Application of the PMC protecting group in the efficient synthesis of 4,4-disubstituted piperidines

Article abstract of DOI:10.1081/SCC-200061570

An efficient synthesis of the 4,4-disubstituted piperidine scaffold 1 was accomplished by treating the PMC N-protected α,β-unsaturated ethyl cyanoacetate 9 with various Grignard reagents (R₁MgX). Subsequent heating at 19°C in a strong base prov

Full text of DOI:10.1081/SCC-200061570

This article was downloaded by: [University of Waikato]
On: 25 May 2014, At: 05:14
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Application of the PMC
Protecting Group in the
Efficient Synthesis of
4,4‐Disubstituted Piperidines
Janet L. Ralbovsky a , Joseph G. Lisko a & Wei He a
a Drug Discovery , Johnson & Johnson
Pharmaceutical Research and Development, LLC ,
Spring House, Pennsylvania, USA
Published online: 16 Aug 2006.
To cite this article: Janet L. Ralbovsky , Joseph G. Lisko & Wei He (2005) Application
of the PMC Protecting Group in the Efficient Synthesis of 4,4‐Disubstituted
Piperidines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:12, 1613-1625, DOI: 10.1081/
SCC-200061570
To link to this article: http://dx.doi.org/10.1081/SCC-200061570
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the

Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 1613–1625, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061570
Application of the PMC Protecting
Group in the Efficient Synthesis of
4,4-Disubstituted Piperidines
Janet L. Ralbovsky, Joseph G. Lisko, and Wei He
Drug Discovery, Johnson & Johnson Pharmaceutical Research and
Development, LLC, Spring House, Pennsylvania, USA
Abstract: An efficient synthesis of the 4,4-disubstituted piperidine scaffold 1 was
accomplished by treating the PMC N-protected a,b-unsaturated ethyl cyanoacetate 9
with various Grignard reagents (R1MgX). Subsequent heating at 1908C in a strong
base provided carboxylic acids 12–20b in good yield. The PMC group was easily
removed at room temperature with 33% HBr in acetic acid.
Keywords: 1,4-Addition, 4,4-disubstituted piperidines, PMC protecting group
INTRODUCTION
Substituted piperidines, well-known scaffolds in pharmaceutical research, are
commonly found in tachykinin receptor antagonists.[1] In the course of our
work to develop biologically active molecules, a method was needed to
synthesize a wide variety of 4,4-disubstituted piperidines (1) (see Fig. 1).
Ultimately, this procedure would allow us to vary R1 and R2 with a variety
of functionality and be amenable to parallel solution phase synthesis.
Although a literature search revealed very limited options in forming this
quaternary center, one reported procedure from Schneider and colleagues
looked promising.[2]
Received in the USA February 16, 2005
Address correspondence to Janet L. Ralbovsky, Drug Discovery, Johnson &
Johnson Pharmaceutical Research and Development, LLC, Welsh and McKean
Roads, P.O. Box 776, Spring House, PA 19477, USA. E-mail: jlisko@prdus.jnj.com
1613

1614
J. L. Ralbovsky, J. G. Lisko, and W. He
Figure 1. 4,4-disubtituted piperidine.
They utilized the 1,4 addition of Grignard reagents to a,b-unsaturated
ethyl cyanoacetates (Scheme 1). Tosylated piperidinone 2 was treated with
ethyl cyanoacetate to provide the a,b-unsaturated ethyl cyanoacetate 3. The
substrate then reacted with Grignard reagents and the 4,4-disubstituted
piperidines 4 were obtained in various yields. The substrates were heated at
a high temperature with a strong base, causing hydrolysis of the cyano
group and further decarboxylation to provide the carboxylic acid 5. They sub-
sequently used refluxing 33% HBr in acetic acid to remove the N-tosyl pro-
tecting group.
Although Schneider and colleagues’ methodology looked attractive
because it enabled us to take advantage of the large number of commercially
available Grignard reagents, we found that removing the N-tosyl group with
refluxing HBr in acetic acid as reported was not compatible with many of
our target compounds. Removal of the N-tosyl group requires harsh con-
ditions; common procedures for removal include not only refluxing HBr in
acetic acid, which Schneider and coworkers used, but also lithium or
sodium naphthalide.[3] Such harsh conditions are not compatible with many
functional groups, including those of our target compounds. Reagents such
as those listed previously are also unattractive for parallel solution phase
synthesis. To utilize Schneider’s methodology, a protecting group was
required that would be stable in a strong base at high temperatures and that
would be capable of being removed more conveniently.
We chose the 2,2,5,7,8-pentamethylchroman-6-sulphonyl (PMC) group,
a protecting group reported by Ramage and Green and developed as an acid
labile protecting group for the guanidine side chain functionality of
arginine.[4] In addition, the PMC group has recently been used as a
Scheme 1. Bochow and Schneider’s synthesis.

