A facile synthesis of racemic 2-aminomethyl-4-oxo-piperidine intermediates

Article abstract of DOI:10.1081/SCC-120018941

Facile access to the 2-substituted piperidine nucleus was achieved by a 3-component hetero Diels-Alder reaction. The use of an appropriately functionalized imine allowed the installation of a protecting group for both the piperidine and 2-position side ch

Full text of DOI:10.1081/SCC-120018941

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A Facile Synthesis of Racemic 2-Aminomethyl-4-oxo-
piperidine Intermediates
Daniel D. Holsworth a c , Farid Bakir a , Roy T. Uyeda a , Yu Ge a , Jesper Lau b , Thomas K.
Hansen b & Henrik Sune Andersen b
a Ontogen Corporation, Department of Chemistry , Carlsbad, California, USA
b MedChem. Research I# and IV‡ , Novo Nordisk A/S, Denmark
c Pfizer Global Research and Development, Department of Chemistry , 2800 Plymouth Road,
Ann Arbor, MI 48105, USA Fax: E-mail:
Published online: 17 Aug 2006.
To cite this article: Daniel D. Holsworth , Farid Bakir , Roy T. Uyeda , Yu Ge , Jesper Lau , Thomas K. Hansen & Henrik Sune
Andersen (2003) A Facile Synthesis of Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:10, 1789-1795, DOI: 10.1081/
SCC-120018941
To link to this article: http://dx.doi.org/10.1081/SCC-120018941
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 10, pp. 1789–1795, 2003
A Facile Synthesis of Racemic
2-Aminomethyl-4-oxo-piperidine Intermediates
1
1
Daniel D. Holsworth,1, Farid Bakir, Roy T. Uyeda,
*
z
Yu Ge,1 Jesper Lau,2,# Thomas K. Hansen,2,
and Henrik Sune Andersen2,#
1Ontogen Corporation, Department of Chemistry,
Carlsbad, California, USA
2MedChem. Research I# and IV,z
Novo Nordisk A/S, Denmark
ABSTRACT
Facile access to the 2-substituted piperidine nucleus was achieved by
a 3-component hetero Diels-Alder reaction. The use of an appropri-
ately functionalized imine allowed the installation of a protecting
group for both the piperidine and 2-position side chain nitrogens
in one step. Also, by employing 2-trimethylsiloxy-1,3-butadiene, a
reduction step was avoided, thus providing rapid entry into the
piperidine core structure. This protocol led to the synthesis of
*Correspondence: Daniel D. Holsworth, Pfizer Global Research and
Development, Department of Chemistry, 2800 Plymouth Road, Ann Arbor,
MI 48105, USA; Fax: 734-622-3107; E-mail: Daniel.holsworth@pfizer.com.
1789
DOI: 10.1081/SCC-120018941
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1790
Holsworth et al.
some racemic 2-aminomethyl-4-oxo-piperidines; intermediates that
were synthesized in multigram quantities.
Key Words: Hetero Diels-Alder; 2-Aminomethyl 1-4-oxo-piperidine.
INTRODUCTION
The piperidine nucleus serves as an essential core for a variety of
natural products as well as a scaffold for drug candidates.[1] During
our research activities, we required a ‘‘masked’’ 2-aminomethyl-4-oxo-
piperidine skeleton (1). In an effort to synthesize the desired scaffold (1)
in an expeditious fashion, it was envisioned that a hetero Diels-Alder
reaction with a functionalized imine moiety would provide rapid entry
into the desired piperidine ring system. This approach also provides a
starting structure with appropriate nitrogen protecting groups present as
well as the desired regiochemistry set in one step[2] (Sch. 1).
Catalysts for the hetero Diels-Alder reaction (Table 1, Entries 1–5)
were chosen from published work,[3] where hetero Diels-Alder reactions
between electron deficient imines and electron rich dienes were successful.
Of primary concern was the electronically rich nature of both the diene as
well as the in-situ generated dienophile (Sch. 2). From the selection of
published catalysts, only BF3–OEt2 (Entry 1) led to low yields of the
desired product (1).
Interestingly, aluminum chloride (Table 1, Entry 6) proved to be the
best catalyst for the preparation of 1, providing the piperidine framework
in 37% yield.
A modest amount (ꢀ11%) of crude trimethylsilyl enol ether (inter-
mediate, Sch. 2) was observed during work-up and after purification.
Exposing the reaction mixture to 1 N HCl for longer periods of
Scheme 1. Retrosynthetic analysis of racemic 2-aminomethyl-4-oxo-piperidine.

