Synthesis of 4-substituted piperidines via a mild and scalable two-step Cu2O-mediated decarboxylation of cyanoesters

Article abstract of DOI:10.1080/00397910500374971

A four-step, high-yielding, kilogram-scale protocol to prepare aldehyde 5 is reported. The key reaction is a mild, two-step Cu₂O-mediated decarboxylation of cyanoester 3 that proceeds in excellent yield. The general applicability of this method

Full text of DOI:10.1080/00397910500374971

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Synthesis of 4‐Substituted Piperidines via a
Mild and Scalable Two‐Step Cu2O‐Mediated
Decarboxylation of Cyanoesters
Brian A. Chauder a , Eric E. Boros a , Kien S. Du a , Wieslaw M. Kazmierski a ,
Cecilia S. Koble a , James B. Thompson a & Elie A. Tabet b
a Metabolic and Viral CEDD Chemistry , GlaxoSmithKline , Research Triangle
Park, North Carolina, USA
b Chemical Development , GlaxoSmithKline , Research Triangle Park, North
Carolina, USA
Published online: 19 Aug 2006.
To cite this article: Brian A. Chauder , Eric E. Boros , Kien S. Du , Wieslaw M. Kazmierski , Cecilia S. Koble ,
James B. Thompson & Elie A. Tabet (2006) Synthesis of 4‐Substituted Piperidines via a Mild and Scalable
Two‐Step Cu2O‐Mediated Decarboxylation of Cyanoesters, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 36:3, 279-284, DOI: 10.1080/00397910500374971
To link to this article: http://dx.doi.org/10.1080/00397910500374971
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Synthetic Communicationsw, 36: 279–284, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500374971
Synthesis of 4-Substituted Piperidines
via a Mild and Scalable Two-Step Cu2O-
Mediated Decarboxylation of Cyanoesters
Brian A. Chauder, Eric E. Boros, Kien S. Du,
Wieslaw M. Kazmierski, Cecilia S. Koble, and
James B. Thompson
Metabolic and Viral CEDD Chemistry, GlaxoSmithKline, Research
Triangle Park, North Carolina, USA
Elie A. Tabet
Chemical Development, GlaxoSmithKline, Research Triangle Park,
North Carolina, USA
Abstract: A four-step, high-yielding, kilogram-scale protocol to prepare aldehyde 5
is reported. The key reaction is a mild, two-step Cu2O-mediated decarboxylation of
cyanoester 3 that proceeds in excellent yield. The general applicability of this methodo-
logy has also been explored.
Keywords: Copper oxide, cyanoesters, decarboxylation, 1,4-Grignard addition
N-Protected 4-substituted piperidines have recently been described as
important intermediates in the synthesis of many useful biological agents
such as CB1, A2b, NK1 and tachykinin antagonists, and in particular MC4R
agonists and CCR5 antagonists.[1]
Received in the USA July 28, 2005
Address correspondence to Brian A. Chauder, Metabolic and Viral CEDD
Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC
27709, USA. Tel.: þ 1-919-483-8432; Fax: þ1-919-315-0430; E-mail: Brian.A.
Chauder@gsk.com
279

280
B. A. Chauder et al.
During the course of recent work, we required multigram quantities of
nitrile 4 and aldehyde 5 (Scheme 1). In fact, only a single report illustrating
the synthesis of similar intermediates was known[1a]
.
This method involved a 1,4-Grignard addition of cyclohexylmagnesium
chloride to a N-Cbz protected cyanoacetate (e.g., 2 ! 3) followed by a
Krapcho decarboxylation[2] under harsh conditions (LiCl/DMSO/1608C).
Unfortunately, this route was not suitable for our synthesis because hydroge-
nolysis, which was used to remove the N-Cbz group, we found was not
compatible with the chloroarenes required for high potency of compounds.
In addition, we desired a robust intermediate suitable for analoging and a
simple replacement of the N-Cbz by N-Boc would be incompatible with
relatively harsh Krapcho conditions.[3] Nevertheless, after considerable
experimentation, we developed a route that addressed both issues. Thus, we
employed the N-Boc protecting group to improve the robustness of our
chemistry and replaced the Krapcho decarboxylation by a novel two-step
saponification/Cu2O-catalyzed decarboxylation sequence under mild
conditions (3 ! 4) (for an example of a copper/isoquinoline-catalyzed
decarboxylation of a cyanoacid at 1608C, see Ref.[4]). The crude nitrile 4
was isolated as a colorless solid that was then used without further purification
in a DIBAL reduction step (4 ! 5). Note that compounds 3, 4, and 5
were isolated and used directly in subsequent reactions without further
purification, and the purities are determined based on NMR and HPLC
analyses.
The general applicability of this methodology was then explored, and
the results from this investigation are presented in Table 1. Treating 3 in
ethanolic NaOH at rt leads to a cyanoacid, which, in the presence of a
catalytic amount of Cu2O in hot MeCN (75–808C), affords the respective
Scheme 1.

