but was immediately
treated with Boc2O in the presence of Et3N in CH2Cl2. Thus, after
flash column chromatography, this provided orthogonally
protected piperidine 1 (Scheme 1). The overall isolated yield for
the preparation of compound 1 from nipecotamide using this pro-
cedure comprising three synthetic steps was 48% (Table 1). As the
starting nipecotamide was racemic, product 1 was also obtained as
a racemic mixture.
Synthesized orthogonally protected piperidin-3-ylmethanamines (1, 7a and 7b) and
piperidin-4-ylmethanamines (4, 8a and 8b)
Starting compound
Final compound
Overall yielda (%)
H
N
Ph
N
O
48
NH2
HN
Boc
1
H
N
Ph
N
The same procedure was then used to prepare the orthogonally
78
protected piperidin-4-ylmethanamine
4 from isonipecotamide
O
NH2
Boc
(Scheme 2). The overall isolated yield for these three steps was
even higher than for the synthesis of compound 1 (78%, Table 1).
We were also interested in the derivatives of compounds 1 and
4 that have an N-alkyl group [–(CH2)2–OMe or –(CH2)3–OMe] on
the aminomethyl side chain. Using the principle of the procedure
described above for the preparation of the parent compounds 1
and 4, we also synthesized compounds 7a and 7b from nipecotic
acid, and compounds 8a and 8b from isonipecotic acid. These syn-
theses confirm the general applicability of our procedure.
Here, nipecotic acid was treated with benzoyl chloride in the
presence of K2CO3 in a THF–H2O mixture, to provide, after acidifi-
cation, carboxylic acid 9 in 95% yield (Scheme 3). Compound 9 was
then converted into orthogonally protected piperidin-3-ylmethan-
amines 7a or 7b in a procedure composed of three reactions.
Purification of the intermediates in these steps was not necessary.
N
H
4
H
N
Ph
N
Boc
N
OH
OH
74
60
OMe
O
O
7a
H
N
Ph
N
Boc
N
OMe
7b
H
Ph
N
N
Carboxylic acid
9 was first treated with a primary amine
56
O
OH
OMe
N
(2-methoxyethylamine or 3-methoxypropylamine) in the presence
of O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetrafluo-
roborate (TBTU) and Et3N in CH2Cl2 at room temperature,12 to pro-
vide the corresponding amides 10a or 10b. Treatment of 10a or
10b with five equivalents of LiAlH4 in anhydrous THF under
reflux11 reduced both of the amide groups into their corresponding
amines 11a or 11b. Compounds 11a and 11b were finally treated
with Boc2O in the presence of Et3N in CH2Cl2. Flash column chro-
matography then provided orthogonally protected piperidines 7a
and 7b. The overall yields for the preparation of compounds 7a
and 7b from nipecotic acid using this procedure composed of four
synthetic steps were 74% and 60%, respectively (Table 1). As the
starting nipecotic acid was racemic, products 7a and 7b were also
obtained as racemic mixtures. The overall yields for preparing
compounds 8a and 8b from isonipecotic acid (Scheme 4) using
the same procedure were 56% and 65%, respectively (Table 1).
In summary, we have developed convenient procedures for the
synthesis of orthogonally protected piperidin-3-ylmethanamine
and piperidin-4-ylmethanamine derivatives that start from com-
mercially available nipecotamide, isonipecotamide, nipecotic acid,
and isonipecotic acid. No purification of the intermediates was
necessary, which helps maintain the high overall yields for our
syntheses. The synthesized 1,3- and 1,4-disubstituted piperidines
Boc
8a
H
N
Ph
N
65
O
OH
N
Boc
OMe
8b
a
Isolated yield of pure product.
Ph
O
Ph
Ph
H
N
i
N
ii (a)
N
ii (b)
N
Boc
N
H
O
NH2
O
NH2
NH2
5
6
4
(not isolated)
Scheme 2. Reagents and conditions: (i) PhCOCl, Et3N, THF, 0 °C to rt, 25 h, 95%; (ii)
(a) LiAlH4, anhydrous THF, rt to reflux, 2 h, under argon, (b) Boc2O, Et3N, CH2Cl2, 0 °C
to rt, 21 h, 82% (for step ii).
Ph
O
Ph
O
Ph
Ph
H
N
ii (a)
ii (b)
ii (c)
i
N
N
N
N
Boc
N
H
N
H
N
OH
OH
R
R
R
O
O
O
7a: R = -(CH2)2-OMe
7b:
9
10a: R = -(CH2)2-OMe
10b: R = -(CH2)3-OMe
11a:
11b:
R = -(CH2)2-OMe
R = -(CH2)3-OMe
R = -(CH2)3-OMe
(not isolated)
(not isolated)
Scheme 3. Reagents and conditions: (i) (a) PhCOCl, K2CO3, THF–H2O, 0 °C to rt, 22 h, (b) 6 M HCl (aq), 0 °C, 95%; (ii) (a) H2N-R, TBTU, Et3N, CH2Cl2, rt, 22 h for 10a and 21 h for
10b, (b) LiAlH4, anhydrous THF, rt to reflux, under argon, 3 h for 11a and 2.5 h for 11b, (c) Boc2O, Et3N, CH2Cl2, 0 °C to rt, 20 h for 7a and 17 h for 7b, 78% for 7a from 9, and 63%
for 7b from 9.
Ko?ak, Urban