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Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates
1791
Table 1. Conditions explored for hetero Diels-Alder reaction. Entry 6 was found
to be the best catalyst/conditions investigated.
Entry #
Catalyst
Temperature (ꢁC)
Solvent
% Yield of 1
1
2
3
4
5
6
BF3–OEt2
Yb(OTf )3
Yb(OTf )3
BF3–OEt2
ZnI2
0
0 to rt
0
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
8
0
0
ꢂ20
0
ꢂ40
0
37
AlCl3
ꢂ78 to rt
Scheme 2. Hetero Diels-Alder reaction for 4-oxo-2-substituted piperidine
synthesis (1).
time (>2 h) during work-up did not improve hydrolysis. Therefore, after
isolation, additional 1 N hydrochloric acid was needed to convert the silyl
intermediate to the 4-oxo-piperidine framework.
We have conducted the hetero Diels-Alder reaction on 15 g scale and
obtained isolated yields of compound 1 in the33–38% range
(see Experimental Section). Once a reliable and efficient synthesis of
compound 1 was in hand, transformation of the 4-keto moiety into
the 1,3-dioxolane provided the fully protected 2-aminomethyl-4-oxo-
piperidine compound 2 (Sch. 3). Liberation of the primary amine with
hydrazine produced another useful 2-aminomethyl-4-oxo-piperidine
building block (compound 3).
In conclusion, the useful 2-substituted-4-oxo-piperidine scaffold
can be rapidly obtained in racemic form in a single step via a hetero
Diels-Alder reaction between an appropriately substituted imine and
2-trimethylsilyl-1,4-butadiene. The utility of this methodology has been
demonstrated in our laboratories by the production of useful synthetic
intermediates for drug discovery.

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1792
Holsworth et al.
Scheme 3. Simpletransformation of compound 1 to racemic 2-aminomethyl-4-
oxo-piperidine building blocks 2 and 3.
EXPERIMENTAL SECTION
All reagents were purchased from Aldrich and used without further
purification. Solvents used were of HPLC grade and used without further
purification. NMR spectra were recorded on a Varian 400 MHz
spectrometer and referenced to the solvent. Melting point values are
uncorrected.
2-[1-(4-Methoxy-benzyl)-4-oxo-piperidin-2-yl-methyl]-
isoindole-1,3-dione (1)
Phthalimidoacetaldehyde diethyl acetal (100 g, 0.38 mol), THF
(600 mL) and 1 N HCl (300 mL) were heated to 80ꢁC for 18 h, then
cooled and the solvent evaporated in vacuo. The semi-solid was diluted
with dichloromethane (600 mL) and the solids filtered (Keep solid!). The
filtrate was washed with saturated sodium bicarbonate (2ꢃ), brine(2 ꢃ)
and dried over magnesium sulfate. Removal of solvent gave a solid, that
was washed with n-butylchlorideto produce22.0 g of (1,3-dioxo-1,3-
dihydro-isoindol-2-yl)-acetaldehyde as a white solid. To the solid that
was put aside, add THF (600 mL), magnesium sulfate and activated
carbon (ꢀ5 g each). The mixture was stirred at rt for 2 h, filtered through
a pad of celite and evaporated in-vacuo to give a brown oil. N-Butyl-
chloride was added to the oil and triturated to form a brown solid.
N-Butylchloride(500 mL) was added again to thesolid and thesolids
collected via suction filtration. 49.64 g of beige solid was obtained. The
49.6 g of beige solid was partially dissolved in 600 mL of chloroform and
stirred 5 min. The insolubles were filtered off and the mother liquor eva-
porated under reduced pressure to obtain 41.20 g of (1,3-Dioxo-1,3-dihy-
dro-isoindol-2-yl)-acetaldehyde as a white solid. Total amount of