4-Substituted Piperidines
Table 1. Preparation of compounds 4 and 5
281
Yield
(2 ! 3), %
Yield
(4), %
Yield
(4 ! 5), %
Entry
Ar
1
2
p-F
3,4-di F
3,4-di Cl
Ph
—
—
—
—
81
—
75
65
78
77
56a
65a
49a
63a
90b
56a
93b
93b
94b
78b
68
59
55
81
87
69
66
64
72
76
3
4
5
m-F
p-OMe
m-Cl
6
7
8
p-CF3
p-SMe
m-OMe
9
10
aYield calculated from 2; estimated by NMR analysis.
bYield calculated from 3; estimated by NMR analysis.
nitriles 4 within 30 min in modest to excellent yields according to NMR
analysis with no chromatography necessary. It should be noted that the
majority of yields reported for nitrile 4 are over the three-step sequence
(2 ! 4) and do not reflect the efficiency of this decarboxylation process
(entries 1–4, 6). However, for several isolated cases (entries 5, 7–10),
when pure 3 was subjected to the decarboxylation conditions, the yields
were nearly quantitative with the exception of entry 10; moreover, the
Grignard additions have been shown to proceed in only modest yields
(entries 5, 7–10) and attempts to improve the yields by using longer
reaction times, various temperatures, and excess Grignard produced no signifi-
cant increase in conversion. Also, Grignard addition of pyridyl magnesium
bromides was unsuccessful, and o-fluorophenyl magnesium bromide did not
give the desired product, presumably because of benzyne formation during
the Grignard preparation.
A slightly modified version of this process was subsequently used to
prepare more than 14 kg of nitrile 4 (see Table 1, entry 5). Substituting
CuCl (3%) for CuI (30%) in the Grignard addition added robustness and
ultimately avoided isolation of the carboxylic acid. In the final step, the
product was isolated by precipitation with water and filtration. Impurities
generated during this process remained in solution and the nitrile was
isolated with high purity.
In summary, the described two-step procedure for saponification/
decarboxylation of cyanoesters is a convenient, mild, and high-yielding
complement to other syntheses of 4,4-disubstituted piperidines. This method
is easily adapted to scaling and its advantages in terms of mildness of
conditions and efficiency over previously reported processes[1a,4] makes it a
good candidate for broader application.

