Convenient strecker reactions of piperidine derivatives with cyclic ketones under aqueous conditions

Article abstract of DOI:10.1080/00397910701845795

Strecker reactions convenient for the preparation of piperidinyl acetonitrile compounds under aqueous conditions are described. The use of TsOH·H2O is the key to afford the desired products in good and reproducible yield. Copyright Taylor & Francis Group,

Full text of DOI:10.1080/00397910701845795

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Synthetic Communications , 38: 1485–1490, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845795
Convenient Strecker Reactions of Piperidine
Derivatives with Cyclic Ketones under
Aqueous Conditions
Yoshinori Murata and Kunio Satake
Department of Pharmaceutical Science, Chemical Research and
Development Group, Pfizer Global Research and Development, Aichi, Japan
Abstract: Strecker reactions convenient for the preparation of piperidinyl acetonitrile
.
compounds under aqueous conditions are described. The use of TsOH H
to afford the desired products in good and reproducible yield.
2
O is the key
Keywords: a-aminonitrile, para-toluenesulfonic acid, Strecker reaction
In the course of structure-activity relationship (SAR) studies to prepare
analgesic compounds through opioid receptors, especially the ORL1
receptor, it was necessary to prepare the piperidine derivatives shown in
Fig. 1. We tried to prepare these compounds, using the Strecker reaction, by
reacting the corresponding piperidines with cyclic ketones in the presence
[
1]
of potassium cyanide (KCN). However, the yield of a-aminonitrile 1
from the reaction of 4 and cycloheptanone (5) with KCN in aqueous HCl
was not reproducible. (Compound 4 was purchased from Acros.) In
contrast, the reaction with the corresponding HCl salt gave 1 in good and
reproducible yield. Although the HCl salt could be routinely isolated after
concentration of solution 4 in HCl/MeOH, it would be more convenient not
to do this. Herein, we report simple conditions for the Strecker reaction of
Received September 6, 2007
Address correspondence to Yoshinori Murata, Department of Pharmaceutical
Science, Chemical Research and Development Group, Pfizer Global Research and Devel-
opment, 5-2 Taketoyo, Aichi 470-2393, Japan. E-mail: japan_ym@yahoo.co.jp
1
485

1
486
Y. Murata and K. Satake
Figure 1. Piperidine derivatives.
piperidine 4 with cyclic ketones to afford a-aminonitriles 1 and 2 using
.
TsOH H O.
2
To isolate the a-aminonitrile easily, we tried to use several acids first, and
.
we found TsOH H O showed good results. Under these conditions, it was not
necessary to isolate the tosylate salt. In practice, reaction of a mixture of 4,
2
.
TsOH H O (1.2 equiv.), cycloheptanone (5) (2 equiv.), and KCN (1.3
2
equiv.) in H O at ambient temperature for 18 h gave the desired product 1
2
in 97% yield as a white solid [Eq. (1)].
To expand the usefulness of this method, cyclooctanone (6) was tried next
Table 1). As shown in the table, the reaction with cyclooctanone (6) is much
(
slower than the reaction with cycloheptanone (5). Higher temperature, less
solvent volume, and excess reagent improved the chemical yield of 2 and
reduced the reaction time (entries 2 and 3). Under reflux conditions,
[2]
formamide 7 was obtained instead of the desired product 2. The use of
aqueous HCl in this reaction gave 2 as a viscous material. Other sulfonic
acids were tried (dodecylbenzenesulfonic acid, DBSA, and camphor
[
3]
sulfonic acid, CSA),
Under optimal conditions, TsOH H O (1.2 equiv.), 6 (3 equiv.), and KCN
but both failed to afford the desired results.
.
2
(
2 equiv.) were heated together at 458C for 18 h to give 2 in 84%
1
yield (2:4 ¼ ca. 30:1 based on H NMR analysis) as a white solid (entry 4).
We also tried to prepare the next target compound 3. In this case, we
found that Strecker reaction of piperidine 8 under similar treatment was

Reactions of Piperidine Derivatives
1487
Table 1. Strecker reaction of 4 with cyclooctanone (6)
a
b
Entry
6 (eq.) KCN (eq.)
H
2
O (vol) Conditions Yield (%)
Ratio 2:4
1
2
3
4
2
2
3
3
3
1.2
1.2
1.2
2
7.4
7.4
5
rt, 2 days
458C, 18 h
458C, 18 h
458C, 18 h
458C, 22 h
54
60
65
84
76
28:1
30:1
25:1
30:1
4:1
5
c
5
2
5
a
Isolated yield.
b
1
Determined by integration of H NMR analysis.
c
.
2
CSA was used instead of TsOH H O.
problematic and only a trace amount of the desired product 9 was obtained as
oil [Eq. (2)]. We thought that the a-aminonitrile product should be separated
as a solid from the reaction solution to improve the chemical yield because the
reaction equilibrium might then shift to the product. Gratifyingly, we found
[
4]
that Strecker reaction of the pyrrole compound 12
condition gave the desired product 13 in 72% as a solid, which is shown in
under optimal
Scheme 1.
In conclusion, a convenient method for the preparation of piperidinyl
.
acetonitriles has been developed. The use of TsOH H O was found to be
2
important to give the a-aminonitriles 1 and 2 in good and reproducible
yield. Isolation of Strecker product 13 as a solid was a key issue to
improve the chemical yield. Further effort to find an optimal condition
is ongoing.
Scheme 1. Strecker reaction of 12 with cyclooctanone (6).