PMC Protecting Group
1615
replacement for the tosyl group in the Mitsunobu reaction of protected
amines.[5] An advantage of the PMC group is that, like the tosyl group, it is
robust enough to withstand many types of functional group transformations.
But, unlike the tosyl group, the PMC group can be easily removed with
HBr in acetic acid at room temperature. Utilization of the PMC protecting
group afforded solutions to the liabilities of the tosyl moiety. The desired
4,4-disubstituted piperidine analogs could be formed in parallel, with fewer
by-products, because of the less severe removal conditions.
RESULTS AND DISCUSSION
The starting PMC protected piperidine was easily synthesized in three steps
(Scheme 2). The commercially available piperidine alcohol 6 was treated
with PMC-Cl, triethylamine in methylene chloride, to yield 7. The alcohol
was oxidized to the ketone with TPAP (tetrapropylammonium perruthenate)
and NMO (4-methylmorpholine-N-oxide) in methylene chloride. The crude
material 8 then reacted with ethyl cyanoacetate, ammonium acetate, acetic
acid, and trimethyl orthoformate in toluene at reflux to give 9 in 75% yield
over three steps.
We compared the reactivity of the tosyl, PMC, and BOC protected piper-
idines upon addition of benzyl Grignard (Table 1). All compounds gave
excellent yields of the cyanoacetate intermediate. Not surprisingly, upon
heating with a strong base, the BOC group did not survive. The PMC and
tosyl piperdines gave very good yields of the desired acid.
Table 2 summarizes the results from treating 9 with various commercially
available Grignard reagents. Using two equivalents of the Grignard reagent
was optimal and most of the additions afforded moderate to good yields.
For example, the addition of benzyl magnesium bromide (12a) and pentyl
magnesium bromide (15a) to 9 gave a 96% and 89% yield respectively.
The methyl derivative 13a was synthesized in 86% yield. However, the
cyclopentyl Grignard (16a) and cyclopropyl Grignard (17a) produced
Scheme 2. Synthesis of PMC N-protected a,b-unsaturated ethyl cyanoacetate.

1616
J. L. Ralbovsky, J. G. Lisko, and W. He
Table 1. Comparison of N-protecting groups
Entry
R
Yield (%)
Yield (%)
10
11
12
t-BOC
tosyl
PMC
96
99
96
trace
73
80
modest 33% and 39% yields respectively. In cases where remaining starting
material was observed, adding additional Grignard reagent during the
course of the reaction did not improve the yield. Example 14a, an important
intermediate because of the allyl group’s potential to be further functionalized,
proceeded in 53% yield. Hydrolysis of the cyano group followed by decarbox-
ylation was achieved using 15% KOH in ethylene glycol at 1908C for 4 h. The
reaction gave good yields with no major single impurity. All compounds were
purified using the CombiFlash by Isco flash chromatography system.
To examine the utility of the methodology, aniline was coupled to the acid
12 using EDC, HOBt in methylene chloride to provide 21 in 75% yield
Table 2. Synthesis of 4,4-disubstituted piperidine scaffolds using various grignard
reagents
Entry
R
Product
Yield (%)
Product
Yield (%)
12
13
14
15
16
17
18
19
20
benzyl
CH3
allyl
12a
13a
14a
15a
16a
17a
18a
19a
20a
96
86
53
89
33
39
48
70
70
12b
13b
14b
15b
16b
17b
18b
19b
20b
80
74
94
81
50
64
84
78
79
n-C5H11
cyclopentyl
cyclopropyl
4-chlorophenyl
phenyl
4-methoxyphenyl

PMC Protecting Group
1617
Scheme 3. Utilization of the resulting 4,4-disubstitued piperidine scaffold for further
synthesis.
(Scheme 3). Removal of the PMC group was accomplished by treating 21 with
33% HBr in acetic acid for 2 h at room temperature. If the reaction went
longer than 2 h, brominated by-products developed. (The allyl group in
example 14 does not survive the conditions to remove the PMC group.
It can only be used as a functional handle. The brominated by-products
were not isolated but could be detected by LC/MS analysis of the crude
reaction mixture.) After purification, the desired piperidine 22 was isolated
in 80% yield. Subsequent reactions were run in parallel using a Radleys
Carousal reaction station.
By utilizing the PMC protecting group, we were able to modify Schneider’s
procedure and develop an efficient synthesis of diverse 4,4-disubstituted piperi-
dines. The relative ease of removal of the PMC protecting group afforded a
parallel solution phase approach to the synthesis of the target compounds.
EXPERIMENTAL
All starting materials were commercially available and were not purified
further before use. All NMR spectra were recorded on a Bruker Avance 300
(300 MHz, 75 MHz) spectrometer in the noted deuterated solvents. Chemical
shifts (d) are given in ppm downfield from TMS. HPLC purities were
afforded by Hewlett-Packard 1050 using a 5% MeCN/H2O–95% MeCN/
H2O gradient and a Supelco Supelcosil column. High-resolution mass
spectra were collected using an Agilent 1100/Micromass LC-MS system.
N-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-piperidin-4-ol (7). A solu-
tion of 4-hydroxypiperidine (2.0 g, 19.7 mmol) in dichloromethane
(75 mL) was treated with triethylamine (3.29 mL, 23.6 mmol) and the
reaction was allowed to stir at room temperature for 10 min. 2,2,5,7,8-
Pentamethylchromane-6-sulfonyl chloride (PMC-Cl) (5.99 g, 19.7 mmol)
was then added and the reaction was allowed to proceed at room temperature
overnight. The reaction mixture was partitioned between saturated ammonium
chloride (75 mL) and dichloromethane (3 ꢀ 75 mL). Combined organic
extracts were dried over Na2SO4, filtered, and reduced. The crude product
(7) was used directly in the next synthetic step without further purification.

