Highly regioselective intermolecular arylation of 1,2,3,4- tetrahydropyridines

Article abstract of DOI:10.1021/ol8018709

(Equation Presented) Using a catalytic amount of PdCl₂(dppf) ·CH₂Cl₂ in combination with Ag₃PO ₄ and NaOAc, a range of arylated 1,2,3,4-tetrahydropyridines are synthesized in good yields and with complete selectivity at the β-position. The reaction is compatible with a variety of electron-donating and electron-withdrawing aryl iodides as well as with heteroaryl iodides. The application of these tetrahydropyridines toward the synthesis of polysubstituted piperidines is also demonstrated.

Full text of DOI:10.1021/ol8018709

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4791-4794
Highly Regioselective Intermolecular
Arylation of 1,2,3,4-Tetrahydropyridines
Guillaume Pelletier, Alexandre Larive´e, and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received August 11, 2008
ABSTRACT
Using a catalytic amount of PdCl2(dppf)·CH2Cl2 in combination with Ag3PO4 and NaOAc, a range of arylated 1,2,3,4-tetrahydropyridines are
synthesized in good yields and with complete selectivity at the ꢀ-position. The reaction is compatible with a variety of electron-donating and
electron-withdrawing aryl iodides as well as with heteroaryl iodides. The application of these tetrahydropyridines toward the synthesis of
polysubstituted piperidines is also demonstrated.
The substituted piperidine moiety is among the most
encountered subunits in pharamacophores and drugs.1 Con-
sequently, their rapid, stereoselective formation has been the
topic of numerous efforts in recent years.2,3 Moreover, it has
been demonstrated that the piperidine ring can be derivatized
to the corresponding indolizidine or quinolizidine rings which
are important scaffolds found in pharmaceutical targets.4
As part of our research program directed toward the
formation of polysubstituted piperidines, we have developed
a process to activate pyridine (1) with an amide and triflic
anhydride, providing a cheap and readily available source
for the nitrogen-containing six-membered cycles (Scheme
1).5 The 1,2-addition of organometallic nucleophiles to an
(1) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (b)
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (c) Daly, J. W.; Garraffo, H. M.;
Spande, T. F. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier,
S. W., Ed.; Pergamon Press: New York, NY, 1999; Vol. 13, p 1. (d)
Schneider, M. J. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 10, p 155.
(2) For recent reviews on the stereoselective syntheses of piperidines,
see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 19, 3693. (c) Weintraub, P. M.; Sabol,
Scheme 1. Formation of 5-Substituted
1,2,3,4-Tetrahydropyridines from Pyridine
J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953
.
(3) For recent examples of stereoselective syntheses of piperidines, see:
(a) Ahari, M.; Perez, A; Menant, C.; Vasse, J.-L.; Szymoniack, J. Org.
Lett. 2008, 10, 2473. (b) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem.
2007, 72, 2046. (c) Amat, M.; Escolano, C.; Lozano, C.; Gomez-Esque´,
A.; Griera, R.; Molins, E.; Bosch, J. J. Org. Chem. 2006, 71, 3804. (d)
Zhang, Y.; Liebeskind, L. S. J. Am. Chem. Soc. 2006, 128, 465. (e) Comins,
D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227. (f) Shintani, R.; Tokunga, N.;
Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. (g) Davis, F. A.;
Rao, A.; Caroll, P. J. Org. Lett. 2003, 5, 3855. (h) Guilloteau-Bertin, B.;
Compe`re, D.; Gil, D.; Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000,
N-pyridinium imidate chiral salt derived from chiral amide
2 has been applied in the synthesis of a range of enantioen-
riched 2-substituted dihydropyridines.5e,f This approach has
139, 1391
.
