Pd2(dba)3-promoted synthesis of 3-N-substituted 4-aryl-1,2,3,6-tetrahydropyridine

Article abstract of DOI:10.1016/j.tetlet.2010.07.043

A novel method for the synthesis of 3-N-substituted 4-aryl-1,2,3,6- tetrahydropyridine 3 is presented. The process is carried out by the allylic bromination of 4-aryl-1,2,3,6-tetrahydropyridines 1 with N-bromosuccinimide in propanoic acid and palladium-catalyzed cross coupling of the corresponding bromide 2 with different N-based nucleophiles.

Full text of DOI:10.1016/j.tetlet.2010.07.043

Tetrahedron Letters 51 (2010) 4886–4889
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd2(dba)3-promoted synthesis of 3-N-substituted
4-aryl-1,2,3,6-tetrahydropyridine
a
a
b
c
Meng-Yang Chang a, , Chung-Han Lin , Yeh-Long Chen , Ru-Ting Hsu , Ching-Yao Chang
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Nursing, ShuZen College of Medicine and Management, Luju, Kaohsiung 821, Taiwan
c Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for the synthesis of 3-N-substituted 4-aryl-1,2,3,6-tetrahydropyridine 3 is presented. The
process is carried out by the allylic bromination of 4-aryl-1,2,3,6-tetrahydropyridines 1 with N-bromo-
succinimide in propanoic acid and palladium-catalyzed cross coupling of the corresponding bromide 2
with different N-based nucleophiles.
Received 3 June 2010
Revised 8 July 2010
Accepted 9 July 2010
Available online 15 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
N-Bromosuccinimide
4-Aryl-1,2,3,6-tetrahydropyridine
Cross coupling
JohnPhos
1. Introduction
mate, and urea. This novel two-step synthesis of 3 from 1
involves an allylic bromination of olefin 1 with N-bromosuccini-
In the field of substituted piperidine libraries, there is a constant
need for new methods for developing medicinal agents. Because
the structural skeleton is known as a building partner in the syn-
thesis of related compounds with potential pharmaceutical activi-
ties, a number of methods have been developed for the use of these
heterocycles along with several applications of these aminopiperi-
dines . The 3-N-substitutent piperidine moiety is a key ingredient
in many therapeutic agents and is used as an important bioactive
component in pharmaceutical research.1 For example, alogliptin
is used for the treatment of diabetes,1a,1b while CP-690550 serves
as a Janus kinase 3 (JAK3) inhibitor for autoimmune disease and
transplant patients.1c In the general preparation of 3-N-substituted
piperidines, the common synthetic methods include nucleophilic
ring-opening of aziridinopiperidine2,3 and ring-closing metathesis
reaction of diallylamine.4
In the preliminary studies, we investigated the interesting rear-
rangement reaction of 4-aryl-1,2,3,6-tetrahydropyridine 1 which
occurred during the preparation of a different framework that
included pyrrolidine, piperidine, azepane, benzoisoquinoline, and
other substances.5 Given the synthetic advantages of this initial
material, an easy strategy was developed for preparing several
N-3-substituted 4-aryl-1,2,3,6-tetrahydropyridines 3a–t. The sub-
stituents included sulfonamide, alkenylamide, arylamide, carba-
mide (NBS) in propanoic acid, followed by the palladium-catalyzed
intermolecular amination of allylic bromide
derivatives.
2 with amine
2. Results and discussion
In the NBS-mediated allylic bromination, olefin 1a was chosen
as the model substrate, as shown in Table 1. Initially, treatment
of olefin 1a with NBS in chloroform provided allylic bromide 2a
in low yield (36%). When the reaction solvent was acetic acid, a
mixture of allylic bromide 2a and bromoacetate 4a was isolated
at a nearly 2:1 ratio. After changing the solvent to propanoic acid,
the ratio of 2a/4b increased to 10/1.6 This study suggested that
propanoic acid with a slight steric hindrance cannot be easily
introduced into the benzylic cation of olefin 1a, and the main
resulting product 2a can be generated via the abstract hydrogen
of olefin 1a. On the other hand, alcohols (e.g., methanol, ethanol,
isopropanol, ethoxyethanol, and water) were introduced into the
reaction, while various bromides 4c–g were presented as the major
products. As shown in entries 3–6, the resulting ratios of 2a/4c–2a/
4f were: 1/8 (81%), 1/10 (78%), 1/10 (66%), and 1/13 (56%). In par-
ticular, the treatment of olefin 1a with NBS in t-butanol generated
a sole bromohydrin 4g (40%) without the formation of 2a (entry 7).
