Synthesis of 4,4-disubstituted piperidine-2-carbonitriles and piperidine-2,6-dicarbonitriles as precursors for newα-amino acids

Article abstract of DOI:10.1055/s-0030-1260186

An easy and straightforward method for the synthesis of 4,4-disubstituted pipecolic acid and piperidine-2,6-dicarboxylic acid derivatives has been developed, based on the addition of cyanide ions to 4,4-disubstituted 1,4-dihydropyridines, which are easily

Full text of DOI:10.1055/s-0030-1260186

3332
PAPER
Synthesis of 4,4-Disubstituted Piperidine-2-carbonitriles and Piperidine-2,6-
dicarbonitriles as Precursors for New a-Amino Acids
S
ynthesis of Cyan
o
o-Substitute
r
d Piperi
n
dines elia E. Schmaunz, Klaus T. Wanner*
Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-University Munich, Butenandtstr. 5–13, 81377 Munich,
Germany
Fax +49(89)218077247; E-mail: klaus.wanner@cup.uni-muenchen.de
Received 22 June 2011; revised 14 July 2011
inhibitor of HIV-1 protease. The structurally related pipe-
Abstract: An easy and straightforward method for the synthesis of
ridine-2,6-dicarboxylic acids are an important class of
compounds as well. For instance, betalains are a well-
known group of antioxidant pigments representing exam-
4,4-disubstituted pipecolic acid and piperidine-2,6-dicarboxylic
acid derivatives has been developed, based on the addition of cya-
nide ions to 4,4-disubstituted 1,4-dihydropyridines, which are easi-
ly accessible by trapping activated N-silylpyridinium ions with ples of 4-substituted derivatives of this type of com-
pounds.14 Moreover, piperidine-2,6-dicarboxylic acids
diorganomagnesium reagents. Acidic hydrolysis of the resulting
4,4-disubstituted piperidine-2-carbonitriles and the individual dia-
are versatile synthons for the synthesis of 2,6-disubstitut-
stereomers of the piperidine-2,6-dicarbonitriles led to the corre-
ed piperidine derivatives, as demonstrated in the construc-
sponding a-amino acids in high yields.
tion of the marine alkaloid halichlorine15 or bridged
lobelane analogues.16
Key words: piperidines, pyridines, carboxylic acids, nitriles, nu-
cleophilic addition, reduction
The synthesis of 2-cyanopiperidines via tetrahydropy-
ridines by a modified Strecker reaction and the subsequent
hydrolysis of the a-aminonitriles to a-amino acids are
In recent years, a number of a-aminonitriles have been de-
widely used and well known for their high efficiency.5 Pi-
veloped for medical use and it has been shown that the ni-
peridine-2,6-dicarbonitriles are commonly prepared by
trile group plays an important role for the biological
the reduction of dipicolinic acid derivatives or the reaction
activity of these compounds.1 Cyanopyrrolidines for ex-
of glutaraldehyde with amines in the presence of a cya-
ample have been the most thoroughly investigated class of
nide source.17 The formation of piperidine-2,6-dicarboni-
DPP-IV inhibitors including vildagliptin that was recently
triles via 1,4-dihydropyridines is rarely reported in
approved for the treatment of type 2 diabetes.1,2 Also a se-
literature. For instance, the hydrocyanation of decahy-
ries of nitrile-based cathepsin inhibitors has been found to
droacridines afforded 2,6-dicyanopiperidines.18 Further-
interact with the active site cysteine residue to form a co-
more, 2,6-dicyanopiperidines were observed as side
valent thioimidate adduct.1,3,4
products when reducing pyridinium salts in the presence
of cyanide ions.19 For the synthesis of 4,4-disubstituted pi-
peridine-2-carbonitriles and pipecolic acids only a few
methods of limited applicability have been published.20,21
Furthermore, for 4,4-disubstituted piperidine-2,6-dicar-
boxylic acids no examples have been reported in literature
so far.
Furthermore, the acidic hydrolysis of a-aminonitriles is
one of the most efficient methods to obtain a-amino
acids.5 Particularly, a-cyanopiperidines are interesting
precursors for the synthesis of pipecolic acid derivatives,
which play a versatile role in medicinal chemistry.
Pipecolic acid is found in several natural products with
remarkable biological activities, such as the immunosup-
pressants Tacrolimus (FK506)6 and Sirolimus (rapamy-
cin)7 or the antitumor antibiotic sandramycin.8 It has also
been inserted instead of proline into a variety of peptido-
mimetics and into peptides to induce significant changes
in bioactivity.9 Especially 4-substituted pipecolic acid de-
rivatives are key components in a number of pharmaceu-
tically important compounds. For instance, the 4-methyl-
substituted pipecolic acid argatroban10 is a potent throm-
bin inhibitor and the structurally related 4-phenyl-substi-
tuted MNAPPA11 acts as a selective trypsin inhibitor. 4-
Substituted pipecolic acids have also attracted attention as
NMDA receptor antagonists12 and as anti-HIV agents,
such as palinavir,13 a highly potent peptidomimetic-based
In this study, we wish to present a facile and versatile syn-
thesis of 4,4-disubstituted piperidine-2-carbonitriles and
piperidine-2,6-dicarbonitriles from easily accessible 4,4-
disubstituted 1,4-dihydropyridines by hydrocyanation and
their transformation to the corresponding 4,4-disubstitut-
ed pipecolic acid and piperidine-2,6-dicarboxylic acid de-
rivatives by acidic hydrolysis.
In a recent paper, we have reported an efficient approach
to 4,4-disubstituted N-silyl-protected 1,4-dihydropy-
ridines, wherein the key step is the trapping reaction of ac-
tivated N-silylpyridinium ions with diorganomagnesium
reagents.22 The resulting 1,4-dihydropyridines have
already been shown to be of high synthetic utility, for ex-
ample, for the preparation of 5-substituted 7,8-benzomor-
phans.23 As demonstrated by the present study, this class
of compounds provides an efficient access to 4,4-disubsti-
SYNTHESIS 2011, No. 20, pp 3332–3342
x
x.
x
x
.
2
0
1
1
Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1260186; Art ID: T63611SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Cyano-Substituted Piperidines
3333
Table 1 Synthesis of Unprotected 4,4-Disubstituted Piperidine-2,6-dicarbonitriles via N-Silyl-Protected 1,4-Dihydropyridines
R
R
R
R
R
R
R
AcOH (15 equiv)
NaCN (3 equiv)
1. TIPSOTf, r.t.
2. R2Mg, –78 °C
+
MeOH, 70 °C
1 h, MW
N
N
N
NC
N
CN
NC
CN
H
H
1a–c
Si
cis-3a–c
trans-3a–c
2a–c
Starting material
Products
Entry
1
a
b
c
R
2
a
b
c
Yield (%)
cis-3
Yield (%)
trans-3
Yield (%)
1
2
3
Et
81
a
b
c
43
44
43
a
b
c
41
40
41
Bn
85a
62
CH2CH2Ph
a Data from the literature.22
tuted piperidine-2-carbonitriles and piperidine-2,6-dicar- hydrocyanation reaction must be the result of thermody-
bonitriles as well. namic control for 3a, which should apply for 3b,c, as well.
The 4,4-disubstituted N-silyl-1,4-dihydropyridines 2a–c In addition, conditions for the monocyanation of 2a–c to
required as starting materials were prepared from the 4- give the protected piperidine-2-carbonitriles 5a–c were
substituted pyridines 1a–c according to the aforemen- studied. A reaction of the 1,4-dihydropyridine 2a (0.057
tioned procedure22 providing them in good yields. The re- M in MeOH), for which only a small excess of acid in re-
sults are listed in Table 1, including 2b, the synthesis of lation to sodium cyanide had been used, had provided a
which had been reported already before.22
mixture in which beside deprotected cis-3a (27%) and
trans-3a (27%) and N-silyl-protected cis-4a (38%) also
small amounts of 5a (8%) were present (1H NMR analy-
sis; Table 2, entry 1). When an excess of sodium cyanide
in relation to acetic acid was used, 5a appeared as sole
product, but in low amounts, because of poor conversion
(1H NMR analysis; Table 2, entry 2).
For the hydrocyanation reactions, the 1,4-dihydropy-
ridines 2a–c were treated with a mixture of acetic acid and
sodium cyanide in MeOH. Heating was performed in a
closed system under microwave irradiation to avoid un-
controlled loss of hydrocyanic acid. After some experi-
mentation, it was found that the transformation is best
accomplished when the 4,4-disubstituted N-silyl-1,4-di- To prevent the removal of the N-silyl group on the one
hydropyridines 2a–c were heated to 70 °C with 3 equiva- hand and to achieve a high conversion on the other hand,
lents of sodium cyanide and 15 equivalents of acetic acid. in additional experiments equal amounts of acetic acid
Then, within 1 hour the reaction went to completion re- and sodium cyanide were employed. Treating 2a with 1
sulting in a mixture consisting of the unprotected diastere- equivalent of acetic acid and sodium cyanide at 70 °C re-
omeric piperidine-2,6-dicarbonitriles cis-3a–c and trans- sulted in a slightly increased consumption of the substrate
3a–c. Upon chromatographic separation of the individual 2a, but this time beside 5a as the clearly predominating
mixtures containing – according to 1H NMR the cis- and product, also 4a was present, though only in small
the trans-isomers, cis-3a–c and trans-3a–c, in a ratio of amounts (1H NMR analysis; Table 2, entry 3). Finally,
~52:48 – the pure diastereomers cis-3a–c and trans-3a–c when the amounts of acetic acid and of sodium cyanide
were obtained in yields of 43–44% and 40–41%, respec- were raised to 3 equivalents (70 °C, 1 h) only small
tively (Table 1).
amounts of the starting material 2a remained. In the reac-
tion mixture 5a still predominated (54%), accompanied
by 4a (40%) and the N-deprotected compounds cis-3a
Additional reactions were performed to determine wheth-
er the ratio of the diastereomers observed for the hydrocy-
anation reactions of 2a–c results from thermodynamic or
kinetic control. When the diastereomerically pure prod-
ucts cis-3a and trans-3a were subjected to the conditions
(3 equiv NaCN, 15 equiv AcOH, 70 °C, 1 h) used for the
hydrocyanation reaction of 2a, the diastereomers equili-
brated and mixtures of diastereomers of equal composi-
1
(3%) and trans-3a (3%, H NMR analysis) (see Table 2,
entry 4). From this mixture 5a could be isolated in 33%
yield. In additional experiments, the reaction time, the
amount of acetic acid, of sodium cyanide, and the concen-
tration of the starting material was varied, but without any
improvement in yield.
tion were formed with the ratio of diastereomers (52:48, For the hydrocyanation of the N-silyl-protected 4,4-diben-
1H NMR analysis) being identical to that of the transfor- zyl-1,4-dihydropyridine 2b, a reoptimization of the reac-
mation of 2a into 3a. Accordingly, the diasteromeric ratio tion conditions was needed, the best result being when 2b
observed for the reaction products 3 obtained from 2 by (0.041 M in MeOH) was treated with 5 equivalents each
of acetic acid and sodium cyanide at 70 °C for 2 hours.
