Palladium-catalyzed cyclization-Heck reaction of allenamides: An approach to 3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives

Article abstract of DOI:10.1021/acs.orglett.6b03364

An efficient one-pot construction of functionalized 3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives via palladium-catalyzed cyclization-Heck reaction of allenamides has been described. The 3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives feature a nonconjugated diene, including one endo-enamine and one exocyclic double bond, which could be used for further transformation. Both aryl and vinyl halides performed very well under the standard conditions, delivering the corresponding products efficiently.

Full text of DOI:10.1021/acs.orglett.6b03364

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Cyclization-Heck Reaction of Allenamides: An
Approach to 3‑Methylene-5-phenyl-1,2,3,4-tetrahydropyridine
Derivatives
Fachao Yan,† Hanbing Liang,† Jian Song,† Jie Cui,† Qing Liu,† Sheng Liu,§ Ping Wang,† Yunhui Dong,*,†
and Hui Liu*,†,§,‡
†School of Chemical Engineering, Shandong University of Technology, 266 West Xincun Road, Zibo 255049, P. R. China
‡The Technical Center of Zibo Entry and Exit Inspection and Quarantine Bureau, Zibo 255031, P. R. China
§College of Materials Science and Engineering, Hunan University, Changsha, Hunan 410082, China
S
* Supporting Information
ABSTRACT: An efficient one-pot construction of functionalized 3-
methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives via palla-
dium-catalyzed cyclization-Heck reaction of allenamides has been
described. The 3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine de-
rivatives feature a nonconjugated diene, including one endo-enamine
and one exocyclic double bond, which could be used for further
transformation. Both aryl and vinyl halides performed very well under
the standard conditions, delivering the corresponding products
efficiently.
unctionalized 3-methylene-5-phenyl-1,2,3,4-tetrahydropyr-
idine derivatives represent a prevalent structural motif
aza-heterocycles, particularly palladium catalysis.2 However, few
examples of the construction of this scaffold have been reported,3
which makes the development of an efficient synthetic route
highly in demand.
Allenamides, functionally derived from allenamines and
bearing the amido group, inducing delocalization of the lone-
pair electrons on nitrogen and therefore exhibiting improved
stability, have become a powerful and versatile building block in
synthetic chemistry.4 Transition-metal-catalyzed cyclization of
allenamides is a versatile strategy in the construction of aza-
heterocycles because acyclic substrates are readily available.4e−g,5
Recently, the transformations of allenamide compounds bearing
F
among natural products and pharmaceuticals with numerous
bioactivities, such as ( )-preclamol (the first autoreceptor-
selective agonist), mesulergine (for treatment of hyperprolacti-
nemia, acromegaly, and Parkinson’s disease), dexetimide (for
control of extrapyramidal symptoms induced by pipothiazine
palmitate), and potential drugs from Bayer, Novartis, and Merck
(Figure 1).1Consequently, selective construction of substituted
olefinic side chains caught our attention. In 2010, Backvall and
̈
co-workers reported a palladium-catalyzed oxidative carbocycli-
zation of aza-enallenes, efficiently delivering five-membered 2,3-
dihydropyrrole motifs (Scheme 1a).6 In 2014, Tong and co-
workers developed a cyclization of vinyl iodide-tethered
allenesulfonamides to give tetrahydropyridine derivatives
catalyzed by palladium (Scheme 1b).7 In 2016, the Arisawa
group demonstrated a ruthenium-catalyzed intramolecular [2 +
2] cycloaddition of allenamide-enes to azabicyclo[3.1.1]-
heptanes (Scheme 1c).8 Notably, all of these reactions are
intramolecular cyclizations. We expected that intermolecular
coupling followed by cyclization could construct the 3-
methylene-5-phenyl-1,2,3,4-tetrahydropyridine skeleton via
Pd−π-allyl intermediate A as shown in Scheme 1.
Figure 1. Bioactive 3-phenylpiperidine derivatives.
3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives
under mild reaction conditions becomes particularly attractive.
