Synthesis of 4-substituted tetrahydropyridines by cross-coupling of enol phosphates

Article abstract of DOI:10.1016/j.tetlet.2005.03.203

Enol phosphates, synthesized from 4-piperidone, react by palladium catalyzed cross-coupling with arylboronic acids and by iron and palladium catalyzed cross-coupling with Grignard reagents to give 4-substituted tetrahydropyridines.

Full text of DOI:10.1016/j.tetlet.2005.03.203

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4261–4263
Synthesis of 4-substituted tetrahydropyridines by cross-coupling
of enol phosphates
Uffe S. Larsen,a,b Lars Martinyc and Mikael Begtrupa,*
aDepartment of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark
bIsotope Chemistry, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
cRadiation Research Department, Risø National Laboratory, DK-4000 Roskilde, Denmark
Received 11 February 2005; revised 17 March 2005; accepted 23 March 2005
Available online 3 May 2005
Abstract—Enol phosphates, synthesized from 4-piperidone, react by palladium catalyzed cross-coupling with arylboronic acids and
by iron and palladium catalyzed cross-coupling with Grignard reagents to give 4-substituted tetrahydropyridines.
Ó 2005 Elsevier Ltd. All rights reserved.
O
Enol phosphates have, in a few cases, proved to work
better in cross-coupling reactions than their triflate
counterparts due to higher stability, higher yield and
easier work up.1 Enol phosphates have been used in
Suzuki,2 Stille,2f,3 Negeshi4 and Kumada-Tamao5
cross-coupling reactions, and have been applied in total
synthesis.6 However, apart from a single exception,2a
only activated (electron poor) enol phosphates have
been used in Suzuki cross-coupling reactions. Unfavour-
able oxidative addition to the catalyst probably explains
the limited application of enol phosphates. Considering
the continuous development of phosphine ligands
increasing the reactivity of aryl chlorides in cross-
coupling synthesis,7 we found it interesting to determine
whether these ligands could enlarge the scope of enol
phosphates in cross-coupling synthesis as well.
OP(OR)2
O
N
Boc
1
i
N
Boc
2a, R=Et 78%
2b R=Ph 85%
Scheme 1. Reagents and conditions: (i) 1, ClP(O)(OR)2 (1.2 equiv),
HMPA (1.4 equiv), KHMDS (1.3 equiv), THF, ꢀ78 °C, 2 h.
Palladium tetrakistriphenylphosphine usually serves
well as a catalyst in cross-coupling reactions between
boronic acids and enol phosphates but did not work in
the present case. Pd(OAc)2/BINAP, Pd(PPh)2Cl2 and
Pd(OAc)2/tri-tert-butylphosphine8 failed to promote
the cross-coupling as well. However, Pd(OAc)2/2-(di-
tert-butylphosphino)biphenyl9 (BuchwaldÕs ligand)
effected cross-coupling using diphenyl phosphate 2b as
the starting material affording N-Boc-4-aryl-1,2,3,6-
tetrahydropyridine (3) (Table 1) in moderate yields.
Optimized conditions were found to entail microwave
assisted heating at 150 °C for 5 min with 5 mol% of cat-
alyst and KF as base in a 1:1 solution of DME:water
(Table 1).
We now report the first Suzuki cross-coupling reactions
of enol phosphates, which take advantage of a highly
activated palladium catalyst designed for cross-coupling
of deactivated aryl chlorides. In addition, we report iron
and palladium catalyzed cross-coupling among enol
phosphates and Grignard reagents. The cross-coupling
reactions provide 4-substituted tetrahydropyridines.
The enol phosphates 2a and 2b were prepared in 78%
and 85% yields from the potassium enolates of N-Boc-
4-piperidone (1) (Scheme 1).
The conditions were quite critical. The reaction only
proceeded when boronic acids were applied as starting
materials, while boronic esters failed to react. Diethyl
phosphate 2a gave only traces of cross-coupling
products. The use of other solvents like toluene, THF,
*
Corresponding author. Tel.: +45 3530 6240; fax: +45 3530 6040;
e-mail: mb@dfuni.dk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.203