10.1021/ol8018709 CCC: $40.75
Published on Web 10/01/2008
2008 American Chemical Society

been used for the expedient stereoselective synthesis of many
biologically active piperidines such as (-)-barrenazines5b and
(-)-CP-99,994.5e Also, it has been reported that chemose-
lective hydrogenation of the resulting dihydropyridine can
form 1,2,3,4-tetrahydropyridine rings 3 in excellent yields.5c
This strategy has been employed in the stereoselective
synthesis of (+)-julifloridine. More recently, we reported that
the 2,5-cis-disubstituted piperidine moiety can be accessed
in three steps from the corresponding substituted 1,2,3,4-
tetrahydropyridine 3.5a
Table 1. Exploration of the Different Reaction Parameters on
the Arylation of 1,2,3,4-Tetrahydropyridines
The formation of the ꢀ-arylated tetrahydropyridine 4
required the activation of the starting enamidine 3 with iodine
followed by a Suzuki coupling. Due to both the sensitivity
of the halide and to moderate yields for the formation of the
corresponding iodide intermediate, we sought to improve this
sequence by using a more direct approach, namely, a
palladium-catalyzed, regioselective arylation of 1,2,3,4-
tetrahydropyridines. The challenge of regioselectivity in some
arylation processes, especially in the Heck reaction with
electron-rich olefins, is an important drawback for a poten-
tially useful method.6
Ripa et al. showed that ꢀ-selectivity could be achieved
with cyclic enol ethers by using a specific nitrogen-containing
directing group and that cyclic enamidines give R-arylation
similarly to their corresponding oxygen-containing parent.7
Recently, Lane et al. reported a highly regioselective
electrophilic substitution for the arylation of the C-3 position
in indoles by increasing the steric bulk of both the ligand
on the palladium and the complexing magnesium salt.8 Also,
Ge et al. showed that high regioselectivity can be achieved
in a direct arylation of enaminones using organotrifluorobo-
rates and Cu(OAc)2.9
entry
catalyst
additive Ph-X yield 6a (%)a
1
2
3
4
5
6
Pd(OAc)2/2 PPh3
Pd(OAc)2
Pd(PCy3)2Cl2
PdCl2
PdCl2(dppf)·CH2Cl2 Ag3PO4
none Ag3PO4
PdCl2(dppf)·CH2Cl2 AgClO4
PdCl2(dppf)·CH2Cl2 AgOAc
PdCl2(dppf)·CH2Cl2 Ag3PO4
PdCl2(dppf)·CH2Cl2 Ag3PO4
PdCl2(dppf)·CH2Cl2 Ag3PO4
PdCl2(dppf)·CH2Cl2 Ag3PO4
none
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-I
Ph-Br
Ph-Cl
Ph-I
Ph-I
5
Ag3PO4
Ag3PO4
Ag3PO4
21
55
59
82
0
7d
8d
9b
10b
11e
12b
26
31
40
5
15
91(84)c
a Yield determined by 1H NMR analysis of the unpurified reaction
mixture using 1,3,5-trimethoxybenzene as an internal standard. b 1.2 equiv
of NaOAc used. c Isolated yield. d 1.8 equiv of additive used. e Reaction
conducted at 100 °C.
improvement in the yield (21%) was observed. Regioselec-
tivity problems in Heck arylation of cyclic enol-ethers have been
adressed by many groups.10 Notably, the use of stoichiometric
amounts of thallium or silver salts gave satisfying results.10c
Also, silver salts are often used to abstract halogen anions to
generate cationic palladium species.11
To arylate enamidine 5a, we initially tested classical Heck
conditions using 10 mol % of Pd(OAc)2 and 20 mol % of
PPh3, NaOAc, and iodobenzene without any other metallic
additive (Table 1, entry 1). This reaction gave a poor yield
for the arylation (∼5%) at the ꢀ-position with large amounts
of unreacted starting material. When 60 mol % of silver
phosphate was added to the reaction (entry 2), a small
In our case, Ag3PO4 could act as an oxidant since
precipitation of Ag0 was detected in the crude mixture of
the reaction. Interestingly, no phosphine ligand was necessary
to achieve significant conversion to the product (entry 4), as
the amidine is known to be a good ligand for palladium.7a,12
Gratifyingly, we found that the reaction proceeds with
PdCl2(dppf)·CH2Cl2 as the catalyst to give an 82% yield as
measured by 1H NMR (entry 5). Further screening of
additives (entries 7 and 8), aryl halides (entries 9 and 10),
reaction temperature13 (entry 11), and equivalents of base
(entry 12) led to an optimized 84% isolated yield. In all these
cases, analysis of the crude NMR showed complete regi-
oselectivity for the ꢀ-position of the enamidine. These
observations are surprising knowing that similar intramo-
lecular Heck reactions employing enamidines as directing
groups gave regioselectively R-arylated tetrahydropyridines
and double bond migration.7a
(4) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (b) Mitchinson,
A.; Nadin, A. J. Chem. Soc., Perkin Trans. 1 2000, n/a, 2862.
(5) (a) Larive´e, A.; Charette, A. B. Org. Lett. 2006, 8, 3955. (b) Focken,
T.; Charette, A. B. Org. Lett. 2006, 8, 2985. (c) Lemire, A.; Charette, A. B.