There are two main difficulties: (1) construction of piperidines
and (2) installation of the aryl group at the 5-position. In the past
decades, transition-metal-catalyzed cyclization has gained
increasing importance as a readily available approach to valuable
Very recently, our group reported a palladium-catalyzed 6-
endo-selective alkyl-Heck reaction of unactivated alkyl iodides to
Received: November 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03364
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Letter
Gratifyingly, the desired piperidine derivative 3ah was obtained
in 29% yield, accompanied by partial decomposition of
allenamide 1a. The combination of Pd(dba)2/PPh3 as the
catalyst did not improve the transformation (entry 2). Then
PdCl2(PPh3)2, PdCl2(dppf), and Pd(PPh3)4 were examined, and
the results showed that Pd(PPh3)4 could increase the yield to
52% (entry 5). Subsequently, various bases were screened
(entries 7−12). Inorganic bases such as K3PO4, Na2CO3,
CH3COONa, and Cs2CO3 did not show an obvious influence
on the reaction, but organic bases exhibited a quite good effect on
the yield. To our delight, Cy2NMe was found to be a good choice,
affording 3a in 85% yield (entry 12). Furthermore, the reaction is
quite sensitive to the temperature. When performed at 50 °C, the
reaction slowed, and the yield decreased to 42% (entry 13).
When the temperature was increased to 100 °C, the reaction
turned messy with some undetermined byproducts (entry 14).
Two control experiments demonstrated that both the catalyst
and base are necessary for this transformation (entries 15 and
16). Finally, Pd(PPh3)4 (10 mol %) and Cy2NMe (2.0 equiv) in
dioxane at 80 °C were chosen as the optimized conditions.
With the optimized conditions in hand, we subsequently
explored the substrate scope of this cascade procedure, and the
results are given in Table 2. Both iodobenzene and
bromobenzene could give the desired product 3aa, although
the yield for bromobenzene was relatively low (54%).
Iodobenzene derivatives bearing an electron-withdrawing
group at the para position, such as nitro, acetyl, and ethyl
ester, performed very well under the standard conditions and
delivered the corresponding piperidine derivatives in good yields
(3ab−ad). A substrate with an ethyl ester at the ortho position
worked smoothly, giving 3ae in 77% yield. Furthermore, the
highly electron-deficient iodobenzene bearing two ethyl esters
could also give 3af efficiently in 65% yield. It is worth noting that
the highly sensitive aldehyde group could survive very well in this
system (3ag). Subsequently, iodobenzenes with various electron-
donating groups were also examined. Substrates including
methoxy or methyl at the ortho, meta, or para position or two
methyl groups gave the desired 3-methylene-5-phenyl-1,2,3,4-
tetrahydropyridine derivatives in moderate to good yields (3ah−
al). Both chloro and fluoro at different positions showed quite
good tolerance of the reaction conditions (3am−aq). 2-
Iodothiophene-substituted 2r delivered the corresponding
product 3ar in 68% yield.
Furthermore, the Boc-protected allenamide 1b was synthe-
sized and subjected to the cascade reaction. Some iodobenzene
derivatives were examined. However, only iodobenzenes with an
electron-withdrawing group could produce stable products, such
as 3bb with nitro and 3bc with acetyl. Iodobenzenes with an
electron-donating group, such as methoxy and methyl, could
form the corresponding products, but they decomposed fully
during column chromatography, which might due to the
sensitive enamine structure. Methanesulfonyl-protected allena-
mides reacted with various iodobenzenes to generate the
corresponding products in moderate yields (3cc, 3cm, and
3co). We also tried to use different protecting groups for the
allenamides, but only the electron-withdrawing groups could
form stable allenamides.
The scope of this palladium-catalyzed cyclization-Heck
reaction was further expanded to vinyl halides. The reaction of
E-(2-bromovinyl)benzene derivatives 2s−w with 1a smoothly
afforded tetrahydropyridine derivatives 3as−aw possessing a
valuable conjugated 1,3-diene, which have potential to be
transformed into more complicated molecules.