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U. S. Larsen et al. / Tetrahedron Letters 46 (2005) 4261–4263
Table 1. Synthesis of 4-aryl tetrahydropyridines
O
O
Bu
N
Boc
4
OP(OR)2
Ar
N
OP(OPh)2
i
64% (R=Ph)
50% (R=Et)
i
+
ArB(OH)2
N
N
Boc
Boc
3
Boc
2b
2
Scheme 2. Reagents and conditions: (i) 2, BuMgCl (2.0 equiv),
TMEDA (2.0 equiv), Fe(acac)3 (6 mol%), THF, ꢀ10 °C ! 0 °C, 1 h.
Entry
1
Ar
Product
Yield (%)
48
3a
O
2
3
3b
3c
46
49
Ph
N
Boc
3a
OP(OR)2
i
MeO
MeO
93% (R=Ph)
69% (R=Et)
N
Boc
4
3d
45
2
Scheme 3. Reagents and conditions: (i) 2, PhMgCl (2.0 equiv),
TMEDA (2.0 equiv), Pd(PPh3)Cl2 (3 mol%), THF, 40 °C, 1 h.
5
6
3e
3f
0
OMe
has been used for this purpose,11 did not improve our
yields. The phenyl phosphate 2b, which has to be stored
cold and under argon, gave better cross-coupling yields
than the corresponding shelf stable ethyl phosphate 2a
(Schemes 2 and 3).
29
NC
7
8
3g
3h
25
28
OHC
O
Enol phosphates derived from 4-piperidones are easy to
prepare. They are versatile starting materials in efficient
palladium or iron catalyzed cross-coupling reactions
giving access to a range of 4-substituted tetrahydropyr-
idines. The highly activated catalyst Pd(OAc)2/2-(di-tert-
butylphosphino)biphenyl has been used for the first time
to promote Suzuki cross-coupling reactions with non-
activated enol phosphate which otherwise fail to react.
Reagents and conditions: (i) 2b, ArB(OH)2 (1.2 equiv) KF (3.8 equiv),
2-(di-tert-butylphosphino)biphenyl (6 mol%), Pd(OAc)2 (5 mol%),
H2O/DME, 150 °C, 5 min.
dioxane and EtOH or other bases such as Na2CO3,
NaOH and Et3N resulted in lower yields. Yields also
dropped significantly at temperatures below 120 °C or
above 160 °C. The yields were influenced both by steric
and electronic effects. Thus a substituent at the 2-posi-
tion of the arylboronic acids impeded cross-coupling
(Table 1, entry 5). Electron attracting substituents led
to lower cross-coupling yields (Table 1, entries 6–8),
while electron donating substituents at C-3 and C-4
did not influence the yield (Table 1, entries 2–4).
Acknowledgements
We want to acknowledge The Danish Academy of
Technical Sciences and Corporate Research Affairs,
Novo Nordisk A/S for financial support.
Grignard reagents have been subjected to cross-coupling
reactions with enol phosphates using nickel, palladium
and iron catalysis.10 In this particular case, the enol
phosphates 2a and 2b did not react with butyl magne-
sium bromide under Pd-catalysis, while Fe(III)acac
catalysis afforded N-Boc-4-butyl-1,2,3,6-tetrahydropyr-
idine 4 (Scheme 2).
Supplementary data
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2005.03.203.
References and notes
Under similar conditions, reaction of 2a and 2b with
phenyl magnesium bromide gave only traces of
cross-coupling products, while Pd-catalysis gave good
yields of N-Boc-4-phenyl-1,2,3,6-tetrahydropyridine 3a
(Scheme 3). Complete consumption of starting material
required addition of TMEDA. It is believed that TME-
DA, by complexation of the Mg-ions formed during the
reaction, enhance the process. NMP, which reportedly
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