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

3334
C. E. Schmaunz, K. T. Wanner
PAPER
Table 2 Synthesis of Protected 4,4-Disubstituted a-Cyanopiperidines
R
R
R
R
R
R
R
R
R
R
AcOH
NaCN
+
+
+
MeOH
MW
N
CN
N
N
NC
N
CN
N
NC
CN
NC
CN
H
H
Si
Si
Si
cis-3a–c
trans-3a–c
2a–c
4a–c
5a–c
Starting material Concn of 2 AcOH NaCN
Temp Time Compound ratioa
Product
Entry
2
a
a
R
(mol/L)
0.057
0.057
0.056
0.057
0.041
(equiv) (equiv) (°C)
(h)
1
(cis-3 + trans-3 +4 + 5)/2 cis-3/trans-3/4/5
Yield (%)b
c
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Bn
4
2
1
3
5
5
5
5
5
3
3
1
3
5
5
5
5
5
70
70
70
70
70
70
70
90
90
100:0
14:86
24:76
83:17
97:3
27:27:38:8
0:0:0:100
0:0:6:94
–
c
1
–
c
1
–
a
b
c
1
3:3:40:54
0:0:20:80
3:3:42:52
3:2:86 :9
4:3:62:31
8:8:63:21
5a
5b
5c
4a
4b
4c
33
66
31
74
48
56
2
CH2CH2Ph 0.038
1
73:27
100:0
100:0
98:2
a
b
c
Et
0.23
0.16
1
Bn
1
CH2CH2Ph 0.14
2
a According to 1H NMR of the crude product.
b Isolated yield.
c Product was not isolated
Then, 20% of 4b and 80% of 5b were present in the crude conversion of the starting material 2c (with 0.14 M the
product (1H NMR analysis) and 5b could be isolated in concentration was insignificantly lower). From the crude
66% yield (Table 2, entry 5). Finally, the hydrocyanation product containing 3c, 4c, and 5c in a ratio of 16:63:21 (1H
of 4,4-bis(2-phenylethyl)-1,4-diyhdroypridine 2c was NMR analysis), 4c was isolated in a yield of 56%
best accomplished by treating 2c (0.038 M in MeOH) with (Table 2, entry 9).
5 equivalents each of acetic acid and sodium cyanide at
To broaden their synthetic utility, the N-silyl-protected
enamines 5a–c have been transformed into the corre-
70 °C for 1 hour. Then, in the crude product, 3c, 4c, and
5c were found in a ratio of 6:42:52 (1H NMR analysis)
sponding N-acetyl derivatives 6a–c. Treating the N-silyl-
from which 5c could be isolated in a yield of 31%
1,2,3,4-tetrahydropyridine-2-carbonitriles 5a–c with
(Table 2, entry 6).
acetyl chloride at room temperature provides the N-acetyl
In addition, the reaction conditions have also been opti- derivatives 6a–c in high yields from 85 to 93%
mized for the synthesis of the N-silyl-protected 4,4-disub- (Scheme 1).
stituted piperidine-2,6-dicarbonitriles 4a–c. In the case of
2a, the best result was obtained when the reaction was car-
O
R
R
R
R
O
ried out at 70 °C with 5 equivalents of acetic acid and so-
dium cyanide with a concentration of 0.23 M in MeOH.
The reaction went to completion within 1 hour. With only
low amounts of two isomers of 3a and 5a being present in
the crude product (1H NMR analysis), 4a could be isolated
in a yield of 74% (Table 2, entry 7).
Cl
CH2Cl2, r.t., 2 h
N
CN
N
CN
Si
5a: R = Et
5b: R = Bn
5c: R = CH2CH2Ph
6a: R = Et, 87%
6b: R = Bn, 93%
For 2b as starting material, the best result was obtained
upon raising the reaction temperature to 90 °C (0.16 M in
MeOH). Then, again within 1 hour the starting material
was completely consumed. From the crude product con-
sisting of 16% of 3b, 21% of 5b, and 63% of 4b (1H
NMR), the latter was obtained in 48% yield (Table 2, en-
try 8). Finally, for the synthesis of 4c, the same reaction
conditions as for 4b were applied except that the reaction
time was extended to 2 hours to effect an almost complete
6c: R = CH2CH2Ph, 85%
Scheme
1
Acetylation of N-silyl-protected 4,4-disubstituted
1,2,3,4-tetrahydropyridine-2-carbonitriles
Moreover, the N-silyl-protected 1,2,3,4-tetrahydropyri-
dine-2-carbonitriles 5a–c appear to be well suited for the
preparation of the saturated piperidine-2-carbonitriles 7a–
c. When treated with sodium cyanoborohydride and hy-
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyano-Substituted Piperidines
3335
Table 3 Synthesis of 4,4-Disubstituted Piperidine-2-carbonitriles and Piperidine-2-carboxylic Acids as Hydrochlorides
R
R
R
R
R
R
NaBH3CN
HCl–Et2O
concd HCl–1,4-dioxane (1:1)
reflux, 3 h
CN
N+
COOH
MeOH
r.t., 1 h
N
CN
N
Cl–
H
H
H
Si
7a–c
8a–c
5a–c
Starting material
Products
Entry
5
a
b
c
R
7
a
b
c
Yield (%)
8
a
b
c
Yield (%)
1
2
3
Et
74
83
84
78
83
87
Bn
CH2CH2Ph
drogen chloride in diethyl ether, the carbonitriles 7a–c are tion reaction, which is in contrast to what had been
formed in good yields (74-84%, Table 3). The nitriles 7a– observed for the starting materials that underwent equili-
c were transformed into the target compounds, the pipe- bration under the condition of their formation as demon-
colic acid derivatives 8a–c, by acidic hydrolysis (concd strated for cis- and trans-3a.
HCl–1,4-dioxane, 1:1; reflux) providing the desired car-
boxylic acid derivatives in good yields (Table 3).
In summary, an easy and straightforward method for the
preparation of 4,4-disubstituted N-unprotected piperi-
Likewise, the piperidine-2,6-dicarboxylic acids cis-9a–c dine-2,6-dicarbonitriles cis-3a–c and trans-3a–c provides
and trans-9a–c were obtained by acidic hydrolysis of the an efficient access to the corresponding diastereomerical-
piperidine-2,6-dicarbonitriles cis-3a–c and trans-3a–c. ly pure 4,4-disubstituted piperidine-2,6-dicarboxylic acid
Interestingly, in each case the transformation proceeds derivatives cis-9a–c and trans-9a–c. Furthermore, the
without any isomerization. Thus, the cis- and the trans- 4,4-disubstituted N-silyl-protected 1,2,3,4-tetrahydropy-
form of the starting compounds lead exclusively to the ridine-2-carbonitriles 5a–c have been prepared. These
corresponding cis- and trans-configured piperidine-2,6- compounds allow the synthesis of the N-acetyl-protected
dicarboxylic acid cis-9a–c and trans-9a–c, respectively. derivatives 6a–c as well as of the saturated N-unprotected
The pure 4,4-disubstituted piperidine-2,6-dicarboxylic 4,4-disubstituted piperidine-2-carbonitriles 7a–c, which
acids cis-9a–c and trans-9a–c were isolated in high yields can be further transformed into the corresponding 4,4-di-
from 83 to 95% (Table 4).
substituted pipecolic acid derivatives 8a–c.
Likely due to the strong acidic reaction conditions, the hy-
drolysis of the nitrile functions is free of any isomeriza-
All solvents and chemicals were obtained from commercial sources
and were used without further purification, unless otherwise stated.
All reactions were performed using flame-dried glassware under an
argon atmosphere. All solvents were freshly dried using standard
procedures.24 Microwave experiments were performed in sealed
glass vials using a Biotage Initiator Microwave Synthesizer. 1H and
13C spectra were recorded on a JNMR-GX 400 (Jeol, 400 MHz) or
a JNMR-GX 500 (Jeol, 500 MHz) spectrometer, respectively. IR
spectra were obtained on a PerkinElmer model 1600 FT-IR spectro-
photometer. Microanalytical data for C, H, and N were determined
on a Heraeus Rapid Analyzer and on an Elementar Vario EL Ana-
lyzer. Flash chromatography was performed with 50–150 mesh alu-
mina (neutral Brockmann activity III).
Table 4 Synthesis of 4,4-Disubstituted Piperidine-2,6-dicarboxylic
Acids
R
R
R
R
concd HCl–1,4-dioxane (1:1)
reflux, 3 h
NC
N
CN
HOOC
Cl–
N+
COOH
H
H
H
9a–c
3a–c
Starting material
Product
Entry
3
R
9
Yield (%)
4,4-Disubstituted Piperidine-2,6-dicarbonitriles 3 and 4 and
1,2,3,4-Tetrahydropyridine-2-carbonitriles 5; General Proce-
dure 1 (GP1)
1
2
3
4
5
6
cis-3a
trans-3a
cis-3b
trans-3b
cis-3c
trans-3c
Et
cis-9a
87
83
85
83
95
96
A solution of 4,4-disubstituted N-triisopropylsilyl-1,4-dihydropyri-
dine 2, AcOH, and NaCN in MeOH was heated under microwave
conditions. After the time given, the reaction was quenched by the
addition of 1.0 M phosphate buffer (pH 7). The aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The crude material was puri-
fied by flash chromatography (alumina) to yield the desired prod-
uct.