Using the water/dioxane (1/1) as the co-solvent, the yield of 4g
could be increased to a 53% yield under the reaction condition.
Determination of the relative ratio of 2a/4 was performed through
* Corresponding author. Tel.: +886 7 3121101x2220; fax: +886 7 3125339.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.043

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 4886–4889
4887
Table 1
Ar
Ar
NBS-mediated allylic bromination of olefin 1aa
NBS (2.5 equiv),
O
O S Ph
O
Ph
Ph
Ph OR
Br
EtCO H, reflux
2
N
N
H
NBS (1.1 equiv),
solvent, reflux
Br
+
Bs
1a or 1b
6a, Ar = Ph (87%)
X-Ray
N
Bs
N
Bs
N
Bs
6b, Ar = 3-CF Ph (72%)
3
4a-4g
1a
2a
X
O
Ar
X
Ar
X
Yieldb (%), 2a/4
OH
OH
Ar
Ar
O
Entry
1
Solvent (10 mL)
MeCO2H
Product 4
NXS (1.1 equiv)
H
Ph OAc
Br
O
MCPBA, CHCl ,
3
N
Bs
1c
N
N
N
Bs
reflux
N
Bs
Bs
59/30
72/7
Ar = 4-FPh
A
B
N
7a, X = Cl (32%)
O
X-Ray
4a
Bs
7b, X = Br (22%)
O
O
Ph
Ph
Scheme 1. NBS-mediated reaction of olefin 1.
Br
2
EtCO2H
N
1H NMR experiments and the provided overall yields were ad-
justed by the isolated products. To determine the allylic bromina-
tion of 4-aryl-1,2,3,6-tetrahydropyridine 1, the optimal condition
was an acidic onecondition. Using this protocol, 2b and 2c were
also provided in 51% and 63% yields.
4b
Bs
OMe
Br
3
4
MeOH
EtOH
9/72
7/71
N
Bs
OEt
4c
As shown in Scheme 1, when attempts were made to treat 1a or
1b with 2.5 equiv of NBS in propanoic acid at reflux, salt 6a or 6b was
obtained in 87% or 72% yields without the formation of 2 or 4. Based
on the above results, we examined the reaction between 1c with m-
chloroperoxybenzoic acid (MCPBA) and NCS or NBS where the major
products 7a or 7b were presented in 32% or 22% yields. A possible
mechanism is proposed in Scheme 1. The initial event may be re-
garded as the formation of intermediate A with a halide-chelated
epoxide. Next, intermediate B was generated via succinimide an-
ion-mediated hydrogen abstraction followed by the ring-opening
of epoxide. Thus, skeleton 7 was afforded by the intramolecular
alkylation, followed by a hydration reaction under the rearrange-
ment process.7 Although the isolated yield was lower, this proposed
method is novel. The structural frameworks of 4a, 4e, 6a, and 7a
were determined using single-crystal X-ray analysis.8
Palladium-catalyzed allylic amination reactions have been
studied extensively over the past decade.9 With a useful catalytic
system, we envisaged that palladium-catalyzed cross-coupling
amination of allylic bromide 2a with benzamide 5a would produce
the skeleton 3. In this work, various palladium catalysts and ligands
were tested, and the results showed a combination of Pd2(dba)3 and
JohnPhos in toluene at reflux with Cs2CO3 as a base, produced
Ph
Ph
Br
N
4d
Bs
OEt
O
Br
Br
5
EtOCH2CH2OH
6/60
N
4e
Bs
O
Ph
6
7
i-PrOH
t-BuOH
4/52
N
4f
Bs
Ph OH
Br
—/40
N
Bs
4g
a
Reactions were performed in various solvents (5 mL) using the following mole
ratios: 1a:NBS = 1:1.1.