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Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates
1793
(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetaldehyde
isolated:
63.20 g
(88%). M.p. ¼ 112–114ꢁC (lit. value: 114ꢁC; Ref.[4]); 1H NMR
(400 MHz, CDCl3) ꢀ: 9.64 (s, 1H), 7.87 (dd, J ¼ 5.6, 2.4, 2H), 7.75 (dd,
J ¼ 5.2, 2.8, 2H), 4.56 (s, 2H); 13C NMR (100 MHz, CDCl3) ꢀ: 47.6, 123.9,
132.1, 134.5, 167.7, 193.7; Anal. calcd for C10H7NO3 (%): C, 63.49;
H, 3.73; N, 7.40; found: C, 63.09; H, 3.73; N, 7.15; MS (APCI) m/z
190.0 (M þ 1).
(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-acetaldehyde (17.3 g, 0.092
moles), 150 mL of dry dichloromethane, molecular sieves (15 g, 4 A),
and 4-methoxybenzylamine (11.9 mL, 0.092 moles) were stirred at rt,
under nitrogen for 1 h. The reaction mixture was filtered and the solution
(imine in dichloromethane) added to an addition funnel containing 2-
trimethylsilyloxy-1,3-butadiene (20.9 mL, 0.12 moles). The resultant mix-
turewas added slowly to a solution of aluminum chloride(14.64 g, 0.11
moles) in dichloromethane (100 mL) previously cooled to ꢂ78ꢁC. Once
theaddition was completethemixturewas allowed to stir for 18 h, slowly
warming to rt. The reaction mixture was cooled to 0ꢁC and 1 N HCl
(100 mL) was added slowly. Once the addition completed, the reaction
mixture was stirred for 2 h. Water was added (0.5 L) and the product
extracted with dichloromethane (Keep aqueous layer). The aqueous
layer was basified with sodium carbonate and extracted with dichloro-
methane. The organic fractions were combined, washed with brine (2ꢃ)
and dried over anhydrous magnesium sulfate. The solvent was removed
in-vacuo to yield a brown solid (35 g). The solid was subjected to
flash chromatography (60:40 hexanes/ethyl acetate) to produce 11.8 g
of 2-[1-(4-methoxy-benzyl)-4-oxo-piperidin-2-yl methyl]-isoindole-1,3-
dione( 1 (Rf ¼ 0.4)) as a yellow solid. Also obtained was 4.6 g of crude
TMS enol ether product (Rf ¼ 0.87, 60 hexanes/40 ethyl acetate). The
crude enol ether was subjected to 1 N HCl for 2 h. The solution was
basified with sodium carbonate and extracted with dichloromethane.
The organic layer was washed with brine and subjected to flash chroma-
tography to yield 1.0 g of additional 1. Total amount of compound 1
isolated: 12.8 g (37%). M.p. ¼ 97–99ꢁC; H NMR (400 MHz, CDCl3) ꢀ
1
7.77 (dd, J ¼ 4.8, 2.8, 2H), 7.69 (dd, J ¼ 5.6, 2.8, 2H), 6.97 (d, J ¼ 8.8,
2H), 6.54 (d, J ¼ 8.8, 2H), 3.88 (q, J ¼ 4.4, 1H), 3.76 (q, J ¼ 19.2, 2H),
3.68 (s, 3H), 3.52ꢂ3.44 (m, 2H), 3.38 (ddd, J ¼ 14, 10, 3.6, 1H), 2.89 (dt,
J ¼ 10, 4.8, 1H), 2.61 (ddd, J ¼ 15, 6, 1.2, 1H), 2.47 (dddd, J ¼ 15, 14, 10,
6, 1H), 2.26 (m, 1H), 2.22 (m, 1H); 13C NMR (100 MHz, CDCl3) ꢀ:
39.0, 39.5, 41.6, 47.7, 55.3, 56.7, 58.2, 113.8, 123.4, 129.7, 130.9, 132.2,
134.1, 158.9, 168.2, 208.7; Anal. calcd for C22H22N2O4 (%): C, 69.77; H,
5.86; N, 7.26; found: C, 69.83; H, 5.86; N, 7.40; MS (APCI) m/z
379.3 (M þ 1).