1618
J. L. Ralbovsky, J. G. Lisko, and W. He
N-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-piperidin-4-one (8). Crude
product (7) (7.24 g, 19.7 mmol) was dissolved in dichloromethane (80 mL)
and the solution was cooled to 08C. The reaction mixture was treated with
4-methylmorpholine-N-oxide (4.62 g, 39.4 mmol) and tetrapropylammonium-
perruthenate (TPAP) (346 mg, 0.985 mmol, 5 mol %) and the solution was
allowed to stir overnight while gradually warming to room temperature.
The reaction mixture was then poured over a plug of silica gel, which was
repeatedly washed with dichloromethane (2 ꢀ 200 mL) and ethyl acetate
(2 ꢀ 200 mL). The combined organic fractions were reduced to afford the
crude product as a light yellow solid. Crude yield: 7.3 grams. Because of
the purity of the crude product (ꢀ90% by HPLC), further purification was
not performed.
Cyano [N-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-piperidin-4-ylidene]-
acetic acid ethyl ester (9). The crude 8 (7.24 g, 19.7 mmol) in anhydrous
toluene (100 mL) was treated with cyanoacetic acid ethyl ester (2.71 mL,
23.9 mmol), ammonium acetate (365 mg, 4.74 mmol), acetic acid (0.717 mL,
11.9 mmol), and trimethylorthoformate (2.54 mL, 23.9 mmol). The reaction
mixture was then heated to reflux until HPLC showed consumption of
starting material. After 5 h of reaction, the mixture was allowed to cool and
was reduced. The resulting oil was taken up in ethyl acetate (100 mL) and
was washed with saturated sodium bicarbonate (100 mL). Combined
organic layers were dried over sodium sulfate, filtered, and reduced. Pure
product was isolated via Isco flash column chromatography using a
heptanes/ethyl acetate solvent system (0% ethyl acetate to 40% ethyl
acetate over 47 min). 6.93 g (75% for 3 steps) of 9 (98% by HPLC) was
obtained as a fluffy white powder. HRMS m/z (M þ H)þ calculated:
461.2111, found: 461.2081. 1H NMR (300 MHz, CDCl3) d 4.28 (q, 2H,
J ¼ 7.14 Hz), 3.41 (m, 4H), 3.23 (t, 2H, J ¼ 5.91 Hz), 2.86 (t, 2H,
J ¼ 6.0 Hz), 2.66 (t, 2H, J ¼ 6.83 Hz), 2.53 (s, 3H), 2.51 (s, 3H), 2.14
(s, 3H), 1.84 (t, 2H, J ¼ 6.80 Hz), 1.37 t, 3H, J ¼ 7.14 Hz), 1.33 (s, 6H).
13C NMR (75 MHz, CDCl3) d 173.3, 161.8, 155.7, 138.4, 126.2, 125.3,
118.9, 115.2, 104.7, 74.6, 62.5, 45.2, 44.9, 35.6, 33.0, 30.9, 27.1, 21.9, 18.6,
17.6, 14.4, 12.6.
Example Procedure for the Grignard Addition
[4-Benzyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-
cyanoacetic acid ethyl ester (12a). A solution of 9 (200 mg, 0.434 mmol) in
THF (2 mL) under nitrogen was cooled to 08C and was treated with benzyl
magnesium bromide (0.868 mL, 0.868 mmol, 1 M solution in THF) via
syringe. The reaction mixture was allowed to stir overnight while gradually
warming to room temperature. Upon completion, the solution was poured
over saturated NH4Cl (15 mL) and organics were extracted with ethyl

