Synthesis of C2-symmetric trans-2,6-diarylpiperidinones via aryl cuprate addition: an unexpected stereochemical outcome

Article abstract of DOI:10.1016/j.tetlet.2007.01.135

An efficient procedure for the preparation of trans-2,6-diaryl piperidinones has been developed. Addition of aryl Grignard reagents to 2-aryl dihydropyridones under catalytic copper promoted conditions generates the trans isomer exclusively, an unprecedented stereochemical event. The X-ray structures of both starting material and product have been solved and shed light on the steric constraints and substrate geometry leading to the observed product. The reaction conditions tolerate a variety of aromatic nucleophiles to generate C₂-symmetric products in good overall yields.

Full text of DOI:10.1016/j.tetlet.2007.01.135

Tetrahedron Letters 48 (2007) 2079–2082
Synthesis of C2-symmetric trans-2,6-diarylpiperidinones via aryl
cuprate addition: an unexpected stereochemical outcome
Christopher L. Hamblett,a,* David L. Sloman,a Laura T. Kliman,a Bruce Adams,a
Richard G. Ballb and Matthew G. Stantona,*
aDepartment of Drug Design and Optimization-Medicinal Chemistry, Merck Research Laboratories,
33 Avenue Louis Pasteur, Boston, MA 02115, United States
bDepartment of Medicinal Chemistry, 126 Lincoln Avenue, PO Box 2000, Merck Research Laboratories,
Rahway, NJ 07065, United States
Received 22 December 2006; revised 17 January 2007; accepted 25 January 2007
Available online 30 January 2007
Abstract—An efficient procedure for the preparation of trans-2,6-diaryl piperidinones has been developed. Addition of aryl Grig-
nard reagents to 2-aryl dihydropyridones under catalytic copper promoted conditions generates the trans isomer exclusively, an
unprecedented stereochemical event. The X-ray structures of both starting material and product have been solved and shed light
on the steric constraints and substrate geometry leading to the observed product. The reaction conditions tolerate a variety of aro-
matic nucleophiles to generate C2-symmetric products in good overall yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The utility of substituted piperidinones as organic build-
ing blocks has driven the development of a variety of
methodologies aimed at the synthesis of a diverse array
of analogues.1 In particular, the utilization of N-acyl-
2,3-dihydro-4-pyridones as synthetic precursors is well
documented by Comins et al. (Fig. 1).2
1,2-addition
electrophilic substitution
O
enolate alkylation
or acetoxylation
[2+2] photocycloaddition
1,4-addition or reduction
R
N
CO2R'
Examples of conjugate Grignard additions under copper
promoted conditions have been reported to give the cis
2,6-disubstituted piperidinones in good yield and
selectivity, Eq. 1.2b Extension of this methodology to
Figure 1. General utility of 2,3-dihydro-4-pyridones.
generate 2,6-diarylpiperidinones has not previously been
disclosed to our knowledge. Subjection of 2-phenyl-3,4-
dihydro-4-pyridone (3) to copper-catalyzed conjugate
addition2a conditions proceeded smoothly to give diaryl
piperidinone 4 in excellent yield, Eq. 2. To our surprise,
O
O
Cl
MgBr
Cl
CuBr-DMS, BF3-OEt2
MeO
MeO
MeO
MeO
N
Cbz
N
Cbz
O
O
PhMgBr
1
2
CuI, THF
>20:1
N
Cbz
N
Cbz
4
(70%)
ð1Þ
3
>20:1
ð2Þ
*
Corresponding authors. Tel.: +1 617 992 2050; fax: +1 617 992 2406
(M.G.S.); e-mail: matthew_stanton@merck.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.135