Org. Lett. 2005, 7, 2747. (d) Lemire, A.; Beaudoin, D.; Grenon, M.;
Charette, A. B. J. Org. Chem. 2005, 70, 2368. (e) Lemire, A.; Grenon, M.;
Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6, 3517. (f) Charette, A. B.;
Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001,
123, 11829.
(6) (a) Calo`, V.; Nacci, A.; Monopoli, A.; Ferola, V. J. Org. Chem.
2007, 72, 2596. (b) Phan, N. T. S.; Van der Sluys, M.; Jones, C. W. AdV.
Synth. Catal. 2006, 348, 609. (c) Cabri, W.; Candiani, I. Acc. Chem. Res.
1995, 28, 2.
(7) (a) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147. (b)
Andersson, C.-L.; Larsson, J.; Hallberg, A. J. Org. Chem. 1990, 55, 5757.
(8) (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (b) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
(9) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130,
3708.
To validate the ꢀ-regioselectivity of the reaction on a
broader scope, we submitted a variety of aryl iodides to the
optimized conditions (Table 2).
(10) (a) Hansen, A. L.; Skrydstrup, T. J. Org. Chem. 2005, 70, 5997.
(b) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg, A. J.
Org. Chem. 2003, 68, 6639. (c) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am.
Chem. Soc. 2001, 123, 8217. (d) Hillers, S.; Sartori, S.; Reiser, O. J. Am.
Chem. Soc. 1996, 118, 2087. (e) Andersson, C.-M.; Hallberg, A.; Daves,
G. D., Jr. J. Org. Chem. 1987, 52, 3529.
(12) For some examples of ligand-free Heck reactions, see: (a) Yao,
Q.; Kinney, E. P.; Yang, Z. J. Org. Chem. 2003, 68, 7528. (b) Jeffery, T.
Tetrahedron 1996, 52, 10113
(13) Similar experiments performed in other polar solvents such as DMA,
NMP, and DME gave significantly lower yields.
.
(11) For a discussion on the Heck mechanism see ref 6c.
4792
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Palladium-Catalyzed Arylation of Various Aryl and
Heteroaryl Iodides with 1,2,3,4-Tetrahydropyridines
Table 3. Palladium-Catalyzed Arylation of Various
2-Substituted 1,2,3,4-Tetrahydropyridines
entry
product
Ar
time (h)
yield (%)a
entry product
R
Ar
time (h) yield (%)a
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
Ph
6
6
6
6
8
12
12
12
16
24
6
12
24
16
84
80
75
85
71
76
68
64
68
55
75
46
32
50
2-Me-C6H4
3-Me-C6H4
4-MeO-C6H4
3,4-OCH2O-C6H3
4-F-C6H4
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
Et
Ph
Ph
Ph
6
6
71
73
73
83
75
58
2-Furyl Ph
6
6
Ph
Ph
Ph
4-MeO-C6H4
3-Me-C6H4
3-CF3-C6H4
6
20
3-Br-C6H4
3-Cl-C6H4
a Isolated yield.
9
4-CO2Et-C6H4
3-CF3-C6H4
1-naphthyl
2-thiophene
3-pyridine
10
11
12
13b
14b
Two possible mechanisms account for the regioselectivity
observed (Scheme 2).14 The first possible pathway illustrates
2-benzofuran
a Isolated yield. b Reaction was conducted with 15 mol % of
PdCl2(dppf)·CH2Cl2.
Scheme 2
.
Proposed Mechanisms for the Arylation of
1,2,3,4-Tetrahydropyridines
Aryl iodides bearing electron-rich substituents underwent
regioselective ꢀ-arylation in good yields after 8 h of reaction
(entries 2-5). Aryl iodides possessing electron-withdrawing
groups required longer reaction times, and slightly lower
yields (55-76%) were obtained (entries 6-10). The more
hindered 1-naphthyl iodide underwent the arylation smoothly
in 75% yield (entry 11). We then tested the reaction with
different heteroaryl iodides, and we were pleased to find that
2-iodothiophene (entry 12, 46% yield), 3-iodopyridine (entry
13, 32% yield), and 2-iodobenzofuran (entry 14, 50% yield)
gave the desired ꢀ-arylated product with moderate yields to
afford a range of valuable 5-heteroaryl 1,2,3,4-tetrahydro-
pyridines that are difficult to synthesize using other methods.
A variety of 2-substituted 1,2,3,4-tetrahydropyridines 5b-5d
(Table 3) were also viable substituents for ꢀ-arylation.