PMC Protecting Group
1619
acetate (3 ꢀ 10 mL). Combined organic extracts were dried over Na2SO4,
filtered, and reduced. The product was obtained via Isco flash column chrom-
atography using a heptanes/ethyl acetate solvent system (0% ethyl acetate to
40% ethyl acetate over 47 min). 230 mg (96%) of 12a was isolated as a white
solid (90% purity by HPLC). HRMS m/z (M þ H)þ calculated: 553.2737,
1
found: 553.2723. H NMR (300 MHz, CDCl3) d 7.16–7.37 (m, 5H), 4.24
(q, 2H, J ¼ 7.14 Hz), 3.60 (s, 1H), 3.38 (m, 4H), 3.03 (s, 1H), 2.94 (s, 1H),
2.63 (t, 2H, J ¼ 6.82 Hz), 2.48 (s, 6H), 2.11 (s, 3H), 1.83 (t, 2H,
J ¼ 6.88 Hz), 1.72 (m, 4H), 1.32 (s, 6H), 1.28 (t, 3H, J ¼ 7.16 Hz). 13C
NMR (75 MHz, CDCl3) d 165.2, 155.5, 138.6, 138.4, 135.5, 131.1, 129.0,
128.9, 128.0, 127.7, 127.4, 125.9, 125.2, 118.9, 115.7, 74.5, 63.2, 44.7,
40.2, 40.0, 39.0, 33.0, 31.1, 27.2, 21.8, 18.5, 17.6, 14.4, 12.6.
Example Procedure for Decarboxylation
[4-Benzyl-1-2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-acetic
acid (12b). 12a (240 mg, 0.446 mmol) was gradually dissolved in a 15%
(w/w) solution of KOH in ethylene glycol (5 mL) upon heating. The
solution was further heated to 1908C and was allowed to stir at that tempera-
ture until HPLC showed consumption of starting materials (4 h). The mixture
was allowed to cool and was diluted with water (50 mL) and 1 N HCl (50 mL).
Organics were extracted with dichloromethane (3 ꢀ 40 mL) and ethyl acetate
(3 ꢀ 40 mL). The combined organic layers were dried over Na2SO4, filtered,
and reduced in vacuo. Purification was achieved via Isco flash column chrom-
atography using a heptanes/ethyl acetate solvent system (0% ethyl acetate to
50% ethyl acetate over 50 min). 175 mg (80%) of 12b was isolated as a white
solid (96% purity by HPLC). HRMS m/z (M þ H)þ calculated: 500.2471,
1
found: 500.2641. H NMR (300 MHz, CDCl3) d 7.19–7.31 (m, 5H), 3.36
(m, 2H), 3.15 (m, 2H), 2.85 (s, 2H), 2.64 (t, 2H, J ¼ 6.76 Hz), 2.52 (s, 3H),
2.51 (s, 3H), 2.33 (s, 2H), 2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.73 Hz), 1.63
(t, 4H, J ¼ 5.09 Hz), 1.33 (s, 6H). 13C NMR (75 MHz, CDCl3) d 179.1,
155.1, 138.2, 138.0, 135.6, 130.4, 128.6, 127.1, 125.7, 124.8, 118.5, 117.6,
74.1, 42.9, 39.8, 35.4, 33.7, 32.7, 26.8, 24.9, 21.5, 18.2, 17.2, 12.2.
Representative Procedure for Alkylation
2-[4-Benzyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-
N-phenyl-acetamide (21). A stirred solution of 12b (140 mg, 0.28 mmol) in
anhydrous THF (5 mL) was treated with aniline (0.28 mL, 0.3 mmol),
1-[(3-dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (57 mg,
0.3 mmol) and 1-hydroxybenzotriazole (41 mg, 0.3 mmol). The reaction was
allowed to stir at room temperature overnight. The solution was partitioned
between saturated sodium bicarbonate (25 mL) and ethyl acetate
(3 ꢀ 15 mL). The combined organic extracts were dried over Na2SO4,

1620
J. L. Ralbovsky, J. G. Lisko, and W. He
filtered, and reduced. Isolation of pure product was achieved via Isco flash
column chromatography using a heptanes/ethyl acetate solvent system (0%
ethyl acetate to 40% ethyl acetate over 42 min). 120 mg (75%) of 21 was
isolated as a white solid (96% purity by HPLC). HRMS m/z (M þ H)þ
calculated: 575.2944, found: 575.2983. 1H NMR (300 MHz, CDCl3) d
7.10–7.51 (m, 10H), 3.35 (m, 2H), 3.19 (m, 2H), 2.97 (s, 2H), 2.64 (t, 2H,
J ¼ 6.77 Hz), 2.52 (s, 3H), 2.51 (s, 3H), 2.25 (s, 2H), 2.12 (s, 3H), 1.83
(t, 2H, J ¼ 6.77 Hz), 1.65 (m, 4H), 1.33 (s, 6H). 13C NMR (75 MHz, CDCl3)
d 169.1, 154.8, 138.0, 137.3, 130.9, 128.9, 127.9, 125.2, 124.4, 124.2, 119.8,
118.3, 73.8, 39.7, 35.5, 34.1, 33.6, 32.3, 30.3, 26.4, 21.2, 17.7, 16.8, 11.8.
Example Procedure for PMC Cleavage
2-(4-Benzyl-piperidin-4-yl)-N-phenyl-acetamide (22). Compound 21
(115 mg, 0.2 mmol) was treated with 33% HBr/AcOH (3 mL) and the
reaction was allowed to stir at room temperature for 2 h. HPLC showed
almost complete consumption of starting material, but allowing the reaction
to run longer afforded a brominated product. The mixture was then quenched
with saturated sodium bicarbonate (5 mL) and the product was extracted repeat-
edly with ethyl acetate (5 ꢀ 25mL). Combined organic layers were dried over
Na2SO4, filtered, and reduced. The resulting syrup was dissolved in ethyl
acetate (2 mL) and upon treatment with ethereal hydrogen chloride (5mL),
the solution became cloudy. The solution was reduced under nitrogen and the
product was recrystallized from ethyl acetate. 55mg (80%) of the desired
product 22 was isolated as an off-white solid (100% purity by HPLC).
HRMS m/z (M þ H)þ calculated: 309.1968, found: 309.1964. 1H NMR
(300MHz, DMSO) d 8.50 (s, 1H), 7.68 (d, 2H, J ¼ 7.87Hz), 7.22–7.32
(m, 8H), 4.59 (s, 1H), 3.20 (m, 4H), 2.91 (s, 2H), 2.42 (s, 2H), 1.67 (m, 4H).
13C NMR (75 MHz, DMSO) d 169.8, 139.4, 137.5, 131.8, 131.2, 128.9,
128.3, 126.6, 123.6, 121.6, 119.7, 43.4, 34.8, 30.9.
Compound Data
4-Benzyl-4-(cyano-ethoxycarbonyl-methyl)-piperidine-1-carboxylic acid
tert-butyl ester (10a). 90% purity as determined by HPLC. HRMS m/z
(M þ H)þ calculated: 387.2285, found: 387.2342. 1H NMR (300 MHz,
DMSO) d 7.26–7.42 (m, 3H), 7.18 (d, 2H, J ¼ 6.55 Hz), 4.15 (q, 2H,
J ¼ 7.14 Hz), 3.70 (s, 1H), 3.32–3.54 (m, 4H), 2.84 (d, 2H, J ¼ 7.05 Hz),
1.74 (m, 2H), 1.54 (m, 2H), 1.35 (s, 9H), 1.23 (t, 3H, J ¼ 7.07 Hz). 13C
NMR (75 MHz, DMSO) d 165.2, 153.9, 135.5, 130.9, 128.5, 128.4, 127.9,
127.8, 116.1, 79.2, 62.9, 43.3, 40.3, 40.0, 39.8, 31.9, 30.7, 27.9, 13.8.
[4-Benzyl-1-(toluene-4-sulfonyl)-piperidin-4-yl]-cyanoacetic acid ethyl
ester (11a). 90% purity as determined by HPLC. HRMS m/z (M þ H)þ