1
488
Y. Murata and K. Satake
EXPERIMENTAL
NMR (1H, 13C) spectra were obtained using JMN-GX270, JEOL. Chemical
shifts are reported in parts per million (ppm) with reference to internal
solvent. HPLC (High Performance Liquid Chromatography) was recorded
on Alliance 2960, Waters. MS (Mass Spectroscopy) was recorded on
Automass 1, JEOL.
Preparation of a-Aminonitrile 1
.
A solution of TsOH H O (1.14 kg, 6.0 mol) in H O (2.0 L) was added
2
2
dropwise to an ice-chilled mixture of 4-(2-ketobenzimidazolinyl)piperidine
4) (1.09 kg, 5.0 mol) in H O (3.0 L), in an ice-cold bath. The addition
was exothermic, and the initial mixture turned into a solution during the
(
2
.
addition. (Mixtures of 4 and TsOH H O sometimes gave a white solid.
2
However, even in this case, Strecker product 1 was obtained in good
yield.) After stirring at rt for 30 min., cycloheptanone (5) (1.18 L, 10 mol)
was added. After an additional 30 min., a solution of KCN (423 g,
6.5 mol) in H O (3.0 L) was added dropwise, and the resulting mixture
2
was stirred at rt for 1 day. Hexane (8.0 L) was then added and stirring was
continued at rt for 4 h. The resulting mixture was filtered through filter
paper. The isolated solids were washed with H O (1.0 L) and hexane
2
(
1.0 L) and then dried in a vacuum oven (708C, 14 h) to afford 1 (1.64 kg,
7%). Based on HPLC analysis , the purity of the isolated product 1 is ca
9.5% and it contains 4 (ca. 0.3%) and unknown impurities (ca. 0.2%).
[7]
9
9
(Under reverse-phase-column conditions, compounds 1 and 4 could not be
separated.)
1
H NMR (CDCl ): d 9.32 (br s, 1H), 7.25–7.00 (m, 4H), 4.45–4.25
3
(
m, 1H), 3.28–3.16 (m, 2H), 2.60–2.10 (m, 4H), 2.26–2.10 (m, 2H),
þ
2
3
.05–1.85 (m, 4H), 1.80–1.40 (m, 8H). MS m/z 338 (M ). IR (KBr):
2
375, 2214, 1697 cm . Anal. calcd for C H N O: C, 70.98; H, 7.74;
1
2
0 26 4
N, 16.55. Found: C, 70.87; H, 7.73; N, 16.44. HPLC condition: column;
Daicel Chiral PAK AD, eluent; hexane/EtOH/Et NH ¼ 85:15:0.1,
2
1
mL/min.
Preparation of a-Aminonitrile 2
Similar treatment of 4 (43.5 g, 200 mmol), TsOH H O (45.7 g, 240 mmol), 6
.
2
(
75.7 g, 600 mmol), and KCN (26 g, 400 mmol) at 458C for 18 h gave 2
1
59.6 g, 84%) as a white solid. H NMR (CDCl ) d 9.90 (br s, 1H), 7.25–
(
3
7
.03 (m, 4H), 4.44–4.26 (m, 1H), 3.24 (d, 2H, J ¼ 10.9 Hz), 2.60–2.28
(
m, 4H), 2.20–1.45 (m, 16H). Anal. calcd for C H N O: C, 71.56; H,
2
1 28 4
8.01; N, 15.89. Found: C, 71.22; H, 8.09; N, 15.70.

Reactions of Piperidine Derivatives
1489
1-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-1-
piperidinyl]cyclooctanecarbonitrile (13)
.
In a 300-mL flask with a reflux condenser, a solution of TsOH H O (20 g,
2
1
05 mmol) in water (20 mL) to a mixture of crude amine 12 was added
[
4]
15.6 g, 87.3 mmol) in water (30 mL) at rt. It turned red. This reaction
(
was exothermic, and the internal temperature reached 338C. The resulting
solution was maintained at that temperature for 10 min. To this solution,
cyclooctanone (6) (13.2 g, 105 mmol) was added, then the resulting mixture
was heated at 458C. To this mixture, a solution of KCN (11.4 g, 175 mmol)
in water (30 mL) was added at 458C. The resulting mixture was stirred at
4
58C for 1 day. The solid was observed, and it was collected by filtration.
The obtained solid was washed with water (50 mL ꢀ 2). A mixture of this
solid (ca. 23 g) and hexane (75 mL, ca. 3 vol) (ca. 1 mg of a-aminonitrile
1
3 was soluble in 1 mL of hexane at rt) was stirred in an ice-cold bath for
5 min to remove excess cyclooctanone (6). The resulting mixture was
1
filtered, and the obtained cake was washed with hexane (15 mL ꢀ 2), then
it was dried in a vacuum oven (458C, 13h) to afford a-aminonitrile 13
(
19.8 g, 72%) as a white solid.
1
H NMR (270 MHz, CDCl ) d 5.75 (s, 2H), 4.04–3.88 (m, 1H), 3.19 (brd,
3
2
H, J ¼ 7.1 Hz), 2.31 (s, 6H), 2.32–1.99 (m, 10H), 1.75–1.43 (m, 10H). MS
þ
(EI direct) m/z: 313 (M ). Anal. calcd. for C H N : C, 76.63; H, 9.97; N,
0 31 3
2
1
3.40. Found: C, 76.39; H, 9.89; N, 13.53.
ACKNOWLEDGMENT
We thank our medicinal chemistry group for their early synthetic efforts. We
also thank Stephane Caron and John Ragan (Pfizer, Chemical R&D, Groton)
for useful discussion and Dave Whritenour (Pfizer, Chemical R&D, Groton)
for proofreading this manuscript.
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