Et
trans-9a
cis-9b
Bn
Bn
trans-9b
cis-9c
CH2CH2Ph
CH2CH2Ph
trans-9c
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

3336
C. E. Schmaunz, K. T. Wanner
PAPER
4,4-Disubstituted N-Acetyl-1,2,3,4-tetrahydropyridine-2-car-
bonitriles 6; General Procedure 2 (GP2)
by flash chromatography (alumina, n-pentane); colorless solid;
yield: 299 mg (62%); mp 81–83 °C; Rf = 0.53 (alumina, n-pentane).
The respective N-silyl-protected 1,2,3,4-tetrahydropyridine-2-car-
bonitrile 5 was dissolved in CH2Cl2 and acetyl chloride was added
and the mixture was stirred at r.t. for 2 h. The aqueous layer was ex-
tracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The crude material was puri-
fied by flash chromatography (alumina) to yield the desired prod-
uct.
IR (KBr): 3083, 3061, 3046, 3026, 2949, 2903, 2889, 2861, 2828,
1668, 1600, 1495, 1461, 1289 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.10 [d, J = 7.4 Hz, 18 H,
CH(CH3)2], 1.21–1.34 [m, 3 H, CH(CH3)2], 1.38–1.49 (m, 4 H,
CH2CH2Ph), 2.55–2.75 (m, 4 H, CH2CH2Ph), 4.18 (d, J = 8.3 Hz, 2
H, NCHCH), 6.19 (d, J = 8.3 Hz, 2 H, NCH), 7.11–7.16 (m, 2 H,
CHAr,p), 7.20 (m, 4 H, CHAr,o), 7.21–7.30 (m, 4 H, CHAr,m).
13C NMR (125 MHz, CDCl3): d = 11.5(d), 17.9 (q), 32.9 (t), 38.6
(s), 47.3 (t), 105.6 (d), 125.3 (d), 128.2 (d), 128.5 (d), 129.8 (d),
144.1 (d).
4,4-Disubstituted Piperidine-2-carbonitriles 7; General Proce-
dure 3 (GP3)
A solution of NaBH3CN (2.5 equiv) in MeOH was added to a solu-
tion of 4,4-disubstituted N-triisopropylsilyl-1,2,3,4-tetrahydropyri-
dine-2-carbonitrile 5 in CH2Cl2. After the addition of 1.0 M HCl in
Et2O (5.0 equiv), the mixture was stirred at r.t. for 1 h and subse-
quently quenched with 1.0 M phosphate buffer (pH 7). The aqueous
layer was extracted with CH2Cl2. The combined organic layers were
dried (MgSO4), and concentrated in vacuo. The crude material was
purified by flash chromatography (alumina) to yield the desired
product.
MS (CI, CH5 ): m/z (%) = 340 (74), 446 (100, [M + H]+).
+
HRMS (ESI+): m/z [M + H]+ calcd for C30H44NSi: 446.3243; found:
446.3230.
Anal. Calcd for C30H43NSi: C, 80.83; H, 9.72; N, 3.14. Found: C,
80.80; H, 9.92; N, 3.14.
4,4-Diethylpiperidine-2,6-dicarbonitrile (3a)
According to GP1 from 2a (100 mg, 0.342 mmol), NaCN (50.2 mg,
1.02 mmol), and AcOH (308 mg, 293 mL, 5.12 mmol) in MeOH (3
mL) at 70 °C for 1 h. Workup was performed with phosphate buffer
(3 mL) and extraction with CH2Cl2 (4 × 5 mL). Purification by flash
chromatography (alumina, n-pentane–Et2O–MeOH, 95:5:2).
4,4-Disubstituted Piperidine-2-carboxylic Acids 8b,c and Pipe-
ridine-2,6-dicarboxylic Acids 9b,c; General Procedure 4 (GP4)
The respective 4,4-disubstituted piperidine-2-carbonitrile 5 or pipe-
ridine-2,6-dicarbonitrile 3 was dissolved in concd HCl–1,4-dioxane
mixture (1:1) and heated to reflux for 3 h. The solvent was evapo-
rated under reduced pressure. The crude material was carefully
washed with Et2O and cold H2O and dried in vacuo to yield the de-
sired product.
trans-3a
Colorless solid; yield: 26.5 mg (41%); mp 33–34 °C; Rf = 0.20 (alu-
mina, n-pentane–Et2O–MeOH, 95:5:2).
IR (KBr): 3323, 2967, 2928, 2882, 2249, 2225, 1466, 1438, 1430,
1383, 1330 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.84 (t, J = 7.4 Hz, 6 H, CH2CH3),
1.45 (dq, J = 14.7, 7.4 Hz, 2 H, CH2CH3), 1.52 (dq, J = 14.7, 7.4
Hz, 2 H, CH2CH3), 1.67–1.77 (m, 4 H, NCHCH2), 2.27 (s, 1 H, NH),
4.08–4.12 (m, 2 H, NCHCN).
4,4-Diethyl-1-triisopropylsilyl-1,4-dihydropyridine (2a)
In analogy to the literature,22 from 1a (215 mg, 228 mL, 2.00 mmol)
and TIPSOTf (674 mg, 591 mL, 2.20 mmol) in CH2Cl2 (15 mL) and
0.4 M Et2Mg in Et2O (5.00 mL) [Et2Mg was prepared according to
the literature25 from 1.0 M EtMgCl in Et2O (50.0 mL) and 1,4-diox-
ane (4.84 g, 4.69 mL, 55.0 mmol)]. Workup was performed with 1.0
M phosphate buffer (10 mL, pH 7) and extraction with CH2Cl2
(4 × 15 mL). Purification by flash chromatography (alumina, n-pen-
tane); colorless solid; yield: 477 mg (81%); mp 32–33 °C; Rf = 0.92
(alumina, n-pentane).
13C NMR (125 MHz, CDCl3): d = 6.9 (q), 28.5 (t), 34.0 (s), 36.0 (t),
41.1 (d), 119.9 (s).
+
MS (CI, CH5 ): m/z (%) = 165 (100), 192 (15, [M + H]+).
HRMS (ESI–): m/z [M + Cl]– calcd for C11H17ClN3: 226.1111;
found: 226.1123.
IR (KBr): 3042, 2959, 2868, 1670, 1459, 1381, 1369, 1286 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.82 (t, J = 7.5 Hz, 6 H, CH2CH3),
1.05 [d, J = 7.5 Hz, 18 H, CH(CH3)2], 1.08 (q, J = 7.5 Hz, 4 H,
CH2CH3), 1.16–1.27 [m, 3 H, CH(CH3)2], 3.92 (d, J = 8.3 Hz, 2 H,
NCHCH), 6.07 (d, J = 8.3 Hz, 2 H, NCH).
13C NMR (100 MHz, CDCl3): d = 10.1 (q), 11.7 (d), 18.1 (q), 37.1
(t), 39.1 (s), 105.7 (d), 129.6 (d).
cis-3a
Colorless solid; yield: 28.4 mg (43%); mp 106–107 °C; Rf = 0.13
(alumina, n-pentane–Et2O–MeOH, 95:5:2).
IR (KBr): 3303, 2971, 2929, 2876, 2248, 1471, 1432, 1386, 1303
cm–1.
+
MS (CI, CH5 ): m/z (%) = 264 (100), 294 (66, [M + H]+).
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H, CH2CH3),
0.84 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.35 (q, J = 7.5 Hz, 2 H,
CH2CH3), 1.37 (q, J = 7.5 Hz, 2 H, CH2CH3), 1.59 (dd, J = 13.6,
11.8 Hz, 2 H, NCHCH2), 1.78–1.84 (m, 2 H, NCHCH2), 2.21 (br t,
J = 4.6 Hz, 1 H, NH), 3.81 (ddd, J = 11.8, 4.6, 2.9 Hz, 2 H, NCH-
CN).
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H35NSi: 293.2539; found:
293.2542.
Anal. Calcd for C18H35NSi: C, 73.64; H, 12.02; N, 4.77. Found: C,
73.34; H, 12.10; N, 4.70.
13C NMR (100 MHz, CDCl3): d = 6.7 (q), 6.9 (q), 23.8 (t), 31.7 (t),
34.4 (s), 37.3 (t), 42.27 (d), 119.0 (s).
4,4-Bis(2-phenylethyl)-1-triisopropylsilyl-1,4-dihydropyridine
(2c)
In analogy to literature,22 from 1c23 (197 mg, 1.07 mmol) and TIPSOTf
(362 mg, 317 mL, 1.18 mmol) in CH2Cl2 (5 mL) and 0.45 M
(PhCH2CH2)2Mg in Et2O (9.54 mL) [(PhCH2CH2)2Mg was pre-
pared according to the literature25 from Mg (6.94 g, 0.285 mol) in
Et2O (30 mL), PhCH2CH2Br (40.7 g, 30.0 mL, 0.220 mol) in Et2O
(100 mL), and 1,4-dioxane (19.3 mg, 18.7 mL, 0.220 mol)] at
–50 °C for 12 h. Workup was performed with 1.0 M phosphate buffer
(10 mL, pH 7) and extraction with CH2Cl2 (4 × 10 mL). Purification
+
MS (CI, CH5 ): m/z (%) = 165 (100), 192 (18, [M + H]+).
HRMS (ESI–): m/z [M + Cl]– calcd for C11H17ClN3: 226.1111;
found: 226.1125.