PMC Protecting Group
1621
1
calculated: 441.1849, found: 441.1851. H NMR (300 MHz, CDCl3) d 7.65
(d, 2H, J ¼ 8.23 Hz), 7.20–7.36 (m, 5H), 7.09 (d, 2H, J ¼ 6.80 Hz), 4.23
(q, 2H, J ¼ 7.15 Hz), 3.45 (s, 1H), 3.14 (m, 4H), 2.80 (d, 2H, J ¼ 7.26 Hz),
2.46 (s, 3H), 1.65 (m, 4H), 1.28 (t, 3H, J ¼ 7.11 Hz). 13C NMR (75 MHz,
CDCl3) d 165.0, 144.2, 135.1, 133.5, 131.1, 130.2, 128.9, 128.0, 127.8,
115.5, 63.3, 44.3, 41.9, 39.9, 39.7, 31.2, 31.1, 21.9, 14.4. Values are compar-
able to literature values.[2]
[4-Benzyl-1-(toluene-4-sulfonyl)-piperidin-4-yl]-acetic acid (11b). 95%
purity as determined by HPLC. Data was comparable to literature values.[2]
Cyano-[4-methyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-
4-yl]-acetic acid ethyl ester (13a). 90% purity as determined by HPLC.
HRMS m/z (M þ H)þ calculated: 477.2424, found: 477.2422. 1H NMR
(300 MHz, CDCl3) d 4.27 (q, 2H, J ¼ 7.16 Hz), 2.44 (s, 1H), 3.08 (m, 4H),
2.66 (t, 2H, J ¼ 6.73 Hz), 2.51 (s, 9H), 2.12 (s, 3H), 1.83 (t, 2H,
J ¼ 6.80 Hz), 1.75 (m, 4H), 1.32 (s, 6H), 1.29 (t, 3H, J ¼ 7.19 Hz). 13C
NMR (75 MHz, CDCl3) d 164.9, 155.5, 138.5, 138.4, 126.1, 125.1, 115.4,
74.5, 63.1, 48.7, 40.2, 40.1, 36.5, 35.3, 34.6, 33.0, 29.4, 27.1, 21.9, 20.6,
18.6, 17.6, 14.5, 12.6.
[4-Methyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-
acetic acid (13b). 95% purity as determined by HPLC. HRMS m/z (M þ H)þ
calculated: 424.2158, found: 242.2151. 1H NMR (300 MHz, CDCl3) d 3.09–
3.27 (m, 4H), 2.65 (t, 2H, J ¼ 6.78 Hz), 2.52 (s, 3H), 2.51 (s, 3H), 2.31 (s, 2H),
2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.78 Hz), 1.48–1.66 (m, 4H), 1.32 (s, 6H), 1.12
(s, 3H). 13C NMR (75 MHz, CDCl3) d176.8, 155.3, 138.5, 138.3, 126.5, 125.0,
74.4, 45.2, 40.4, 36.6, 33.1, 32.0, 27.1, 24.1, 21.9, 18.6, 17.6, 12.6.
[4-Allyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-cyano-
acetic acid ethyl ester (14a). 90% purity as determined by HPLC. HRMS m/z
(M þ H)þ calculated: 503.2580, found: 503.2576. 1H NMR (300 MHz,
CDCl3) d 5.71 (m, 1H), 5.24 (m, 2H), 4.24 (q, 2H, J ¼ 7.12 Hz), 3.61
(s, 1H), 3.35 (m, 2H), 3.12 (m, 2H), 2.63 (t, 2H, J ¼ 6.76 Hz), 2.52 (s, 3H),
2.51 (s, 3H), 2.41 (d, 2H, J ¼ 5.89 Hz), 2.12 (s, 3H), 1.83 (t, 2H,
J ¼ 6.81 Hz), 1.73 (m, 4H), 1.33 (s, 6H), 1.32 (t, 3H, J ¼ 7.26 Hz). 13C
NMR (75 MHz, CDCl3) d 171.1, 164.7, 155.1, 138.2, 138.0, 131.1, 125.6,
124.8, 120.9, 118.5, 115.2, 74.1, 62.8, 45.3, 39.5, 38.9, 36.9, 32.7, 26.8,
21.5, 21.0, 18.2, 17.2, 14.2. 14.0, 12.2.
[4-Allyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-acetic
acid (14b). 97% purity as determined by HPLC. HRMS m/z (M þ H)þ calcu-
lated: 450.2315, found: 450.2266. 1H NMR (300 MHz, CDCl3) d 5.74
(m, 1H), 5.13 (m, 2H), 3.21 (m, 4H), 2.65 (t, 2H, J ¼ 6.77 Hz), 2.52
(s, 3H), 2.51 (s, 3H), 2.36 (s, 2H), 2.26 (d, 2H, J ¼ 7.45 Hz), 2.12 (s, 3H),