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C. L. Hamblett et al. / Tetrahedron Letters 48 (2007) 2079–2082
further examination of the product by NMR revealed
that the trans-2,6-diphenyl piperidinone was formed
exclusively, an unprecedented stereochemical outcome.
tors favoring observed product and is consistent with
extensive solution NMR studies.5
A crystal structure of product piperidinone 4 was also
solved (Fig. 3). This structure adopts a twist boat type
conformation alleviating both A1,3-strain and diaxial
interactions that would be present in a chair conforma-
tion. Inference from both crystal structures favors a
model wherein the transition state adopts a pseudo twist
boat conformation to alleviate all steric interactions and
to allow for stereoelectronically preferred axial bond
formation.
Comins and co-workers has proposed that the high
cis-stereoselectivity1c,2a,b in the synthesis of 2 arises from
stereoelectronically preferred axial attack3 of the
cuprate reagent via a chair-like transition state where
the existing aryl substituent lies pseudoaxial to avoid
A
group.
1,3-interactions4 with the sterically sizable N-CBz
O
N
O
Ph
A1,3 - Interactions
O
O
Ar
A number of conditions were explored for this aryl cup-
rate addition (Table 1). In the absence of a copper cata-
lyst the reaction did proceed but in low yield (entry 1).
In the presence of a copper source, such as CuI, CuCN,
or CuBrÆSMe2, aryl addition also gave exclusively trans-
piperidinone 4, but in improved yields. The general
applicability of this reaction using a variety of copper
N
Ph
O
O
Ar
R-M
In order to fully understand the reactivity of the unsat-
urated piperidinone 3, a high quality X-ray crystal struc-
ture was solved (Fig. 2). This structure reveals that the
compound exists in a half boat conformation, which is
set up for axial delivery opposite the face of the existing
phenyl group providing the observed trans product.
This model accounts for both steric and electronic fac-
Figure 2. X-ray structure of 3.
Figure 3. X-ray structure of 4.
Table 1. Control experiments
O
O
PhMgBr
catalyst
N
CO2R
N
CO2R
4
3
Entry
Catalyst
Solvent
R
Yield (%)
Trans:cis
1
2
3
None
CuI
CUCN
CuBr–DMS
BF3–OEt2
CuI
CuI
CuI
CuI
THF
THF
THF
Bn
Bn
Bn
26
70
68
>20:1
>20:1
>20:1
a
4
5
6
7
8
THF
1,4-Dioxane
DME
THF
THF
Bn
Bn
Bn
Et
68
<5
<5
76
>20:1
NA
NA
>20:1
>20:1
C(CH3)2CCl3
61b
a Excess reagent employed (CuBr–DMS, 3 equiv; BF3–OEt2, 16 equiv).
b Excess catalyst employed (1.75 equiv).

C. L. Hamblett et al. / Tetrahedron Letters 48 (2007) 2079–2082
2081
sources indicates that subtle changes in aryl cuprate
aggregation state likely have little influence on either
the yield or selectivity of the reaction.6 Choice of solvent
is critical for the success of the reaction and the highest
yields are achieved when the reaction is performed in
THF. It is important to note that the reaction afforded
piperidinone 4 in very low yield when performed in
DME or 1,4-dioxane (entries 5 and 6).
trans-piperidinone and none of the cis product suggests
that the sterics of the N-acyl group play a very limited
role in the stereochemical outcome of the aryl addition.
Given the potential utility of C2-symmetric piperidi-
nones further investigations were initiated. The sub-
strate scope of this aryl conjugate addition was
examined (Table 2).8 Both electron-rich (entry 4) and
electron poor (entry 2) aryl cuprates were tolerated
and in all cases provided exclusively the trans-2,6-diaryl-
piperidinone. Sterically demanding aryl cuprates such as
napthyl, 2,5-dimethyl (entries 5 and 10, respectively)
gave product in good overall yields. In addition, the
use of halogen and heteroatom substituents extends
the scope of this methodology (entries 2–4, 6, 7, 9).
To investigate the role of the N-acyl group on the stereo-
chemical outcome of the aryl addition, we prepared a
variety of N-acyl derivatives. Both ethyl carbamate
(entry 7) and benzyl carbamate (entry 2) gave exclusively
the trans addition products, which suggest that a p-
stacking7 assembly in the transition state between the
phenyl group of the carbamate and the existing phenyl
group of the piperidinone likely does not play a role
for delivery of the phenyl cuprate reagent. The fact that
the sterically large trichloro-Boc group also leads to the
In summary, we have discovered an unprecedented ste-
reospecific aryl cuprate addition to 2-aryl dihydropyri-
dones. C2-symmetric piperidinones bearing aryl
substituents may be valuable both as intermediates for
ligands/catalysts employed in asymmetric transforma-
tions and as versatile synthetic precursors. The scope
of the efficient trans cuprate addition described herein
allows for expeditious and variable tuning of the
ligand/catalyst design. To that end, studies aimed at
extension of this methodology to enantioselective prep-
arations9 of diaryl piperidinones are underway.
Table 2. Substrate scope for the aryl conjugate additiona
O
O
OMe
ArMgBr
CuI, THF, 0 oC
ArMgBr
CBzCl, THF, 0 o
(70-95%)
C
Ar
N
Cbz
Ar
N
Cbz
>20:1
Ar
N
Entry
1
Ar
Yield (%)
attack from top
face hindered
due to large
phenyl substituent -
cis product not observed
70
R-M
2
56
F3C
O
O
3
4
72
74
N
F
O
preferred axial
attack leading
to trans product
MeO
R-M
5
6
7
44
33
46
Acknowledgment
F
F
The authors would like to acknowledge Dr. Ben Munoz
for helpful discussions with the development of this
methodology and Grace Bi for chromatographic
analysis.
Me2N
Me
Supplementary data
8
47
59
46
NMR characterization studies. Crystallographic data
for the structures in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as Supple-
mentary Publication Numbers CCDC 631813 and
CCDC 631814. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk]. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.01.135.
Cl
9
Me
10b
Me
a Reaction conditions: 1.75 equiv ArMgBr, 0.2 equiv CuI.
b Modification: the reaction was performed at 4 °C overnight.