4,4-Dibenzylpiperidine-2,6-dicarbonitrile (3b)
According to GP1, from 2b (104 mg, 0.248 mmol), NaCN (36.5 mg,
0.745 mmol) and AcOH (224 mg, 213 mL, 3.72 mmol) in MeOH (3
mL) at 70 °C for 1 h. Workup was performed with phosphate buffer
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyano-Substituted Piperidines
3337
(3 mL) and extraction with CH2Cl2 (4 × 5 mL). Purification by flash
chromatography (alumina, n-pentane–Et2O–MeOH, 90:10:2).
cis-3c
Colorless solid; yield: 32.1 mg (43%); mp 116–118 °C; Rf = 0.07
(alumina, n-pentane–Et2O–MeOH, 90:10:2).
trans-3b
IR (KBr): 3308, 3060, 3026, 2928, 2854, 2247, 1653, 1636, 1602,
1496, 1454 cm–1.
Colorless solid; yield: 31.4 mg (40%); mp 72–76 °C; Rf = 0.20 (alu-
mina, n-pentane–Et2O–MeOH, 90:10:2).
1H NMR (400 MHz, CDCl3): d = 1.66–1.81 (m, 6 H, CH2CH2Ph,
NCHCH2), 1.97 (m, 2 H, NCHCH2), 2.25 (br s, 1 H, NH), 2.51–2.60
(m, 2 H, CH2CH2Ph), 2.60–2.68 (m, 2 H, CH2CH2Ph), 3.87 (dd,
J = 11.5, 2.7 Hz, 2 H, NCHCN), 7.13–7.27 (m, 6 H, CHAr,o, CHAr,p),
72.9–7.36 (m, 4 H, CHAr,m).
13C NMR (100 MHz, CDCl3): d = 29.1 (t), 29.2 (t), 34.6 (t), 35.0 (s),
37.9 (t), 42.0 (t), 42.2 (d), 118.8 (s), 126.3 (d), 126.5 (d), 128.1 (d),
128.3 (d), 128.7 (d), 128.8 (d), 141.1 (s), 141.3 (s).
IR (KBr): 3319, 3084, 3060, 3027, 2925, 2855, 2248, 2225, 1635,
1602, 1582, 1494, 1454, 1326 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.73 (dd, J = 14.0, 6.9 Hz, 2 H,
NCHCH2), 1.86 (dd, J = 14.0, 4.4 Hz, 2 H, NCHCH2), 2.26 (br s, 1
H, NH), 2.78 (d, J = 13.8 Hz, 2 H, CH2Ph), 2.88 (d, J = 13.8 Hz, 2
H, CH2Ph), 4.24 (ddd, J = 6.9, 4.4, 2.2 Hz, 2 H, NCHCN), 7.07–
7.16 (m, 4 H, CHAr,o), 7.24–7.37 (m, 6 H, CHAr,m, CHAr,p).
13C NMR (100 MHz, CDCl3): d = 33.7 (t), 36.1 (s), 41.2 (d), 44.3
(t), 119.9 (s), 126.9 (d), 128.4 (d), 131.2 (d), 136.0 (s).
MS (ESI+): m/z (%) = 317.2 (62, [M – CN]+), 335.2 (14, [M – HCN
+ NH4]+), 339.2 (100, [M – HCN + Na]+), 344.2 (11, [M + H]+).
MS (ESI+): m/z (%) = 311.2 (91, [M – HCN + Na]+), 316.2 (67, [M
HRMS (EI, 70 eV): m/z [M]+ calcd for C23H25N3: 343.2048; found:
343.2080.
+ H]+), 338.1 (100, [M + Na]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H21N3: 315.1735; found:
315.1742.
4,4-Diethyl-1-triisopropylsilylpiperidine-cis-2,6-dicarbonitrile
(4a)
cis-3b
According to GP1, from 2a (50.8 mg, 0.173 mmol), NaCN (42.4
mg, 0.865 mmol), and AcOH (52.0 mg, 49.5 mL, 0.865 mmol) in
MeOH (0.75 mL) at 70 °C for 1 h. Workup was performed with
phosphate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL).
Purification by flash chromatography (alumina, n-pentane–CHCl3,
5:5); colorless solid; yield: 44.4 mg (74%); mp 146–147 °C;
Rf = 0.55 (alumina, n-pentane–CHCl3, 5:5).
Colorless solid; yield: 34.5 mg (44%); mp 93–97 °C; Rf = 0.28 (alu-
mina, n-pentane–Et2O–MeOH, 90:10:2).
IR (KBr): 3306, 3061, 3027, 2926, 2856, 2248, 1629, 1601, 1493,
1453, 1301 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.71 (dd, J = 13.6, 11.5 Hz, 2 H,
NCHCH2), 1.77 (br dd, J = 13.6, 2.9 Hz, 2 H, NCHCH2), 2.00 (br s,
1 H, NH), 2.62 (s, 2 H, CH2Ph), 2.77 (s, 2 H, CH2Ph), 4.05 (dd,
J = 11.5, 2.9 Hz, 2 H, NCHCN), 6.98–7.04 (m, 2 H, CHAr,o), 7.08–
7.17 (m, 2 H, CHAr,o), 7.24–7.41 (m, 6 H, CHAr,m, CHAr,p).
13C NMR (100 MHz, CDCl3): d = 35.6 (t), 36.8 (s), 41.6 (t), 42.7
(d), 46.1 (t), 118.6 (s), 127.0 (d), 127.3 (d), 128.4 (d), 128.7 (d),
130.6 (d), 131.2 (d), 135.3 (s), 135.7 (s).
IR (KBr): 2973, 2947, 2925, 2868, 2888, 2858, 2224, 1464, 1379,
1370 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.81 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.93 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.15 [d, J = 6.6 Hz, 18 H,
CH(CH3)2], 1.18–1.29 [m, 5 H, CH(CH3)2, CH2CH3], 1.46 (dd,
J = 14.2, 6.4 Hz, 2 H, NCHCH2), 1.97 (br d, J = 14.2 Hz, 2 H,
NCHCH2), 2.12 (q, J = 7.4 Hz, 2 H, CH2CH3), 4.17 (dd, J = 6.4, 1.9
Hz, 2 H, NCHCN).
MS (ESI+): m/z (%) = 311.2 (100, [M – HCN + Na]+), 316.1 (19, [M
+ H]+), 338.0 (41, [M + Na]+).
13C NMR (100 MHz, CDCl3): d = 6.4 (q), 7.4 (q), 11.7 (d), 18.2 (q),
24. 5 (t), 33.0 (s), 34.1 (t), 36.6 (t), 41.2 (d), 120.3 (s).
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H21N3: 315.1735; found:
315.1732.
MS (ESI+): m/z (%) = 365.3 (44, [M + NH4]+), 712.6 (100, [2 M +
NH4]+).
4,4-Bis(2-phenylethyl)piperidine-2,6-dicarbonitrile (3c)
According to GP1, from 2c (96.2 mg, 0.216 mmol), NaCN (31.7
mg, 0.647 mmol) and AcOH (194 mg, 185 mL, 3.24 mmol) in
MeOH (3 mL) at 70 °C for 1 h. Workup was performed with phos-
phate buffer (3 mL) and extraction with CH2Cl2 (4 × 5 mL). Purifi-
cation by flash chromatography (alumina, n-pentane–Et2O–MeOH,
90:10:2).
HRMS (EI, 70 eV): m/z [M]+ calcd for C20H37N3Si: 347.2757;
found: 347.2752.
Anal. Calcd for C20H37N3Si: C, 69.10; H, 10.73; N, 12.09. Found:
C, 69.10; H, 10.74; N, 12.01.
4,4-Dibenzyl-1-triisopropylsilylpiperidine-cis-2,6-dicarboni-
trile (4b)
trans-3c
According to GP1, from 2b (50.8 mg, 0.122 mmol), NaCN (29.9
mg, 0.609 mmol), and AcOH (36.6 mg, 34.9 mL, 0.609 mmol) in
MeOH (0.75 mL) at 90 °C for 1 h. Workup was performed with
phosphate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL).
Purification by flash chromatography (alumina, n-pentane–CHCl3,
5:5); colorless solid; yield: 27.8 mg (48%); mp 170 °C; Rf = 0.52
(alumina, n-pentane–CHCl3, 5:5).
Colorless solid; yield: 30.2 mg (41%); mp 53–56 °C; Rf = 0.10 (alu-
mina, n-pentane–Et2O–MeOH, 90:10:2).
IR (KBr): 3321, 3085, 3061, 3025, 3001, 2941, 2863, 2247, 2223,
1636, 1602, 1496, 1454, 1325 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.73–1.98 (m, 8 H, CH2CH2Ph,
NCHCH2), 2.17 (br s, 1 H, NH), 2.60 (td, J = 12.9, 5.1 Hz, 2 H,
CH2CH2Ph), 2.67 (td, J = 12.9, 5.3 Hz, 2 H, CH2CH2Ph), 4.17 (dd,
J = 6.8, 4.5 Hz, 2 H, NCHCN), 7.20–7.27 (m, 6 H, CHAr,o, CHAr,p),
7.28–7.36 (m, 4 H, CHAr,m).
13C NMR (100 MHz, CDCl3): d = 29.3 (t), 34.6 (s), 36.7 (t), 39.2 (t),
41.2 (d), 119.6 (s), 126.2 (d), 128.3 (d), 128.6 (d), 141.4 (s).
IR (KBr): 3061, 3027, 2947, 2867, 2232, 1602, 1494, 1455, 1371,
1335, 1225 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.93 [d, J = 7.2 Hz, 18 H,
CH(CH3)2], 1.00–1.12 [m, 3 H, CH(CH3)2], 1.75 (dd, J = 14.3, 6.5
Hz, 2 H, NCHCH2), 1.90 (br d, J = 14.3 Hz, 2 H, NCHCH2), 2.45
(s, 2 H, CH2Ph), 3.55 (s, 2 H, CH2Ph), 4.19 (dd, J = 6.5, 1.4 Hz, 2
H, NCHCN), 6.83–6.93 (m, 2 H, CHAr,o), 7.13–7.23 (m, 3 H,
CHAr,m, CHAr,p), 7.24–7.30 (m, 1 H, CHAr,p), 7.30–7.37 (m, 2 H,
CHAr,m), 7.45–7.51 (m, 2 H, CHAr,o).