1622
J. L. Ralbovsky, J. G. Lisko, and W. He
1.83 (t, 2H, J ¼ 6.88 Hz), 1.60 (m, 4H), 1.33 (s, 6H). 13C NMR (75 MHz,
CDCl3) d 176.7, 155.3, 138.2, 138.3, 133.2, 126.5, 125.0, 119.6, 118.8,
74.4, 41.0, 40.4, 40.1, 34.9, 34.5, 33.0, 27.2, 21.8, 18.5, 17.5, 12.6.
Cyano-[1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-4-pentyl-piperidin-4-
yl]-acetic acid ethyl ester (15a). 94% purity as determined by HPLC. HRMS
1
m/z (M þ H)þ calculated: 533.3050, found: 533.3065. H NMR (300 MHz,
CDCl3) d 4.24 (q, 2H, J ¼ 7.12 Hz), 3.61 (s, 1H), 3.31 (m, 2H), 3.10
(m, 2H), 2.65 (t, 2H, J ¼ 6.74 Hz), 2.52 (s, 3H), 2.51 (s, 3H), 2.13 (s, 3H),
1.81 (t, 2H, J ¼ 7.07 Hz), 1.71 (m, 4H), 1.33 (s, 6H), 1.26–1.32 (m, 11H),
0.89 (m, 3H). 13C NMR (75 MHz, CDCl3) d 165.2, 155.5, 138.4, 126.0,
125.1, 118.9, 115.8, 74.5, 63.1, 45.9, 39.9, 39.2, 33.3, 33.1, 32.6, 32.3, 32.2,
27.2, 22.9, 22.8, 21.9, 18.6, 17.6, 14.4, 14.3, 12.6.
[1-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-4-pentyl-piperidin-4-yl]-
acetic acid (15b). 95% purity as determined by HPLC. HRMS m/z (M þ H)þ
1
calculated: 480.2784, found: 480.2780. H NMR (300 MHz, CDCl3) d 3.18
(m, 4H), 2.65 (t, 2H, J ¼ 6.72 Hz), 2.52 (s, 3H), 2.51 (s, 3H), 2.35 (s, 2H),
2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.88 Hz), 1.59 (m, 4H), 1.32 (s, 6H), 1.25–
1.28 (m, 8H), 0.87 (m, 3H). 13C NMR (75 MHz, CDCl3) d 168.3, 155.3,
138.5, 138.3, 126.5, 125.0, 118.7, 74.4, 47.2, 40.7, 40.2, 36.8, 34.8, 34.7,
33.1, 32.7, 27.1, 22.9, 22.8, 21.8, 18.6, 17.6, 14.4, 12.6.
Cyano-[4-cyclopentyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-
4-yl]-acetic acid ethyl ester (16a). 91% purity as determined by HPLC.
HRMS m/z (M þ H)þ calculated: 531.2893, found: 531.2593. 1H NMR
(300 MHz, CDCl3) d 4.24 (q, 2H, J ¼ 7.09 Hz), 3.92 (s, 1H), 3.38 (m, 4H),
2.65 (t, 2H, J ¼ 6.79 Hz), 2.52 (s, 3H), 2.51 (s, 3H), 2.13 (s, 3H), 1.83
(t, 2H, J ¼ 6.61 Hz), 1.77 (m, 4H), 1.60 (m, 9H), 1.32 (s, 6H), 1.29 (t, 3H,
J ¼ 7.15 Hz). 13C NMR (75 MHz, DMSO) d 165.4, 154.2, 137.4, 137.1,
126.4, 123.7, 118.7, 117.6, 74.1, 63.1, 42.9, 38.2, 38.7, 37.7, 37.3, 32.2,
31.8, 28.1, 26.4, 21.8, 20.7, 18.1, 18.0, 17.9, 16.9.
[4-Cyclopentyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-
yl]-acetic acid (16b). 97% purity as determined by HPLC. HRMS m/z
(M þ H)þ calculated: 478.2628, found: 478.2620. 1H NMR (300 MHz,
CDCl3) d 3.39 (m, 2H), 3.06 (m, 2H), 2.65 (t, 2H, J ¼ 6.73 Hz), 2.53
(s, 3H), 2.52 (s, 3H), 2.43 (s, 2H), 2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.86 Hz),
1.53–1.62 (m, 13H), 1.32 (s, 6H). 13C NMR (75 MHz, CDCl3) d 178.3,
154.9, 138.1, 137.9, 126.2, 124.6, 118.4, 74.0, 46.1, 39.8, 37.0, 36.7, 32.7,
31.2, 26.8, 26.1, 25.6, 21.5, 18.2, 17.2, 12.2.
Cyano-[4-cyclopropyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-
piperidin-4-yl]-acetic acid ethyl ester (17a). 90% purity as determined
by HPLC. HRMS m/z (M þ H)þ calculated: 503.2580, found: 503.2579.