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1794
Holsworth et al.
2-[8-(4-Methoxy-benzyl)-1,4-dioxa-8-aza-spiro[4.5]dec-7-yl
methyl]-isoindole-1,3-dione (2)
A 500 mL flask, equipped with a reflux condensor and Dean-Stark
trap was charged with compound 1 (3.0 g, 7.9 mmol), toluene (210 mL),
ethylene glycol (3.62 mL, 20 equiv.), pyridinum p-toluenesulfonate
(1.22 g, 4.8 mmol), and molecular sieves (4 A, 1.5 g). Thereaction mixture
was heated to 140ꢁC for 18 h. The reaction mixture was cooled to rt,
diluted in ethyl acetate (500 mL) and washed with saturated sodium
bicarbonate(3 ꢃ 100 mL), and brine(3 ꢃ 100 mL). Theorganic layre
was dried over anhydrous magnesium sulfate, filtered and concentrated
in-vacuo to yield an oil. The oil was subjected to column chromatography
(80% ethyl acetate/20% hexanes) to yield 2.51 g (75%) of 2-[8-(4-
methoxy-benzyl)-1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl]-isoindole-
1,3-dione (2) as an orangesemi-solid. 1H NMR (400 MHz, CDCl3) ꢀ: 7.76
(dd, J ¼ 5.6, 3.2, 2H), 7.66 (dd, J ¼ 5.6, 3.2, 2H), 6.98 (dd, J ¼ 6.8, 2, 2H),
6.52 (dd, J ¼ 6.4, 1.6, 2H), 4.23 (dd, J ¼ 14, 8.6, 1H), 3.93 (dddd, J ¼ 9.6,
7.2, 6, 4.4, 2H), 3.87 (dddd, J ¼ 9.6, 7.6, 6.4, 4.4, 2H), 3.81 (d, J ¼ 13.6,
1H), 3.66 (s, 3H), 3.48 (ddd, J ¼ 19.6, 14, 5.6, 2H), 3.15 (dddd, J ¼ 17.2,
13.2, 9.2, 3.6, 1H), 3.06 (dddd, J ¼ 18.8, 13.6, 10.4, 5.2, 1H), 2.50 (dddd,
J ¼ 13.2, 10.4, 6.4, 4, 1H), 1.85 (dddd, J ¼ 13.6, 6.4, 5.2, 1.2, 1H),
1.69–1.50 (m, 3H); 13C NMR (100 MHz, CDCl3) ꢀ: 31.8, 34.6, 40.1,
46.7, 55.3, 56.3, 56.6, 64.6, 107.6, 113.6, 123.3, 129.8, 131.8, 132.5,
133.9, 158.6, 168.5; Anal. calcd for C24H26N2O5ꢄ1.5 H2O (%): C, 64.13;
H, 6.50; N, 6.23; found: C, 64.25; H, 5.75; N, 6.14; MS (APCI) m/z 423.1
(M þ 1).
2-[8-(4-Methoxy-benzyl)-1,4-dioxa-8-aza-spiro[4.5]dec-7-yl]-
methylamine (3)
2-[8-(4-Methoxy-benzyl)-1,4-dioxa-8-aza-spiro[4.5]dec-7-yl methyl]-
isoindole-1,3-dione (2, 2.50 g, 5.9 mmol), was dissolved in ethanol
(45 mL) and anhydrous hydrazine (0.93 mL, 29.6 mmol) added dropwise.
The reaction was complete within 5 h at rt. The reaction mixture was
evaporated to dryness under reduced pressure and the resultant solid
dissolved in chloroform (40 mL). The solution was filtered to separate
insolubles. The filtrate was concentrated, redissolved in chloroform and
filtered once again. This procedure was repeated (ꢀ5 times) until no
precipitate occurred and compound was pure by 1H NMR. 2-[8-(4-meth-
oxy-benzyl)-1,4-dioxa-8-aza-spiro[4.5]dec-7-yl]-methylamine (3) was
isolated in 95% yield (1.63 g), as a yellow semi-solid. 1H NMR

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Racemic 2-Aminomethyl-4-oxo-piperidine Intermediates
1795
(400 MHz, CDCl3) ꢀ: 7.22 (d, J ¼ 8.8, 2H), 6.84 (d, J ¼ 8.8, 2H), 3.94
(dddd, J ¼ 6.4, 5.2, 4, 2, 2H), 3.92 (dddd, J ¼ 9.2, 6, 4, 1.6, 2H), 3.88
(d, J ¼ 13.2, 1H), 3.78 (s, 3H), 3.34 (d, J ¼ 13.2, 1H), 3.04 (dd, J ¼ 13.6,
5.2, 1H), 2.92 (dd, J ¼ 13.2, 5.6, 1H), 2.85 (dddd, J ¼ 12.8, 10.4, 6, 4.4,
1H), 2.73 (m, 1H), 2.40 (ddd, J ¼ 13.2, 9.6, 4, 1H), 1.76 (m, 2H),
1.65–1.59 (m, 2H); 13C NMR (100 MHz, CDCl3) ꢀ: 32.8, 36.2, 42.9,
47.5, 55.5, 55.9, 59.7, 64.4, 64.5, 107.8, 114.0, 130.1, 131.1, 158.9; Anal.
calcd for C16H24N2O3 ꢄ 1.0 H2O (%): C, 61.91; H, 8.44; N, 9.03; found: C,
61.83; H, 7.98; N, 8.77; MS (APCI) m/z 293.2 (M þ 1).
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Received in the USA August 16, 2002

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