MS (ESI+): m/z (%) = 317.2 (100, [M – CN]+), 335.2 (46, [M –
HCN + NH4]+), 339.2 (63, [M – HCN + Na]+), 344.2 (21, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C23H25N3: 343.2048; found:
343.2078.
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

3338
C. E. Schmaunz, K. T. Wanner
PAPER
13C NMR (100 MHz, CDCl3): d = 11.6 (d), 17.8 (q), 33.2 (t), 34.4
(s), 41.2 (d), 43.4 (t), 46.8 (t), 120.4 (s), 126.5 (d), 126.6 (d), 128.0
(d), 128.1 (d), 131.4 (d), 131.5 (d), 136.1 (s), 136.9 (s).
MS (ESI–): m/z (%) = 506 (100, [M + Cl]–).
HRMS (EI, 70 eV): m/z [M]+ calcd for C30H41N3Si: 471.3070;
4,4-Dibenzyl-1-triisopropylsilyl-1,2,3,4-tetrahydropyridine-2-
carbonitrile (5b)
According to GP1, from 2b (51.5 mg, 0.124 mmol), NaCN (30.3
mg, 0.618 mmol), and AcOH (37.1 mg, 35.3 mL, 0.618 mmol) in
MeOH (3 mL) at 70 °C for 2 h. Workup was performed with phos-
phate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL). Purifi-
cation by flash chromatography (alumina, n-pentane–CHCl3, 9:1);
colorless solid; yield: 36.1 mg (66%); mp 95–97 °C; Rf = 0.83 (alu-
mina, n-pentane–CHCl3, 9:1).
found: 471.3074.
4,4-Bis(2-phenylethyl)-1-triisopropylsilylpiperidine-cis-2,6-di-
carbonitrile (4c)
IR (KBr): 3082, 3061, 3028, 2944, 2890, 2865, 2228, 1633, 1602,
1494, 1453, 1266, 1255 cm–1.
According to GP1, from 2c (45.6 mg, 0.102 mmol), NaCN (25.1
mg, 0.511 mmol), and AcOH (30.7 mg, 29.3 mL, 0.511 mmol) in
MeOH (0.75 mL) at 90 °C for 2 h. Workup was performed with
phosphate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL).
Purification by flash chromatography (alumina, n-pentane–CHCl3,
5:5); colorless solid; yield: 28.8 mg (56%); mp 141–145 °C;
Rf = 0.55 (alumina, n-pentane–CHCl3, 5:5).
1H NMR (500 MHz, CDCl3): d = 0.87 [d, J = 7.4 Hz, 9 H,
CH(CH3)2], 0.90 [d, J = 7.4 Hz, 9 H, CH(CH3)2], 1.01– 1.12 [m, 3
H, CH(CH3)2], 1.82 (dd, J = 14.1, 5.1 Hz, 1 H, NCHCH2), 1.98 (dt,
J = 14.1, 2.2 Hz, 1 H, NCHCH2), 2.55 (d, J = 13.2 Hz, 1 H, CH2Ph),
2.66 (d, J = 13.2 Hz, 1 H, CH2Ph), 3.09 (d, J = 13.3 Hz, 1 H,
CH2Ph), 3.27 (d, J = 13.3 Hz, 1 H, CH2Ph), 4.14 (dd, J = 5.1, 2.5
Hz, 1 H, NCHCN), 4.54 (dd, J = 8.2, 1.8 Hz, 1 H, NCHCH), 6.04
(d, J = 8.2 Hz, 1 H, NCHCH), 6.96–7.01 (m, 2 H, CHAr,o), 7.06–
7.16 (m, 3 H, CHAr,m, CHAr,p), 7.24–7.29 (m, 1 H, CHAr,p), 7.30–7.40
(m, 4 H, CHAr,o, CHAr,m).
13C NMR (125 MHz, CDCl3): d = 11.4 (d), 17.7 (q), 17.8 (q), 32.4
(t), 36 9 (s), 41.9 (d), 45.5 (t), 48.3 (t), 108.3 (d), 121.7 (s), 126.0
(d), 126.2 (d), 127.5 (d), 127.8 (d), 130.9 (d), 131.0 (d), 131.6 (d),
137.4 (s), 137.6 (s).
IR (KBr): 3085, 3063, 3026, 2945, 2891, 2867, 2225, 1635, 1603,
1497, 1455 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.16 [d, J = 6.7 Hz, 18 H,
CH(CH3)2], 1.19–1.30 [m, 3 H, CH(CH3)2], 1.59 (dd, J = 14.3, 6.4
Hz, 2 H, NCHCH2), 1.62–1.67 (m, 2 H, CH2CH2Ph), 2.13 (br d,
J = 14.3 Hz, 2 H, NCHCH2), 2.45–2.54 (m, 2 H, CH2CH2Ph), 2.58–
2.65 (m, 2 H, CH2CH2Ph), 2.69–2.77 (m, 2 H, CH2CH2Ph), 4.23
(dd, J = 6.4, 1.6 Hz, 2 H, NCHCN), 7.16–7.24 (m, 4 H, CHAr,p
,
CHAr,o), 7.26–7.38 (m, 6 H, CHAr,o, CHAr,m).
+
MS (CI, CH5 ): m/z (%) = 170 (86), 289 (60), 353 (100), 418 (92),
13C NMR (125 MHz, CDCl3): d = 11.7 (d), 18.2 (q), 28.6 (t), 29.9
(t), 33.5 (s), 34.7 (t), 37.2 (t), 41.1 (d), 44.7 (t), 120.2 (s), 125.9 (d),
126.1 (d), 128.2 (d), 128.5 (d), 128.6 (d), 141.7 (s), 141.7 (s).
445 (65, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C29H40N2Si: 444.2961;
found: 444.2982.
MS (ESI+): m/z (%) = 226.1 (43), 473.3 (26, [M – CN]+), 522.3
(100, [M + Na]+).
4,4-Bis(2-phenylethyl)-1-triisopropylsilyl-1,2,3,4-tetrahydropy-
ridine-2-carbonitrile (5c)
HRMS (ESI+): m/z [M + Na]+ calcd for C32H45N3Si + Na: 522.3280;
found: 522.3275.
According to GP1, from 2c (51.4 mg, 0.115 mmol), NaCN (28.3
mg, 0.577 mmol), and AcOH (34.6 mg, 33.0 mL, 0.577 mmol) in
MeOH (3 mL) at 70 °C for 1 h. Workup was performed with phos-
phate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL). Purifi-
cation by flash chromatography (alumina, n-pentane–CHCl3, 9:1);
colorless oil; yield: 17.1 mg (31%); Rf = 0.83 (alumina, n-pentane–
CHCl3, 9:1).
4,4-Diethyl-1-triisopropylsilyl-1,2,3,4-tetrahydropyridine-2-
carbonitrile (5a)
According to GP1, from 2a (50.1 mg, 0.171 mmol), NaCN (25.1
mg, 0.511 mmol), and AcOH (30.7 mg, 29.3 mL, 0.511 mmol) in
MeOH (3 mL) at 70 °C for 1 h. Workup was performed with phos-
phate buffer (2 mL) and extraction with CH2Cl2 (4 × 3 mL). Purifi-
cation by flash chromatography (alumina, n-pentane–CHCl3, 9:1);
colorless oil; yield: 18.2 mg (33%); Rf = 0.88 (alumina, n-pentane–
CHCl3, 9:1).
IR (film): 3061, 3025, 2943, 2866, 2227, 1635, 1602, 1496, 1454,
1265 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.12 [d, J = 7.4 Hz, 9 H,
CH(CH3)2], 1.15 [d, J = 7.4 Hz, 9 H, CH(CH3)2], 1.22–1.33 [m, 3 H,
CH(CH3)2], 1.62–1.70 (m, 1 H, CH2CH2Ph), 1.73–1.81 (m,1 H,
CH2CH2Ph), 1.92 (dd, J = 14.0, 5.1 Hz, 1 H, NCHCH2), 2.02–2.20
(m, 3 H, CH2CH2Ph, NCHCH2), 2.54–2.62 (m, 2 H, CH2CH2Ph),
2.63–2.73 (m, 2 H, CH2CH2Ph), 4.32 (dd, J = 5.1, 2.5 Hz, 1 H,
NCHCN), 4.66 (dd, J = 8.2, 1.8 Hz, 1 H, NCHCH), 6.15 (d, J = 8.2
Hz, 1 H, NCHCH), 7.13–7.33 (m, 10 H, CHAr).
13C NMR (125 MHz, CDCl3): d = 11.7 (d), 18.0 (q), 18.1 (q), 29.7
(t), 30.5 (t), 34.4 (s), 35.7 (t), 42.0 (d), 42.3 (t), 42.4 (t), 108.5 (d),
121.1 (s), 125.6 (d), 125.8 (d), 128.3 (d), 128.4 (d), 128.5 (d), 128.5
(d), 130.1 (d), 142.5 (s), 142.7 (s).
IR (film): 3026, 2963, 2946, 2893, 2868, 2229, 1635, 1462, 1412,
1380, 1265 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.78 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.86 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.10 [d, J = 7.3 Hz, 9 H,
CH(CH3)2], 1.13 [d, J = 7.3 Hz, 9 H, CH(CH3)2], 1.19–1.30 [m, 4 H,
CH(CH3)2, CH2CH3], 1.35 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3),
1.69 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 1.74 (dd, J = 14.0, 5.1 Hz,
1 H, NCHCH2), 1.82 (dq, J = 14.8, 7.4 Hz, 1 H, CH2CH3), 1.96 (dt,
J = 14.0, 2.2 Hz, 1 H, NCHCH2), 4.25 (dd, J = 5.1, 2.5 Hz, 1 H,
NCHCN), 4.55 (dd, J = 8.2, 1.8 Hz, 1 H, NCHCH), 6.06 (d, J = 8.2
Hz, 1 H, NCHCH).