PMC Protecting Group
1623
1H NMR (300 MHz, CDCl3) d 4.26 (q, 2H, J ¼ 7.11 Hz), 3.94 (d, 1H,
J ¼ 3.63 Hz), 3.45 (m, 4H), 2.65 (t, 2H, J ¼ 6.70 Hz), 2.55 (s, 3H), 2.54
(s, 3H), 2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.78 Hz), 1.57 (m, 4H), 1.32
(s, 6H), 1.26 (m, 3H), 0.28–0.45 (m, 5H). 13C NMR (75 MHz, CDCl3) d
162.3, 155.2, 137.2, 126.2, 124.0, 117.7, 73.3, 61.9, 42.4, 38.9, 38.8, 37.2,
31.9, 28.2, 27.5, 25.9, 20.7, 17.4, 17.3, 16.4, 13.3, 11.4, 0.0, 20.2.
[4-Cyclopropyl-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-piperidin-4-yl]-
acetic acid (17b). 95% purity as determined by HPLC. HRMS m/z (M þ H)þ
1
calculated: 450.2315, found: 450.2251. H NMR (300 MHz, CDCl3) d 3.38
(m, 2H), 2.97 (t, 2H, J ¼ 10.51 Hz), 2.65 (t, 2H, J ¼ 6.75 Hz), 2.52 (s, 3H),
2.50 (s, 3H), 2.46 (s, 2H), 2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.86 Hz), 1.53
(m, 4H), 1.32 (s, 6H), 0.37 (m, 4H), 0.35 (m, 1H). 13C NMR (75 MHz,
CDCl3) d 177.5, 154.7, 137.9, 137.7, 125.9, 124.4, 118.1, 73.8, 40.2, 39.7,
33.2, 32.5, 31.6, 26.5, 22.4, 21.2, 20.0, 17.9, 16.9, 13.8, 11.9, 0.0.
[4-(4-Chlorophenyl)-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-
piperidin-4-yl]-cyanoacetic acid ethyl ester (18a). 90% purity as determined
by HPLC. HRMS m/z (M þ H)þ calculated: 573.2191, found: 573.2206.
1H NMR (300 MHz, CDCl3) d 7.37 (d, 2H, J ¼ 8.68 Hz), 7.27 (d, 2H,
J ¼ 8.63 Hz), 3.98 (q, 2H, J ¼ 7.15 Hz), 3.59 (s, 1H), 3.45 (m, 2H), 2.89
(t, 2H, J ¼ 11.75 Hz), 2.64 (t, 2H, J ¼ 6.62 Hz), 2.50 (s, 3H), 2.49
(s, 3H), 2.12 (s, 3H), 1.83 (t, 2H, J ¼ 6.85 Hz), 1.32 (s, 6H), 1.03 (t, 3H,
J ¼ 7.15 Hz), 0.90 (m, 4H). 13C NMR (75 MHz, CDCl3) d 164.2, 155.6,
138.6, 138.4, 135.9, 134.7, 129.7, 129.4, 129.0, 125.9, 125.2, 118.9, 115.0,
74.5, 63.1, 50.5, 43.3, 40.7, 40.6, 33.3, 33.2, 33.0, 27.1, 17.6, 14.5, 14.0,
12.6, 11.7.
[4-(4-Chlorophenyl)-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-
piperidin-4-yl]-acetic acid (18b). 93% purity as determined by HPLC.
HRMS m/z (M þ H)þ calculated: 520.1925, found 520.1922. 1H NMR
(300 MHz, CDCl3) d 7.19–7.31 (m, 4H), 3.31 (m, 2H), 3.05 (t, 2H,
J ¼ 9.48 Hz), 2.64 (t, 2H, J ¼ 6.76 Hz), 2.58 (s, 2H), 2.50 (s, 3H), 2.49
(s, 3H), 2.24 (m, 2H), 2.04 (m, 2H), 1.83 (t, 2H, J ¼ 6.74 Hz), 1.32 (s, 6H).
13C NMR (75 MHz, CDCl3) d 175.2, 155.4, 141.6, 138.5, 138.3, 133.0,
129.2, 128.4, 126.3, 125.1, 118.8, 74.5, 46.4, 40.8, 39.1, 35.0, 33.1, 27.1,
21.9, 18.5, 17.5, 12.5.
Cyano-[1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-4-phenyl-piperidin-
4-yl]-acetic acid ethyl ester (19a). 96% purity as determined by HPLC.
HRMS m/z (M þ H)þ calculated: 539.2580, found: 539.2590. 1H NMR
(300 MHz, DMSO) d 7.07–7.60 (m, 5H), 3.90 (q, 2H, J ¼ 7.05 Hz), 3.36
(m, 4H), 3.33 (s, 1H), 2.63 (m, 2H), 2.41 (s, 6H), 2.08 (s, 3H), 1.95 (t, 4H,
J ¼ 11.90 Hz), 1.83 (t, 2H, J ¼ 6.51 Hz), 1.29 (s, 6H), 0.94 (t, 3H,
J ¼ 7.11 Hz). 13C NMR (75 MHz, DMSO) d 164.3, 154.3, 137.5, 137.2,