The isolated products are >95% pure as judged by 1H NMR analysis.
b
Table 2
Pd-Catalyzed cross-coupling reactiona
Ar
Ar
Ar
R
1
Br
N
NBS, EtCO H
2
NHR R 5, toluene, JohnPhos
1
2
R
2
reflux
N
Pd (dba) , Cs CO , reflux
2
3
2
3
N
N
Bs
Bs
Bs
1a, Ar = Ph
2a, Ar = Ph (72%)
3a~3t
18 cases
(t-Bu) P
2
1b, Ar = 3-CF Ph
2b, Ar = 3-CF Ph (51%)
3
3
1c, Ar = 4-FPh
2c, Ar = 4-FPh (63%)
JohnPhos
Entry
1
Bromide 2
Nucleophile 5
Product/Yieldb (%)
Entry
10
Bromide 2
Nucleophile 5
Product/Yieldb (%)
O
O
S
O
NH2
Me
NH2
O
H
H
N
N
Me
S
2a
2a
5h
5a
O
O
N
N
Bs
3a / 81
Bs
3j / 76
(continued on next page)

4888
M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 4886–4889
Table 2 (continued)
Entry
Bromide 2
Nucleophile 5
Product/Yieldb (%)
Entry
11
Bromide 2
Nucleophile 5
Product/Yieldb (%)
O
CF3
O
S
O
NH2
NH2
O
S
H
N
H
N
2
2b
2a
5a
5i
O
O
N
N
Bs
3k / 71
3b / 42
Bs
F
O
O
S
O
F
NH2
NH2
O
S
H
N
F
H
N
3
2c
12
2a
5a
5j
O
N
O
O
Bs
3l / 70
N
Bs
3c / 63
O
O
S
O
NH2
NH2
H
N
O
F
F
H
N
O
S
O
F
4
5
6
7
2a
2a
2a
2a
13
14
15
16
2a
2a
2a
2a
O
5b
N
Bs
N
Bs
(S)-5k
3d / 78
3m / 68
O
O
NH2
NO2
H
N
H
N
H
N
NH2
N
H
O2N
5l
O
O
O
O
O
O
O
O
5c
N
Bs
N
Bs
F
3n / 46
3e / 74
O
MeO
O
NH2
OMe
H
N
H
N
H
N
NH2
N
H
MeO
5m
5d
N
Bs
N
Bs
OMe
3o / 41
3f / 70
O
O
NH2
NH2
O
H
N
H
N
S
O
O
5n
S
5e
N
Bs
N
Bs
3g / 75
3h / 41
3p / 48
O
O
NH2
NH2
O
H
N
H
N
5f
8
9
2a
2a
17
18
2a
2a
5o
N
Bs
N
Bs
3q / 50
3r / 74
O
NH2
NH
H
N
N
O
N
Bs
N
Bs
5p
5g
3i / 49
a
Reactions were performed in toluene (2 mL) using the following mole ratios: 2:5:Pd2(dba)3:JohnPhos:Cs2CO3 = 1:1:0.025:0.05:1.2.
The isolated products 3 are >95% pure as judged by 1H NMR analysis.