MS (FAB+, NBA): m/z (%) = 184.1 (52), 367.1 (100), 429.1 (36),
13C NMR (100 MHz, CDCl3): d = 7.3 (q), 8.1 (q), 11.7 (d), 18.0 (q),
18.1 (q), 31.7 (t), 31.9 (t), 34.0. (s), 35.4 (t), 42.1 (d), 109.4 (d),
121.4 (s), 129.4 (d).
446.2 (55), 472.2 (54, [M]+).
HRMS (FAB+, NBA): m/z [M]+ calcd for C31H44N2Si: 472.3274;
found: 472.3264.
+
MS (CI, CH5 ): m/z (%) = 321 (100, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C19H36N2Si: 320.2648;
found: 320.2663.
1-Acetyl-4,4-diethyl-1,2,3,4-tetrahydropyridine-2-carbonitrile
(6a)
According to GP2, from 5a (27.8 mg, 0.0867 mmol) and AcCl (13.6
mg, 12.4 mL, 0.173 mmol) in CH2Cl2 (2 mL). Workup was per-
formed with phosphate buffer (2 mL) and extraction with CH2Cl2
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyano-Substituted Piperidines
3339
(4 × 2 mL). Purification by flash chromatography (alumina, gradi-
ent n-pentane–EtOAc, 90:10, then n-pentane–EtOAc–MeOH,
90:10:2); colorless oil; yield: 15.6 mg (87%); Rf = 0.32 (silica gel,
n-pentane–EtOAc–MeOH, 90:10:2).
(td, J = 12.7, 5.3 Hz, 1 H, CH2CH2Ph), 5.06 (dd, J = 8.6, 1.7 Hz, 1
H, NCHCH), 5.46 (dd, J = 6.0, 2.7 Hz, 1 H, NCHCN), 6.57 (d,
J = 8.6 Hz, 1 H, NCHCH), 7.14–7.36 (m, 10 H, CHAr).
13C NMR (125 MHz, CDCl3): d = 21.3 (q), 29.8 (t), 30.2 (t), 32.9 (t),
35.2 (s), 37.7 (d), 40.5 (t), 41.1 (t), 116.1 (d), 118.2 (s), 122.3 (d),
126.0 (d), 126.1 (d), 128.2 (d), 128.4 (d), 128.5 (d), 128.6 (d), 141.6
(s), 141.7 (s), 168.0 (s).
IR (film): 3064, 2967, 2940, 2880, 2239, 1681, 1647, 1458, 1436,
1414, 1377, 1334, 1306, 1243 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 7.5 Hz, 3 H, CH2CH3),
0.91 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.28–1.47 (m, 2 H, CH2CH3),
1.68–1.82 (m, 3 H, CH2CH3, NCHCH2), 2.10 (ddd, J = 14.5, 2.8,
1.7 Hz, 1 H, NCHCH2), 2.23 (s, 3 H, COCH3), 4.97 (dd, J = 8.6, 1.7
Hz, 1 H, NCHCH), 5.38 (dd, J = 6.0, 2.8 Hz, 1 H, NCHCN), 6.50
(d, J = 8.6 Hz, 1 H, NCHCH).
13C NMR (100 MHz, CDCl3): d = 7.5 (q), 7.8 (q), 21.3 (q), 30.4 (t),
30.6 (t), 32.6 (t), 34.9 (s), 37.8 (d), 117.0 (d), 118.4 (s), 121.8 (d),
168.0 (s).
+
MS (CI, CH5 ): m/z (%) = 359 (100, [M + H]+).
HRMS (ESI+): m/z [M + H]+ calcd for C24H27N2O: 359.2123; found:
359.2117.
4,4-Diethylpiperidine-2-carbonitrile (7a)
According to GP3, from 5a (139 mg, 0.434 mmol) in CH2Cl2 (3
mL), NaBH3CN (68.2 mg, 1.09 mmol) in MeOH (3 mL), and 1.0 M
HCl in Et2O (2.17 mL). Workup was performed with phosphate
buffer (4 mL) and extraction with CH2Cl2 (4 × 4 mL). Purification
by flash chromatography (alumina, gradient n-pentane, then n-pen-
tane–Et2O, 95:5, then n-pentane–Et2O–MeOH, 95:5:3); colorless
oil; yield: 53.5 mg (74%); Rf = 0.22 (alumina, n-pentane–Et2O–
MeOH, 95:5:3).
+
MS (CI, CH5 ): m/z (%) = 207 (100, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C12H18N2O: 206.1419;
found: 206.1397.
1-Acetyl-4,4-dibenzyl-1,2,3,4-tetrahydropyridine-2-carboni-
trile (6b)
IR (film): 3315, 2964, 2939, 2880, 2852, 2243, 1643, 1459, 1380
cm–1.
According to GP2, from 5b (34.9 mg, 0.0785 mmol) and AcCl (9.2
mg, 8.4 mL, 0.12 mmol) in CH2Cl2 (2 mL). Workup was performed
with phosphate buffer (2 mL) and extraction with CH2Cl2 (4 × 2
mL). Purification by flash chromatography (alumina, gradient
CHCl3, then CHCl3–MeOH, 97:3); colorless solid; yield: 23.9 mg
(93%); mp 54–56 °C; Rf = 0.89 (alumina, CHCl3–MeOH, 97:3).
1H NMR (400 MHz, CDCl3): d = 0.75 (t, J = 7.4 Hz, 3 H, CH2CH3),
0.79 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.25–1.51 (m, 6 H, CH2CH3,
NCH2CH2), 1.59 (dd, J = 13.6, 8.6 Hz, 1 H, NCHCH2), 1.69 (ddd,
J = 13.6, 4.1, 1.2 Hz, 1 H, NCHCH2), 1.78 (br s, 1 H, NH), 2.77
(ddd, J = 12.6, 8.8, 3.9 Hz, 1 H, NCH2), 2.96 (ddd, J = 12.6, 6.0, 4.1
Hz, 1 H, NCH2), 3.83 (dd, J = 8.6, 4.1 Hz, 1 H, NCHCN).
IR (KBr): 3103, 3084, 3060, 3028, 3003, 2927, 2856, 2239, 1681,
1649, 1603, 1495, 1452, 1444, 1414, 1377, 1333, 1306, 1244 cm–1.
13C NMR (100 MHz, CDCl3): d = 6.9 (q), 7.0 (q), 26.9 (t), 29.6 (t),
33.8 (s), 34.2 (t), 37.8 (t), 40.4 (t), 43.1 (d), 121.2 (s).
1H NMR (500 MHz, CDCl3): d = 1.88 (dd, J = 14.4, 6.0 Hz, 1 H,
NCHCH2), 2.09 (ddd, J = 14.4, 3.0, 1.6 Hz, 1 H, NCHCH2), 2.09 (s,
3 H, COCH3), 2.61 (d, J = 13.5 Hz, 1 H, CH2Ph), 2.77 (d, J = 13.5
Hz, 1 H, CH2Ph), 3.04 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.27 (d,
J = 13.4 Hz, 1 H, CH2Ph), 4.98 (dd, J = 8.6, 1.6 Hz, 1 H, NCHCH),
5.28 (dd, J = 6.0, 3.0 Hz, 1 H, NCHCH2), 6.52 (d, J = 8.6 Hz, 1 H,
NCHCH), 6.95–7.03 (m, 2 H, CHAr,o), 7.15–7.25 (m, 3 H, CHAr),
7.27–7.38 (m, 5 H, CHAr).
13C NMR (125 MHz, CDCl3): d = 21.1 (q), 31.2 (t), 37.3 (s), 37.6
(d), 45.0 (t), 47.0 (t), 115.9 (d), 118.7 (s), 123.1 (d), 126.6 (d), 126.7
(d), 127.9 (d), 128.2 (d), 130.6 (d), 131.2 (d), 136.4 (s), 136.7 (s),
167.8 (s).
MS (ESI+): m/z (%) = 167.2 (14, [M + H]+), 306.3 (100, [2 M –
CN]+).
HRMS (ESI+): m/z [M + H]+ calcd for C10H19N2: 167.1548; found:
167.1543.
4,4-Dibenzylpiperidine-2-carbonitrile (7b)
According to GP3, from 5b (54.2 mg, 0.122 mmol) in CH2Cl2 (2
mL), NaBH3CN (19.1 mg, 0.305 mmol) in MeOH (2 mL), and 1.0
M HCl in Et2O (609 mL). Workup was performed with phosphate
buffer (4 mL) and extraction with CH2Cl2 (4 × 4 mL). Purification
by flash chromatography (alumina, gradient n-pentane, then n-pen-
tane–Et2O, 95:5, then n-pentane–Et2O–MeOH, 95:5:3); colorless
solid; yield: 29.3 mg (83%); mp 55–57 °C; Rf = 0.15 (alumina, n-
pentane–Et2O–MeOH, 95:5:2).
+
MS (CI, CH5 ): m/z (%) = 115 (37), 331 (66, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C22H22N2O: 330.1732;
found: 330.1739.
IR (KBr): 3441, 3059, 3026, 2927, 2852, 2243, 1654, 1637, 1600,
1494, 1452 cm–1.
1-Acetyl-4,4-bis(2-phenylethyl)-1,2,3,4-tetrahydropyridine-2-
carbonitrile (6c)
1H NMR (500 MHz, CDCl3): d = 1.40 (br dt, J = 13.8, 3.6 Hz, 1 H,
NCH2CH2), 1.47 (ddd, J = 13.8, 9.6, 4.6 Hz, 1 H, NCH2CH2), 1.67
(dd, J = 13.6, 9.5 Hz, 1 H, NCHCH2), 1.75 (ddd, J = 13.6, 3.9, 1.0
Hz, 1 H, NCHCH2), 1.87 (br s, 1 H, NH), 2.66 (d, J = 13.5 Hz, 1 H,
CH2Ph), 2.71 (d, J = 13.5 Hz, 1 H, CH2Ph), 2.76 (d, J = 13.5 Hz, 2
H, CH2Ph), 3.00 (ddd, J = 12.8, 9.6, 3.6 Hz, 1 H, NCH2), 3.07 (dt,
J = 12.8, 4.6 Hz, 1 H, NCH2), 4.05 (dd, J = 9.5, 3.9 Hz, 1 H, NCH-
According to GP2, from 5c (39.9 mg, 0.0844 mmol) and AcCl (13.2
mg, 12.0 mL,.0169 mmol) in CH2Cl2 (2 mL). Workup was per-
formed with phosphate buffer (2 mL) and extraction with CH2Cl2
(4 × 2 mL). Purification by flash chromatography (alumina, gradi-
ent n-pentane–EtOAc, 90:10, then n-pentane–EtOAc–MeOH,
90:10:2); colorless solid; yield: 25.6 mg (85%); mp 118–121 °C;
Rf = 0.31 (alumina, n-pentane–EtOAc–MeOH, 90:10:2).