Scheme 1. Reactions of Allenamides Bearing Olefinic Side
Chains
construct 5-phenyl-1,2,3,6-tetrahydropyridine derivatives.9 To
develop versatile methodologies for the synthesis of piperidine
derivatives, the intermolecular coupling and cyclization-Heck
reaction was achieved. Herein we are pleased to report a
palladium-catalyzed strategy for the synthesis of valuable 3-
methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivatives fea-
turing a nonconjugated diene, including one endo-enamine and
one exocyclic double bond. Notably, the reaction proceeds with
high C1 cyclization selectivity, and no C3 cyclization product is
detected.
Initially, our study commenced with the cascade reaction of
allenamide 1a with 1-iodo-4-methoxybenzene (2h) catalyzed by
Pd(OAc)2/PPh3 using K2CO3 as the base (Table 1, entry 1).
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
base
K2CO3
t (°C) yield (%)
1
2
Pd(OAc)2
Pd(dba)2
PPh3
PPh3
−
−
−
−
−
−
−
−
−
−
−
−
−
−
80
80
80
80
80
80
80
80
80
80
80
80
50
100
80
80
29
23
37
33
52
32
41
26
43
68
73
85
42
57
NR
NR
K2CO3
K2CO3
K2CO3
K2CO3
K2PO3
3
PdCl2(PPh3)2
PdCl2(dppf)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
−
4
5
6
7
Na2CO3
CH3COONa
Cs2CO3
TEA
8
9
10
11
12
13
14
15
16
DIPEA
Cy2NMe
Cy2NMe
Cy2NMe
−
Cy2NMe
a
Reaction conditions: 1a (0.2 mmol), 2h (0.4 mmol), [Pd] (0.02
b
mmol), base (0.4 mmol), solvent (2.0 mL), N2, 5 h. Isolated yields.
B
DOI: 10.1021/acs.orglett.6b03364
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Letter
Table 2. Scope of Coupling−Cyclization-Heck Reaction of
Scheme 2. Proposed Mechanism
a b
,
Allenamides
palladium complex 4, and subsequent insertion of allenamide 1a
would form π-allylpalladium intermediate 5. Subsequently, 6-
exo-trig cyclization and β-hydrogen elimination would generate
the 3-methylene-5-phenyl-1,2,3,4-tetrahydropyridine derivative
3ah. Under the standard conditions, we could isolate only the six-
membered cyclization product 3ah, and no four-membered
cyclization product was detected, which might be due to the high
ring strain.
In conclusion, we have demonstrated a palladium-catalyzed
methodology for the synthesis of valuable 3-methylene-5-phenyl-
1,2,3,4-tetrahydropyridine derivatives featuring a nonconjugated
diene, including one endo-enamine and one exocyclic double
bond, which could be used for the further preparation of
industrially and pharmaceutically important piperidine-contain-
ing compounds. Both aryl and vinyl halides performed very well
under the standard conditions, delivering the corresponding
products efficiently. Further synthetic applications are ongoing in
our laboratory, and we are trying to realize the four-membered
cyclization reaction via ligand and substrate regulation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03364.
Synthetic procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dyh651118@126.com.
*E-mail: huiliu1030@sdut.edu.cn.
ORCID
Hui Liu: 0000-0001-8916-6055
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
a
■
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (0.02
b
We thank the National Natural Science Foundation of China
(21302057 and 21405095), the Young Talents Joint Fund of
Shandong Province (ZR2015JL005), CPSF (2016M590736),
Special Funding for Postdoctoral Innovation Project of
Shandong Province (201501002), and The Technology Project
of General Administration of Quality Supervision, Inspection
mmol), Cy2NMe (0.4 mmol), dioxane (2.0 mL), N2, 8 h. Isolated
yields are shown.
A hypothesized mechanism of this transformation is shown in
Scheme 2. Oxidative addition of Pd(PPh3)4 to 2h would afford
C
DOI: 10.1021/acs.orglett.6b03364
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Letter
Lofstedt, J.; Dorange, I.; Backvall, J.-E. J. Am. Chem. Soc. 2002, 124,
̈
̈
and Quarantine (2016IK202). We are grateful for the support
from Zibo Positive Additive Co., Ltd.
11246. (f) Persson, A. K. Å.; Jiang, T.; Johnson, M. T.; Backvall, J.-E.
̈
Angew. Chem., Int. Ed. 2011, 50, 6155.
(7) (a) Xie, Z.; Wu, P.; Cai, L.; Tong, X. Tetrahedron Lett. 2014, 55,
REFERENCES
■
2160. (b) Qiu, Y.; Yang, B.; Zhu, C.; Backvall, J.-E. Angew. Chem., Int. Ed.
̈
(1) (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
̈
̈
2016, 55, 6520.
(b) Cody, W. L.; Holsworth, D. D.; Powell, N. A.; Jalaie, M.; Zhang, E.;
Wang, W.; Samas, B.; Bryant, J.; Ostroski, R.; Ryan, M. J.; Edmunds, J. J.
Bioorg. Med. Chem. 2005, 13, 59. (c) Hu, X. E.; Kim, N. K.; Gray, J. L.;
Almstead, J.-I. K.; Seibel, W. L.; Ledoussal, B. J. Med. Chem. 2003, 46,
3655. (d) Petukhov, P. A.; Zhang, J.; Wang, C.; Ye, Y.; Johnson, K. M.;
Kozikowski, A. P. J. Med. Chem. 2004, 47, 3009. (e) He, S.; Lai, Z.; Dai,
X.; Xiao, D.; London, C.; Zorn, N.; Nargund, R.; Palani, A.; Mccomas, C.
C.; Li, P.; Peng, X.; Soll, R. WO2014205592A1, 2014. (f) Zimmerman,
K.; Baeschlin, D. K.; Moussaoui, S. EP1961742A1, 2008. (g) Jeske, M.;
(8) Nada, T.; Yoneshige, Y.; Ii, Y.; Matsumoto, T.; Fujioka, H.; Shuto,
S.; Arisawa, M. ACS Catal. 2016, 6, 3168.
(9) Dong, X.; Han, Y.; Yan, F.; Liu, Q.; Wang, P.; Chen, K.; Li, Y.; Zhao,
Z.; Dong, Y.; Liu, H. Org. Lett. 2016, 18, 3774.
Heimback, D.; Rohrig, S.; Cancho Grande, Y.; Schneider, D.; Rester, U.;
̈
Bender, E.; Meininghaus, M.; Zimmermann, K.; Zubov, D.; Buchmuller,
̈
B.; von Degenfeld, G.; Gerdes, C.; Gerisch, M.; Gnoth, M. J.; Gericke, K.
M. US2012046268A1, 2012.
(2) (a) Trost, B. M.; Krische, M. J. Synlett 1998, 1998, 1. (b) Aubert, C.;
Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813. (c) Zhang, Z.; Zhu,
G.; Tong, X.; Wang, F.; Xie, X.; Wang, J.; Jiang, L. Curr. Org. Chem. 2006,
10, 1457. (d) Bruneau, C. NATO Sci. Ser. II 2007, 243, 375. (e) Michelet,
̂
V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268.
(f) Majumdar, K. C.; Chattopadhyay, B.; Maji, P. K.; Chattopadhyay, S.
K.; Samanta, S. Heterocycles 2010, 81, 795. (g) Nakamura, I.; Yamamoto,
Y. Chem. Rev. 2004, 104, 2127. (h) Yamamoto, Y. Chem. Rev. 2012, 112,
4736. (i) Wu, X.; Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1.
(3) Murugesan, S.; Jiang, F.; Achard, M.; Bruneau, C.; Der
́
ien, S. Chem.
Commun. 2012, 48, 6589.
(4) (a) Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis;
John Wiley & Sons: New York, 1984. (b) Sainsbury, M. In Second
Supplements to the 2nd Edition of Rodd’s Chemistry of Carbon Compounds;
Elsevier: Oxford, U.K., 1991; Chapter 2b, p 84. (c) Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vols. 1 and 2. (d) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263. (e) Wei, L.; Xiong, H.; Hsung, R. P. Acc.
Chem. Res. 2003, 36, 773. (f) Ma, S. Chem. Rev. 2005, 105, 2829. (g) Lu,
T.; Lu, Z.; Ma, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862.
(5) (a) Du, Y.-F.; Hsung, R. P. In Asymmetric Synthesis II; Wiley-VCH:
Weinheim, Germany, 2013; p 239. (b) Standen, P. E.; Kimber, M. C.
Curr. Opin. Drug Discovery Dev. 2010, 13, 645. (c) Parthasarathy, K.;
Jeganmohan, M.; Cheng, C. H. Org. Lett. 2006, 8, 621. (d) Wang, Y.;
Zhang, P.; Liu, Y.; Xia, F.; Zhang, J. Chem. Sci. 2015, 6, 5564. (e) Jia, M.;
Monari, M.; Yang, Q.; Bandini, M. Chem. Commun. 2015, 51, 2320.
́
(f) Faustino, H.; Varela, I.; Mascarenas, J. L.; Lopez, F. Chem. Sci. 2015,
̃
6, 2903. (g) Hu, H.; Wang, Y.; Qian, D.; Zhang, Z.; Liu, L.; Zhang, J. Org.
Chem. Front. 2016, 3, 759. (h) Yang, X.; Toste, F. D. Chem. Sci. 2016, 7,
2653. (i) Wang, Y.; Zhang, P.; Qian, D.; Zhang, J. Angew. Chem., Int. Ed.
2015, 54, 14849. (j) Suar
M.; Rubio, E.; Gonzalez, J. M. Adv. Synth. Catal. 2012, 354, 1651. (k) Li,
X.; Zhu, L.; Zhou, W.; Chen, Z. Org. Lett. 2012, 14, 436. (l) Faustino, H.;
Bernal, P.; Castedo, L.; Lopez, F.; Mascarenas, J. L. Adv. Synth. Catal.
2012, 354, 1658. (m) Bernal-Albert, P.; Faustino, H.; Gimeno, A.;
Asensio, G.; Mascarenas, J. L.; Lopez, F. Org. Lett. 2014, 16, 6196.
(n) Suarez-Pantiga, S.; Hernandez-Díaz, C.; Rubio, E.; Gonzalez, J. M.
́ ́
ez-Pantiga, S.; Hernandez-Díaz, C.; Piedrafita,
́
́
̃
́
́
́
́
Angew. Chem., Int. Ed. 2012, 51, 11552. (o) Zhou, W.; Li, X.; Li, G.; Wu,
Y.; Chen, Z. Chem. Commun. 2013, 49, 3552. (p) Li, G.; Zhou, W.; Li, X.;
Bi, Q.; Wang, Z.; Zhao, Z.; Hu, W.; Chen, Z. Chem. Commun. 2013, 49,
4770. (q) Faustino, H.; Lopez, F.; Castedo, L.; Mascarenas, L. M. Chem.
́
̃
Sci. 2011, 2, 633. (r) Pirovano, V.; Decataldo, L.; Rossi, E.; Vicente, R.
Chem. Commun. 2013, 49, 3594. (s) Francos, J.; Grande-Carmona, F.;
Faustino, H.; Iglesias-Siguenza, J.; Díez, E.; Alonso, I.; Fernan
́
dez, R.;
̈
Lassaletta, J. M.; Lop
14322.
(6) (a) Faustino, H.; Alonso, I.; Mascarenas, J. L.; Lop
́
ez, F.; Mascarenas, J. L. J. Am. Chem. Soc. 2012, 134,
̃
́
ez, F. Angew.
̃
Chem., Int. Ed. 2013, 52, 6526. (b) Persson, A. K. Å.; Backvall, J.-E.
̈
Angew. Chem., Int. Ed. 2010, 49, 4624. (c) Persson, A. K. Å.; Johnston, E.
V.; Backvall, J.-E. Org. Lett. 2009, 11, 3814. (d) Zhu, C.; Yang, B.; Jiang,
̈
́
T.; Backvall, J.-E. Angew. Chem., Int. Ed. 2015, 54, 9066. (e) Franzen, J.;
̈
D
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