1624
J. L. Ralbovsky, J. G. Lisko, and W. He
137.1, 128.7, 127.5, 127.4, 125.9, 123.7, 118.7, 115.8, 74.2, 61.8, 49.4, 42.7,
39.2, 38.9, 38.7, 32.2, 31.7, 26.4, 20.7, 17.8, 16.8, 13.5, 11.9.
[1-(2,2,5,7,8-Pentamethylchroman-6-sulfonyl)-4-phenyl-piperidin-4-yl]-
acetic acid (19b). 95% purity as determined by HPLC. HRMS m/z (M þ H)þ
calculated: 486.2315, found: 486.2309. 1H NMR (300 MHz, CDCl3) d 7.19–
7.35 (m, 5H), 3.32 (m, 2H), 3.07 (m, 2H), 2.63 (t, 2H, J ¼ 6.77 Hz), 2.58
(s, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.30 (m, 2H), 2.11 (s, 3H), 2.01 (m, 2H),
1.82 (t, 2H, J ¼ 6.86 Hz), 1.32 (s, 6H). 13C NMR (75 MHz, DMSO) d
171.8, 154.2, 143.6, 137.4, 137.2, 128.3, 126.7, 126.1, 123.6, 118.7, 74.1,
46.0, 40.3, 38.9, 38.7, 38.5, 33.8, 31.8, 26.4, 20.7, 17.8, 16.9, 11.9.
Cyano-[4-(4-methoxyphenyl)-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-
piperidin-4-yl]-acetic acid ethyl ester (20a). 93% purity as determined by
HPLC. HRMS m/z (M þ H)þ calculated: 569.2686, found: 569.2679. 1H
NMR (300 MHz, DMSO) d 7.28 (d, 2H, J ¼ 8.85Hz), 6.95 (d, 2H,
J ¼ 8.82Hz), 4.35 (s, 1H), 3.93 (q, 2H, J ¼ 7.07Hz), 3.76 (s, 3H), 3.33
(m, 4H), 2.63 (t, 2H, J ¼ 6.32Hz), 2.42 (s, 6H), 2.07 (s, 3H), 1.91 (m, 4H),
1.81 (t, 2H, J ¼ 6.68 Hz), 1.28 (s, 6H), 0.98 (t, 3H). 13C NMR (75 MHz,
DMSO) d 164.4, 158.4, 154.3, 137.5, 137.2, 128.7, 125.9, 123.7, 118.7,
115.8, 114.0, 74.2, 61.8, 55.0, 49.7, 42.3, 39.5, 39.2, 38.9, 38.7, 31.9, 26.4,
20.7, 17.8, 16.9, 13.5, 11.9.
[4-(4-Methoxyphenyl)-1-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)-
piperidin-4-yl]-acetic acid (20b). 95% purity as determined by HPLC.
HRMS m/z (M þ H)þ calculated: 516.2421, found: 516.2433. 1H NMR
(300 MHz, CDCl3) d 7.21 (d, 2H, J ¼ 8.85 Hz), 6.85 (d, 2H, J ¼ 8.81 Hz),
3.79 (s, 3H), 3.32 (m, 2H), 3.06 (m, 2H), 2.63 (t, 2H, J ¼ 6.75 Hz), 2.56
(s, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.27 (m, 2H), 1.82 (t, 2H, J ¼ 6.87 Hz),
1.32 (s, 6H). 13C NMR (75 MHz, DMSO) d 171.9, 157.3, 137.4, 137.2,
127.8, 126.1, 123.6, 118.7, 113.6, 74.1, 54.9, 44.5, 38.9, 38.7, 37.9, 33.9,
31.8, 26.4, 22.1, 17.8, 16.9, 11.9.
ACKNOWLEDGMENTS
We thank Diane Gauthier for NMR assistance and Rob Kavash for
discussions.
REFERENCES
1. For a recent review, see Bhatia, M. Curr. Med. Chem. 2003, 2, 19.
2. (a) Bochow, H.; Schneider, W. Chem. Ber. 1975, 108, 3475; (b) Hund, G.;
Schneider, W. Chem. Ber. 1980, 113, 401.

PMC Protecting Group
1625
3. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley
and Sons, Inc.: New York, 1991; pp. 379–380.
4. Ramage, R.; Green, J. Tetrahedron Lett. 1987, 28, 228.
5. (a) Wisniewski, K.; Kolodziejczyk, A. S. Tetrahedron Lett. 1997, 38, 483;
(b) Kolodziejczyk, A. S.; Sugajska, E.; Falkiewicz, B.; Wisniewski, K. Synlett
1999, 10, 1606.