CN), 7.05–7.15 (m, 4 H, CHAr,o), 7.19–7.34 (m, 6 H, CHAr,m
CHAr,p).
,
IR (KBr): 3083, 3064, 3026, 2961, 2946, 2928, 2912, 2858, 2234,
1681, 1646, 1602, 1495, 1455, 1412, 1374, 1339, 1327, 1299, 1244
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.74 (ddd, J = 13.8, 10.8, 6.6 Hz,
1 H, CH2CH2Ph), 1.81 (ddd, J = 13.8, 10.8, 6.6 Hz, 1 H,
CH2CH2Ph), 1.96 (dd, J = 14.5, 6.0 Hz, 1 H, NCHCH2), 2.03–2.17
(m, 2 H, CH2CH2Ph), 2.25 (s, 3 H, COCH3), 2.30 (ddd, J = 14.5,
2.7, 1.7 Hz, 1 H, NCHCH2), 2.52–2.70 (m, 3 H, CH2CH2Ph), 2.76
13C NMR (100 MHz, CDCl3): d = 31.6 (t), 36.1 (s), 36.5 (t), 40.8 (t),
42.8 (t), 43.3 (d), 45.5 (t), 120.8 (s), 126.4 (d), 126.6 (d), 128.0 (d),
128.2 (d), 130.9 (d), 131.3 (d), 136.9 (s, 1 C, CAr), 137.1 (s).
+
MS (CI, CH5 ): m/z (%) = 264 (100, [M – CN]+), 291 (3, [M + H]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C20H22N2: 290.1783; found:
290.1801.
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

3340
C. E. Schmaunz, K. T. Wanner
PAPER
4,4-Bis(2-phenylethyl)piperidine-2-carbonitrile (7c)
According to GP3, from 5c (83.4 mg, 0.176 mmol) in CH2Cl2 (2
mL), NaBH3CN (27.7 mg, 0.441 mmol) in MeOH (2 mL), and 1.0
M HCl in Et2O (882 mL). Workup was performed with phosphate
buffer (4 mL) and extraction with CH2Cl2 (4 × 4 mL). Purification
by flash chromatography (alumina, gradient n-pentane, then n-pen-
tane–Et2O, 95:5, then n-pentane–Et2O–MeOH, 95:5:3); colorless
oil; yield: 47.1 mg (84%); Rf = 0.10 (silica gel, n-pentane–EtOAc–
MeOH, 80:20:2).
J = 13.1, 3.8 Hz, 1 H, NCH2), 4.37 (dd, J = 13.2, 2.8 Hz, 1 H,
NCHCO2H), 7.01–7.07 (m, 2 H, CHAr,o), 7.18–7.24 (m, 1 H,
CHAr,p), 7.24–7.33 (m, 5 H, CHAr,o, CHAr,m, CHAr,p), 7.33–7.40 (m,
2 H, CHAr,m).
13C NMR (125 MHz, CD3OD): d = 29.6 (t), 33.8 (t), 37.2 (s), 40.9
(t), 41.8 (t), 46.6 (t), 54.2 (d), 127.7 (d), 127.9 (d), 129.3 (d), 129.4
(d), 132.0 (d), 132.4 (d), 137.7 (s), 138.3 (s), 171.7 (s).
MS (FAB+, NBA): m/z (%) = 310.4 (100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C20H24NO2:
IR (film): 3331, 3084, 3060, 3024, 2934, 2861, 2243, 1643, 1602,
1495, 1453 cm–1.
310.1807; found: 310.1821.
1H NMR (400 MHz, CDCl3): d = 1.49–1.89 (m, 8 H, CH2CH2Ph,
NCH2CH2, NCHCH2, NH), 1.95 (ddd, J = 14.0, 12.8, 5.2 Hz, 1 H,
CH2CH2Ph), 2.52–2.74 (m, 4 H, CH2CH2Ph), 2.87 (ddd, J = 12.4,
8.1, 4.0 Hz, 1 H, NCH2), 3.06 (ddd, J = 12.4, 6.4, 4.0 Hz, 1 H,
NCH2), 3.94 (dd, J = 6.8, 5.3 Hz, 1 H, NCHCN), 7.15–7.27 (m, 6 H,
CHAr,o, CHAr,p), 7.27–7.35 (m, 4 H, CHAr,m).
13C NMR (100 MHz, CDCl3): d = 29.3 (t), 29. 4 (t), 34.4 (s), 35.1
(t), 37.9 (t), 38.4 (t), 39.9 (t), 40.2 (t), 43.1 (d), 121.0 (s), 126.0 (d),
126.1 (d), 128.3 (d), 128.4 (d), 128.6 (d), 128.6 (d), 142.2 (s), 142.3
(s).
4,4-Bis(2-phenylethyl)piperidine-2-carboxylic Acid Hydrochlo-
ride (8c)
According to GP4, from 7d (20.4 mg, 0.0641 mmol) in concd HCl–
1,4-dioxane solution (1:1, 3 mL); colorless solid; yield: 20.9 mg
(87%); mp 219–223 °C (dec.).
IR (KBr): 3060, 3025, 2936, 2863, 2806, 2470, 1739, 1602, 1495,
1454 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.99–1.78 (m, 4 H, CH2CH2Ph,
NCH2CH2, NCHCH2), 1.82–1.95 (m, 3 H, CH2CH2Ph, NCH2CH2),
2.30 (br dt, J = 14.3, 3.0 Hz, 1 H, NCHCH2), 2.61–2.69 (m, 4 H,
CH2CH2Ph), 3.21 (td, J = 13.3, 2.9 Hz, 1 H, NCH2), 3.29–3.36 (m,
1 H, NCH2), 4.14 (dd, J = 12.9, 3.0 Hz, 1 H, NCHCOOH), 7.15–
7.20 (m, 2 H, CHAr,p), 7.20–7.24 (m, 2 H, CHAr,o), 7.24–7.32 (m, 6
H, CHAr,o, CHAr,m).
MS (ESI+): m/z (%) = 292.2 (100, [M – CN]+), 319.2 (99, [M + H]+),
610.4 (45, [2 M – CN]+).
HRMS (EI, 70 eV): m/z [M]+ calcd for C22H26N2: 318.2096; found:
318.2109.
13C NMR (100 MHz, CD3OD): d = 30.3 (t), 30.6 (t), 32.3 (t), 34.8
(t), 35.6 (s), 36.5 (t), 41.0 (t), 43.5 (t), 54.2 (d), 127.0 (d), 127.1 (d),
129.4 (d), 129.5 (d), 129.6 (d), 129.6 (d), 143.4 (s), 143.5 (s), 171.6
(s).
MS (FAB+, NBA): m/z (%) = 338.5 (100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C22H28NO2:
4,4-Diethylpiperidine-2-carboxylic Acid Hydrochloride (8a)
A solution of 7a (20.4 mg, 0.123 mmol) in concd HCl–1,4-dioxane
(1:1, 3 mL) was heated to reflux for 3 h. The solvent was evaporated
under reduced pressure and the crude material was washed with
Et2O (3 × 1.5 mL). For further purification, the residue was first dis-
solved in MeOH (2 mL), and treated with 2.0 M TMSCHN2 in Et2O
(125 mL) at r.t. for 0.5 h.26 Then, the solvent was evaporated under
reduced pressure, the crude material was dissolved in CH2Cl2 (2
mL) and insoluble impurities were filtered off. The solvent was
evaporated under reduced pressure. The product was heated in con-
cd HCl (2 mL) to reflux for 2 h and concentrated in vacuo; colorless
solid; yield: 21.2 mg (78%); mp 231–242 °C (dec.).
338.2120; found: 338.2131.
4,4-Diethylpiperidine-trans-2,6-dicarboxylic Acid Hydrochlo-
ride (trans-9a)
A solution of trans-3a (24.1 mg, 0.126 mmol) in concd HCl–1,4-di-
oxane (1:1, 3 mL) was heated to reflux for 3 h. The solvent was
evaporated under reduced pressure and the crude material was
washed with Et2O (3 × 1.5 mL). For further purification, the residue
was first dissolved in MeOH (2 mL), and treated with 2.0 M
TMSCHN2 in Et2O (252 mL) at r.t. for 0.5 h.26 Then, the solvent was
evaporated under reduced pressure, the crude material was dis-
solved in CH2Cl2 (2 mL) and insoluble impurities were filtered off.
The solvent was evaporated under reduced pressure. The product
was heated in concd HCl (2 mL) to reflux for 2 h and concentrated
in vacuo; colorless solid; yield: 27.9 mg (83%); mp 112–119 °C.
IR (KBr): 2966, 2936, 2883, 2812, 2692, 2651, 2566, 2510, 2459,
1747, 1397, 1202, 1185 cm–1.
1H NMR (500 MHz, CD3OD): d = 0.86 (t, J = 7.5 Hz, 3 H,
CH2CH3), 0.87 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.30–1.41 (m, 2 H,
CH2CH3), 1.45–1.61 (m, 4 H, CH2CH3, NCH2CH2, NCHCH2), 1.72
(br d, J = 14.4 Hz, 1 H, NCH2CH2), 2.11 (br d, J = 14.4 Hz, 1 H,
NCHCH2), 3.13 (br t, J = 12.9 Hz, 1 H, NCH2), 3.28 (br d, J = 12.9
Hz, 1 H, NCH2), 4.04 (dd, J = 12.9, 2.2 Hz, 1 H, NCHCO2H).