282
B. A. Chauder et al.
EXPERIMENTAL
Preparation of Compound 3
A solution of the halobenzene (59.28 mmol) in THF (120 mL) was added
dropwise to a mixture of Mg turnings (1.59 g, 65.4 mmol) at rt under an
inert atmosphere. After the Mg metal was consumed (5–8 h), the suspension
was added dropwise to a mixture of 2 (5.0 g, 17 mmol) and cuprous iodide
(800 mg, 4.2 mmol) in THF (50 mL) at 08C (15 min of addition time). The
reaction mixture was stirred for 0.5 h at 08C, warmed to rt, tirred an additional
2 h (reaction progress monitored by HPLC analysis), and quenched with sat.
aqueous NH4Cl solution (100 mL). Ethyl acetate (500 mL) was added, and
the layers were separated. The organic layer was washed with a saturated
brine solution, dried (Na2SO4), and concentrated to give a crude material,
which was purified by column chromatography on silica gel using 4:1
hexanes–ethyl acetate as eluent (Table 1, entry 5). 1H NMR (400 MHz,
CDCl3) d 7.37–7.26 (m, 4H); 3.99 (br q, 2H, J ¼ 7.1 Hz); 3.95–3.91
(m, 2H); 3.58 (s, 1H); 2.95–2.83 (m, 2H); 2.52 (ddd, 2H, J ¼ 6.1, 4.0,
3.2 Hz); 2.10–1.95 (m, 2H); 1.43 (s, 9H); 1.06 (t, 3H, J ¼ 7.1 Hz); MS(ES)
m/e 391.
Preparation of Compound 4
To compound 3 (12.8 mmol) in EtOH (30 mL) was added 4 M aqueous sodium
hydroxide solution (30 mL, 120 mmol). The resulting solution was stirred at rt
for 6.5 h. Aqueous HCl (2 N) was added dropwise at 08C, and the mixture was
adjusted to pH ꢀ5. The solution was extracted with ethyl acetate
(2 ꢀ 250 mL); the ethyl acetate layers were combined and washed with
water and brine, dried (Na2SO4), and concentrated to afford the crude acid
as a rigid foam, which was used without further purification (yield estimated
at 75–85% according to NMR analysis). This crude acid (9.90 mmol) was
dissolved in MeCN (30 mL), and cupric oxide (355 mg, 0.025 mmol) was
added. This mixture was heated at reflux for 30 min (vigorous loss of CO2)
and cooled to rt. Water (75 mL) was added, and the mixture was filtered
through a pad of Celite. Evaporation of the acetonitrile gave 4 as an oil that
1
crystallized on standing (85–91%) (Table 1, entry 5). H NMR (400 MHz,
CDCl3) d 7.41–7.36 (m, 1H); 7.17–7.14 (m, 1H); 7.08–6.97 (m, 2H);
3.78–3.71 (m, 2H); 3.08 (dt, 2H, J ¼ 10.5, 2.6 Hz); 2.54 (s, 2H); 2.31–2.23
(m, 2H); 1.86 (tt, 2H, J ¼ 10.2, 3.9 Hz); 1.44 (s, 9H); MS(ES) m/e 319.
Kilogram-scale Preparation of 4
To the solution of 3 (1 eq) in toluene and THF (approximately 6 vol) was
added 1M NaOH (7.7 vol, 3 eq). The mixture was stirred and heated at

4-Substituted Piperidines
283
about 348C while the reaction was monitored by HPLC analysis (typically
16 h). The layers were separated, and the aqueous layer was washed with
MTBE (3 vol). The aqueous layer was cooled to 0–58C. Following the
addition of EtOAc (6 vol), the aqueous layer was acidified to pH 2–3 by
addition of 6 N HCl (ꢀ1.3 vol, 3 eq) over about 30 min, ensuring a pH of
less than 3. The mixture was warmed to 208C, and the layers were
separated. The organic layer was concentrated under vacuum to about 3 vol
and was used directly in the next step.
Cu2O (0.1 eq) and MeCN (6.5 vol) were heated to 75–808C. The crude
carboxylic acid in EtOAc (3 vol) was added over at least 30 min while main-
taining a reaction temperature of 72–788C. The reaction was monitored by
HPLC analysis. When the reaction was complete (10–15 min), the mixture
was cooled to 0–108C and EtOAc (3.7 vol) and 1 N HCl (4.6 vol) were
added. The mixture was warmed to room temperature, and the layers were
separated. The organic layer was washed twice more with 1 N HCl (4.6 vol
each). The organic layer was concentrated under vacuum to a minimum
volume, and about 1.9 vol of MeOH was added. The solution was heated to
about 40–508C. Water (ꢀ1.2 vol) was added until the solution became
cloudy in appearance, while maintaining the temperature at 40–508C. The
solution was cooled over 30 min to 208C and additional water (2.9 vol) was
added to the slurry. The solid (4) was collected by filtration and dried in a
vacuum oven at 50–558C.
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