The yields were relatively constant with different 2-sub-
stituted tetrahydropyridines; 2-ethyl (5b), 2-phenyl (5c), and
2-furyl (5d) tetrahydropyridines all yielded ꢀ-arylation
products in 71-73% (entries 1-3). The reaction with the
2-phenyl-substituted starting material 5c also tolerated a
variety of functional groups on the aryl coupling partner,
such as an electron-rich 4-MeO (entry 4) and an electron-
poor 3-CF3 (entry 6), with yields comparable to when the
enamidine 5a was used.
a mechanism where the reaction proceeds via a Heck-type
carbo-metalation followed by an anti-ꢀ-hydride elimination
to form the product 4. The second possible pathway involves
an electrophilic substitution from the enamidine 3. Subse-
quent deprotonation mediated by NaOAc, followed by
reductive elimination, can lead to the formation of the
observed tetrahydropyridine 4.
Having a range of substituted tetrahydropyridines in hand,
these products were subjected to hydrogenation conditions
(Table 4). Treatment of cyclic enamidines with Pd/C and a
strong Lewis acid (BF3·OEt2) under a hydrogen atmosphere
produced piperidines in high yields and good stereocontrol
(4:1-6:1) favoring the cis isomer (entries 1-4).
Additionally, the cyclic enamidines were found to be
efficiently transformed to 3-aryl-3-piperidinols upon treat-
ment with dimethyldioxirane (DMDO) at -78 °C (Table 5,
entries 1-3). The relative stereochemistry was confirmed
by an NOE study of piperidinol 9b.15 Only one diastereoi-
(14) For a detailed discussion on arylation mechanisms involving
enamines or indoles, see refs 8 and 9.
(15) See Supporting Information for NOE spectra analysis.
(16) (a) Macchia, B.; Macchia, M.; Martinelli, A.; Martinotti, E.;
Orlandini, E.; Romagnoli, F.; Scatizzi, R. Eur. J. Med. Chem. 1997, 32,
231. (b) Balsamo, A.; Barili, P. L.; Gagliardi, A.; Lapucci, A.; Macchia,
B.; Macchia, F.; Bergamaschi, M. Eur. J. Med. Chem. 1982, 17, 285.
1
somer was detected by H NMR analysis of the crude
Org. Lett., Vol. 10, No. 21, 2008
4793

The amidine group can be removed by treatment with in
situ generated AlH3 and one-pot protection of the free amine
with benzoyl chloride (Scheme 3). This cleavage sequence
Table 4. Hydrogenation of Various 2,5-Substituted
1,2,3,4-Tetrahydropyridines
Scheme 3. Synthesis of a Benzoylated 2,5-cis-Piperidine
entry
product
Ar
yield (%)a
dr (cis:trans)b
1
2
3
4
8a
8b
8c
8d
Ph
98
76
90
81
6:1
5:1
5:1
4:1
4-MeO-C6H4
3-Me-C6H4
3-CF3-C6H4
a Isolated yield of the mixture of diastereoisomers. b Determined by 1H
NMR analysis of the crude mixture.
was performed without epimerization in 81% yield for
product cis-10a.
mixture. 3-Aryl-3-piperidinols are found in non-natural
polysubstituted piperidinols that are agonists of R-adrenergic
receptors.16
In summary, we developed a regioselective intermolecular
arylation for the synthesis of a broad variety of 5-aryl and
5-heteroaryl 1,2,3,4-tetrahydropyridines that avoids the pre-
activation of the enamidine with iodine. These products were
smoothly transformed into highly functionalized piperidines
by a diastereoselective hydrogenation and a tandem epoxi-
dation-nucleophile opening sequence. Mechanistic inves-
tigations to explain the regioselectivity of this reaction are
ongoing and will be reported in due course.
Table 5. Formation of Polysubstituted 3-Aryl-3-piperidinol
Using a Tandem Epoxidation-Methanol Opening Reaction
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada & Co., Boehringer
Ingelheim (Canada) Ltd., and the Universite´ de Montre´al.
G.P. is grateful to FQRNT (Que´bec) for a postgraduate
fellowship.
entry
product
R1
Ar
yield (%)a
1
2
3
9a
9b
9c
Ph
Et
Me
Ph
Ph
3-Cl-C6H4
87
91
81
Supporting Information Available: Experimental pro-
cedures and data for each reaction. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. Only one diastereoisomer was observed.
OL8018709
4794
Org. Lett., Vol. 10, No. 21, 2008