13C NMR (125 MHz, CD3OD): d = 7.3 (q), 7.5 (q), 24.2 (t), 31.5 (t),
32.9 (t), 35.0 (s), 35.9 (t), 41.1 (t), 54.3 (d), 171.8 (s).
MS (FAB+, NBA): m/z (%) = 186.2 (100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C10H20NO2:
IR (KBr): 3136, 3046, 2969, 2940, 2811, 1731, 1403, 1251 cm–1.
1H NMR (500 MHz, CD3OD): d = 0.85 (t, J = 7.5 Hz, 6 H,
CH2CH3), 1.39 (q, J = 7.5 Hz, 4 H, CH2CH3), 1.87–1.99 (m, 4 H,
NCHCH2), 4.30 (t, J = 6.5 Hz, 2 H, NCHCO2H).
186.1494; found: 186.1500.
13C NMR (125 MHz, CD3OD): d = 7.3 (q), 29.1 (t), 34.6 (t), 35.4
(s), 52.7 (d), 171.8 (s).
4,4-Dibenzylpiperidine-2-carboxylic Acid Hydrochloride (8b)
According to GP4, from 7b (13.4 mg, 0.0461 mmol) in concd HCl–
1,4-dioxane (1:1, 3 mL); colorless solid; yield: 13.2 mg (83%); mp
>252 °C (dec.).
MS (FAB+, NBA): m/z (%) = 185.3 (100, [M – CO2H – Cl]+), 230.4
(95, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C11H20NO4:
230.1392; found: 230.1391.
IR (KBr): 3059, 3028, 2939, 2852, 2785, 1750, 1600, 1587, 1495,
1454, 1395, 1192, 1180 cm–1.
4,4-Diethylpiperidine-cis-2,6-dicarboxylic Acid Hydrochloride
(cis-9a)
A solution of cis-3a (24.7 mg, 0.129 mmol) in concd HCl–1,4-diox-
ane (1:1, 3 mL) was heated to reflux for 3 h. The solvent was evap-
orated under reduced pressure and the crude material was washed
1H NMR (500 MHz, CD3OD): d = 1.60 (t, J = 13.8 Hz, 1 H,
NCHCH2), 1.61–176 (m, 2 H, NCH2CH2), 2.09 (br dt, J = 14.3, 2.8
Hz, 1 H, NCHCH2), 2.63 (d, J = 13.6 Hz, 1 H, CH2Ph), 2.67 (d,
J = 13.6 Hz, 1 H, CH2Ph), 2.93 (d, J = 13.8 Hz, 1 H, CH2Ph), 3.06
(d, J = 13.8 Hz, 1 H, CH2Ph), 3.23–3.33 (m, 1 H, NCH2), 3.42 (td,
Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

PAPER
Synthesis of Cyano-Substituted Piperidines
3341
with Et2O (3 × 1.5 mL). For further purification, the residue was
first dissolved in MeOH (2 mL), and treated with 2.0 M TMSCHN2
in Et2O (258 mL) at r.t. for 0.5 h.26 Then, the solvent was evaporated
under reduced pressure, the crude material was dissolved in CH2Cl2
(2 mL) and insoluble impurities were filtered off. The solvent was
evaporated under reduced pressure. The product was heated in
concd HCl (2 mL) to reflux for 2 h and concentrated in vacuo; col-
orless solid; yield: 29.7 mg (87%); mp >252 °C (dec.).
4,4-Bis(2-phenylethyl)piperidine-trans-2,6-dicarboxylic Acid
Hydrochloride (trans-9c)
According to GP4 from trans-3c (23.8 mg, 0.0693 mmol) in concd
HCl–1,4-dioxane (1:1, 4 mL); colorless solid; yield: 27.4 mg
(95%); mp >252 °C (dec.).
IR (KBr): 3059, 3025, 3002, 2935, 2864, 2640, 2547, 2434, 1740,
1602, 1581, 1495, 1454, 1223 cm–1.
1H NMR (500 MHz, CD3OD): d = 1.66–1.80 (m, 4 H, CH2CH2Ph),
2.12 (d, J = 6.3 Hz, 4 H, NCHCH2), 2.58–2.73 (m, 4 H,
CH2CH2Ph), 4.39 (t, J = 6.3 Hz, 2 H, NCHCO2H), 7.14–7.20 (m, 2
H, CHAr,p), 7.20–7.24 (m, 4 H, CHAr,o), 7.24–7.32 (m, 4 H, CHAr,m).
13C NMR (125 MHz, CD3OD): d = 30.4 (t), 35.3 (t), 35.8 (s), 39.9
(t), 52.8 (d), 127.1 (d), 129.4 (d), 129.6 (d), 143.2 (s), 171.6 (s).
MS (FAB+, NBA): m/z (%) = 382.1 (100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C23H28NO4:
IR (KBr): 3054, 2969, 2943, 2883, 2796, 2726, 1759, 1458, 1373,
1248, 1190 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.86 (t, J = 7.4 Hz, 3 H,
CH2CH3), 0.89 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.36 (q, J = 7.4 Hz, 2
H, CH2CH3), 1.47 (t, J = 14.0 Hz, 2 H, NCHCH2), 1.55 (q, J = 7.4
Hz, 2 H, CH2CH3), 2.09 (br d, J = 14.3 Hz, 2 H, NCHCH2), 3.82
(dd, J = 13.5, 2.9 Hz, 2 H, NCHCO2H).
13C NMR (100 MHz, CD3OD): d = 7.4 (q), 7.6 (q), 24.3 (t), 33.0 (t),
35.5 (t), 36.1 (s), 55.1 (d), 172.6 (s).
382.2018; found: 382.2018.
MS (FAB+, NBA): m/z (%) = 185.2 (90, [M – CO2H – Cl]+), 230.3
4,4-Bis(2-phenylethyl)piperidine-cis-2,6-dicarboxylic Acid Hy-
drochloride (cis-9c)
According to GP4, from cis-3c (27.9 mg, 0.0812 mmol) in concd
HCl–1,4-dioxane (1:1, 4 mL); colorless solid; yield: 32.7 mg
(96%); mp >252 °C (dec.).
(100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C11H20NO4:
230.1392; found: 230.1391.
Anal. Calcd for C11H20ClNO4: C, 49.72; H, 7.59; N, 5.27. Found: C,
49.97; H, 7.66; N, 5.55.
IR (KBr): 3054, 3025, 2935, 2865, 2801, 2594, 2470, 1762, 1601,
1496, 1454, 1385 cm–1.
4,4-Dibenzylpiperidine-trans-2,6-dicarboxylic Acid Hydrochlo-
ride (trans-9b)
According to GP4, from trans-3b (18.0 mg, 0.0571 mmol) in concd
HCl–1,4-dioxane (1:1, 3 mL); colorless solid; yield: 18.5 mg
(83%); mp 183–187 °C (dec.).
1H NMR (500 MHz, CD3OD): d = 1.67 (t, J = 14.0 Hz, 2 H,
NCHCH2), 1.71–1.77 (m, 2 H, CH2CH2Ph), 1.89–1.96 (m, 2 H,
CH2CH2Ph), 2.30 (br d, J = 14.3 Hz, 2 H, NCHCH2), 2.57–2.72 (m,
4 H, CH2CH2Ph), 4.17 (dd, J = 13.4, 2.8 Hz, 2 H, NCHCO2H),
7.13–7.24 (m, 4 H, CHAr,o, CHAr,p), 7.24–7.33 (m, 6 H, CHAr,o
CHAr,m).
,
IR (KBr): 3152, 3059, 3028, 3002, 2932, 2855, 2801, 1730, 1605,
1542, 1495, 1454, 1403, 1286, 1245 cm–1.
13C NMR (125 MHz, CD3OD): d = 30.4 (t), 30.6 (t), 34. 5 (t), 35.8
(t), 36.6 (s), 43.6 (t), 54.2 (d), 127.1 (d), 127.1 (d), 129.4 (d), 129.5
(d), 129.6 (d), 129.7 (d), 143.1 (s), 143.3 (s), 171.0 (s).
MS (FAB+, NBA): m/z (%) = 382.1 (100, [M – Cl]+).
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C23H28NO4:
1H NMR (400 MHz, CD3OD): d = 1.92 (dd, J = 14.6, 7.7 Hz, 2 H,
NCHCH2), 2.13 (dd, J = 14.6, 4.8 Hz, 2 H, NCHCH2), 2.71 (d,
J = 13.6 Hz, 2 H, CH2Ph), 2.78 (d, J = 13.6 Hz, 2 H, CH2Ph), 4.43
(dd, J = 7.7, 4.8 Hz, 2 H, NCHCO2H), 7.13–7.20 (m, 4 H, CHAr,o),
7.23–7.29 (m, 2 H, CHAr,p), 7.29–7.38 (m, 4 H, CHAr,m).
13C NMR (100 MHz, CD3OD): d = 32.7 (t), 37.4 (s), 44.6 (t), 52.7
(d), 128.0 (d), 129.5 (d), 132.2 (d), 137.6 (s), 171.9 (s).
382.2018; found: 382.2020.
MS (FAB+, NBA): m/z (%) = 354.4 (100, [M – Cl]+).
Acknowledgment
HRMS (FAB+, NBA): m/z [M – Cl]+ calcd for C21H24NO4:
354.1705; found: 354.1703.
We thank Dr. Lars Allmendinger for the discussion of NMR data
and Katharina Heimberger for editorial assistance.
4,4-Dibenzylpiperidine-cis-2,6-dicarboxylic Acid Hydrochlo-
ride (cis-9b)
References
According to GP4, from cis-3b (10.5 mg, 0.0333 mmol) in concd
HCl–1,4-dioxane (1:1, 3 mL); colorless solid; yield: 11.0 mg
(85%); mp >252 °C (dec.).
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Synthesis 2011, No. 20, 3332–3342 © Thieme Stuttgart · New York

3342
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