b
compound 3a in 81% yield.10 These conditions were applied to a
diverse range of N-based nucleophiles 5.11 The dr value of the prod-
uct 3m is 53:47 as found by chiral phase HPLC. Each of the resulting 3
obtained was in 41–81% yields, which reflected the reactivity of 5. A
typical procedure offers a general and efficient alternative to the SN
reaction of 2 with various 5. As shown in Table 2, 16 N-based nucle-
ophiles of 5 included arylamides 5a–e, alkenylamides 5f–g, sulfona-
mides 5h–k, ureas 5l–m, carbamates 5n–o, and alkylamine 5p.12
This proposed method provides an advantage over the SN
reaction of 2 as it offers the possibility of employing 5 with either
electron-donating groups or electron-withdrawing groups. For ani-
Ar
Ar
H
N
H
N
H
N
H
H , Pd/C
2
POCl ,
3
Cl
H
EA
O
O
P O
2
5
N
N
Bs
N
Bs
8a (78%)
8b (60%)
(for 8a)
Bs
3a, Ar = Ph
3b, Ar = 3-CF Ph
9a (64%) X-Ray
3
Scheme 2. Reaction of compound 3a.

M.-Y. Chang et al. / Tetrahedron Letters 51 (2010) 4886–4889
4889
Makowski, T.; Mazur, D. J.; Phillips, J.; Ripin, D. H. B.; Ruggeri, S. G.; Stearns, J. F.;
White, T. D. Org. Process Res. Dev. 2005, 9, 51; (e) Lim, H.-J.; Jung, M. H.; Lee, I. Y.
C.; Park, W. K. Bull. Korean Chem. Soc. 2006, 27, 1371.
line, the desired skeleton 3 was isolated in a lower yield (13%). At-
tempts to perform the reaction with acyclic or cyclic imides (e.g.,
acetamide, succinimide, phthalimide) failed, which may be due
to an insufficient nucleophilicity of imides. Hydrogenation of 3a
and 3b yielded 8a and 8b in 78% and 60% yields (Scheme 2). The
results showed that the treatment of 8a with P2O5 in POCl3 at re-
flux temperature produced benzonaphthyridine 9a in 52% yield.13
The structural frameworks of 3d, 3g, 3k, and 9a were determined
by single-crystal X-ray analysis.14
4. Other methods: (a) Barco, A.; Benetti, S.; Casolari, A.; Pollini, G. P.; Spalluto, G.
Tetrahedron Lett. 1990, 31, 3039; (b) Reilly, M.; Anthony, D. R.; Gallagher, C.
Tetrahedron Lett. 2003, 44, 2927; (c) Langlois, N.; Calvez, O. Tetrahedron Lett.
2000, 41, 8285; (d) Jiang, J.; Qing, J.; Gong, L.-Z. Chem. Eur. J. 2009, 15, 7031; (e)
Toumieux, S.; Compain, P.; Martin, O. R. J. Org. Chem. 2008, 73, 2155.
5. (a) Chang, M.-Y.; Pai, C.-L.; Lin, C.-Y. Tetrahedron Lett. 2006, 47, 3641; (b) Chang,
M.-Y.; Lin, C.-Y.; Hung, C.-Y. Tetrahedron 2007, 63, 3312; (c) Chang, M.-Y.; Kung,
Y.-H.; Ma, C.-C. Tetrahedron Lett. 2007, 48, 199; (d) Chang, M.-Y.; Lin, C.-H.;
Chen, Y.-L.; Chang, C.-Y.; Hsu, R.-T. Org. Lett. 2010, 12, 1176; (e) Chang, M.-Y.;
Lin, C.-H.; Chen, Y.-L.; Hsu, R.-T.; Chang, C.-Y. Tetrahedron Lett. 2010, 51, 3154.
6. (a) Carabateas, P. M. J. Med. Chem. 1970, 13, 167; (b) Chen, F.; Jiang, X.; Er, J. C.;
Yeung, Y. Y. Tetrahedron Lett. 2010, 51, 3433.
3. Conclusion
7. Surmont, R.; Verniest, G.; Thuring, J. W.; MacDonald, G.; Deroose, F.; De Kimpe,
N. J. Org. Chem. 2010, 75, 929.
In summary, we have successfully presented a synthetic meth-
odology for producing novel 3-N-substituted 4-aryl-1,2,3,6-tetra-
hydropyridines involving NBS-mediated allylic bromination and
followed by a palladium-catalyzed cross-coupling amination. Un-
der the Pd2(dba)3/JohnPhos/Cs2CO3 system, the allylic bromides
could couple with a wide range of N-based nucleophiles, such as
arylamide, alkenylamide, sulfonamide, urea, and carbamate, etc.
Several structures of the target products were nicely confirmed
by X-ray crystal analysis. The structure–activity studies of desulfo-
nated 3-aminopiperidines 3 and hydrogenated benzonaphthyri-
dine 9a in the phenylpiperidine selective serotonin reuptake
inhibitors (PSSRI)15 will be investigated in subsequent works.
8. CCDC 769429 (4a), CCDC 773606 (4e), CCDC 775901 (6a) and CCDC 769428
(7a) contain the supplementary crystallographic data for this paper. This data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk).
9. (a) Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis;
Wiley: Chichester, UK, 1997; (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 395; (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
10. For reviews on palladium-catalyzed C–N bond formation, see: (a) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338; (b) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318; (c)
Trost, B. M.; van Vranken, D. L. Chem. Rev. 1996, 96, 375; (d) Trost, B. M.;
Fandrick, D. R. Aldrichim. Acta 2007, 40, 59; (e) Serra-Muns, A.; Pleixats, R. J.
Organomet. Chem. 2010, 695, 1231. and references cited therein.
11. A representative procedure of skeleton 3 is as follows: A oven-dried sealed
tube was charged with Pd2(dba)3 (2.5 mol %), Johnphos (5.0 mol %), N-based
nucleophile 5 (0.5 mmol), allylic bromide 2a (0.5 mmol), Cs2CO3 (0.6 mmol),
and degassed toluene (2 mL). The sealed tube was evacuated and back-filled
with nitrogen three times and then heated to reflux temperature with stirring
for 10 h. The reaction mixture was allowed to cool to rt, diluted with toluene,
and filtered through a pad of Celite. 0.5 N HCl (2 mL) was added to the reaction
mixture and the solvent was concentrated. The residue was extracted with
dichloromethane (3 Â 20 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford the crude product. Purification
on silica gel (hexane/AcOEt = 3/1–1/1) afforded skeleton 3. Representative data
for compound 3a: mp = 200–201 °C; HRMS (ESI, M++1) calcd for C24H23N2O3S
419.1429, found 419.1430; 1H NMR (400 MHz): d 7.84–7.81 (m, 2H), 7.72–7.69
(m, 2H), 7.63–7.24 (m, 11H), 6.50 (d, J = 8.8 Hz, 1H), 6.29 (dd, J = 2.4, 4.8 Hz,
1H), 5.41 (dd, J = 2.0, 8.8 Hz, 1H), 4.32 (dd, J = 4.8, 17.6 Hz, 1H), 4.04 (ddd,
J = 1.2, 2.0, 12.0 Hz, 1H), 3.38 (dt, J = 2.4, 17.6 Hz, 1H), 2.79 (dd, J = 2.8, 12.4 Hz,
1H); 13C NMR (100 MHz): d 167.22, 136.73, 135.74, 135.54, 134.00, 133.14,
131.67, 129.24 (2Â), 128.76 (2Â), 128.54 (2Â), 128.27, 127.66 (2Â), 127.10
(2Â), 125.32 (2Â), 122.85, 49.52, 45.64, 44.77; Anal. Calcd for C24H22N2O3S: C,
68.88; H, 5.30; N, 6.69. Found: C, 69.02; H, 5.51; N, 6.91.
12. For amide, see: (a) Li, X.; Vince, R. Bioorg. Med. Chem. 2006, 14, 5742;
Sulfonamide, see: (b) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5,
4373; Carbamate, see: (c) Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz,
L. Org. Lett. 2003, 5, 2207; (d) Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003,
5, 27; (e) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3311.
13. Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Aelterman, W.; De Kimpe, N.
Tetrahedron 2000, 56, 7313.
14. CCDC 776153 (3d), CCDC 776152 (3g), CCDC 776198 (3k) and CCDC 775902
(9a) contain the supplementary crystallographic data for this paper. This data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q099003).
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