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C. L. Hamblett et al. / Tetrahedron Letters 48 (2007) 2079–2082
Asymmetric Chemical Transformations; Doyle, M. P., Ed.;
References and notes
JAI: Greenwich, CT, 1995; Vol. 1, pp 151–192; (d) Feringa,
B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH:
Weinheim, Germany, 2002; pp 224–258.
1. (a) Stevens, R. Acc. Chem. Res. 1984, 17, 289; (b) Comins,
D. L. J. Heterocycl. Chem. 1999, 36, 1491; (c) Neipp, C. E.;
Martin, S. F. J. Org. Chem. 2003, 68, 8867.
7. Jones, G. B.; Chapman, B. J. Synthesis 1995, 5, 475.
8. General procedure for the preparation of aryl piperidinones
using CuI as a catalyst: A suspension of copper iodide
(62 mg, 0.33 mmol) in THF (10 mL) was cooled to 0 °C and
treated with phenyl magnesium bromide (2.85 mmol,
2.85 mL of a 1 M solution) and stirred for 30 min. A
solution of dihydropyridone 3 (0.5 g, 1.63 mmol) in THF
(10 mL) was added to the reaction mixture at 0 °C and the
resulting solution was stirred at this temperature for 2 h.
The reaction mixture was quenched with ammonium
chloride/ammonium hydroxide solution and partitioned
between water and ethyl acetate. The organics were dried
over sodium sulfate, filtered, and evaporated in vacuo.
Purification by flash column chromatography (15–25%
ethyl acetate/hexanes) gave 0.44 g (70%) of piperidinone 4
as a white solid.
9. (a) Comins, D. L.; Dehghani, A. J. Org. Chem. 1995, 60,
794; (b) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123,
11829; (c) Lemire, A.; Grenon, M.; Pourashraf, M.;
Charette, A. B. Org. Lett. 2004, 6, 3517; (d) Klegraf, E.;
Follman, M.; Schollmeyer, D.; Kunz, H. Eur. J. Org. Chem.
2004, 3346; (e) Lemire, A.; Charette, A. B. Org. Lett. 2005,
7, 2747.
2. (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27,
4549; (b) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am.
Chem. Soc. 1988, 110, 7445; (c) Comins, D. L.; LaMunyon,
D. H. Tetrahedron Lett. 1989, 30, 5053; (d) Comins, D. L.;
Zeller, E. Tetrahedron Lett. 1991, 32, 5889; (e) Comins, D.
L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994,
116, 4719.
3. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; Chapter 6.
4. (a) Paulson, H.; Todt, K. Angew. Chem., Int. Ed. Engl.
1966, 5, 899; (b) Scott, J. W.; Durham, L. J.; deJongh, H.
A. P. Tetrahedron Lett. 1967, 8, 2381; (c) Chow, Y. L.;
Colon, C. J.; Tam, J. N. S. Can. J. Chem. 1968, 46, 2821; (d)
Johnson, F. Chem. Rev. 1968, 68, 375; (e) Fraser, R. R.;
Grindley, T. B. Tetrahedron Lett. 1974, 15, 4169; (f) Quick,
J.; Mondello, C.; Humora, M.; Brennan, T. J. Org. Chem.
1978, 43, 2705.
5. See Supplementary data for a detailed analysis of the NMR
studies performed.
6. (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
771; (b) Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis. In Tetrahedron Organic Chemistry
Series; Pergamon: Oxford, 1992; Vol. 9; (c) Feringa, B.
L.; Vries, A. H. M.. In Advances in Catalytic Processes: