Access to Cycloalkeno[ c]-Fused Pyridines via Pd-Catalyzed C(sp2)-H Activation and Cyclization of N-Acetyl Hydrazones of Acylcycloalkenes with Vinyl Azides

Article abstract of DOI:10.1021/acs.orglett.0c02466

A novel Pd(II)-catalyzed vinylic C-H activation and cyclization has been developed, reacting a series of small, medium, and large N-acetyl hydrazones of acylcycloalkenes with vinyl azides to access diverse cycloalkeno[c]-fused pyridine scaffolds. This protocol provides progress in C(sp2)-H bond activation of medium to large cycloalkenes, and the target products can be obtained in a specific regioselectivity with good functional group tolerance and a broad substrate scope.

Full text of DOI:10.1021/acs.orglett.0c02466

pubs.acs.org/OrgLett
Letter
Access to Cycloalkeno[c]‑Fused Pyridines via Pd-Catalyzed C(sp2)−H
Activation and Cyclization of N‑Acetyl Hydrazones of
Acylcycloalkenes with Vinyl Azides
Biao Nie, Wanqing Wu, Qingyun Ren, Zhongqing Wang, Ji Zhang, Yingjun Zhang,*
and Huanfeng Jiang*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02466
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Supporting Information
ACCESS
ABSTRACT: A novel Pd(II)-catalyzed vinylic C−H activation and cyclization has been developed, reacting a series of small,
medium, and large N-acetyl hydrazones of acylcycloalkenes with vinyl azides to access diverse cycloalkeno[c]-fused pyridine
scaffolds. This protocol provides progress in C(sp2)−H bond activation of medium to large cycloalkenes, and the target products can
be obtained in a specific regioselectivity with good functional group tolerance and a broad substrate scope.
ycloalkeno[c]-fused pyridines are core components in
scope and complex starting materials or require a multistep
procedure. Beyond that, hydrogenation of isoquinoline also
offered an entry into 5,6,7,8-tetrahydroisoquinoline (THIQ), a
cyclohexeno[c]-fused pyridine, suffering with difficulty in
chemoselectivity control.9 All of these methods are limited to
the synthesis of five- to eight-membered cycloalkeno[c]-fused
pyridines. Therefore, the development of novel protocols for
the construction of cycloalkeno[c]-fused pyridines is still highly
desirable.
Over the decades, transition metal-catalyzed C−H activation
has become an important tool for the synthesis of pyridines in
an atom- and step-economical fashion.10 There are two main
routes for accessing cycloalkeno[c]-fused pyridines by a C−H
activation strategy. The first strategy targeted the C−H bond
of pyridines, using C−H cyclization of pyridines to construct a
fused alicyclic ring on the pyridine skeleton.11 The other one
targeted the C(sp2)−H bond of cycloalkenes, employing C−H
1
bioactive pharmaceuticals,2
Cmany natural products,
OLED materials,3 and chelating ligands4 that have various
biological activities and important applications (Figure 1).5
Much effort has been dedicated to the synthesis of such
pyridine motifs. Traditional approaches to cycloalkeno[c]-
fused pyridines involve Diels−Alder reaction (Scheme 1A),6
transition metal-catalyzed [2+2+2] cycloaddition reaction
(Scheme 1B),7 and ring-closing metathesis (RCM) reaction.8
However, most of the methods often suffer from a limited
Received: July 24, 2020
Figure 1. Representative compounds containing the cycloalkeno[c]-
fused pyridine motif.
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A

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azide 2a were used as the model substrates to optimize the
reaction parameters. After screening different conditions, we
found that pyridine product 3aa was obtained in 75% yield
under the best reaction condition (Scheme 2): 1 (0.2 mmol),
Scheme 1. Access to Cycloalkeno[c]-Fused Pyridines
Scheme 2. Substrate Scope of N-Acetyl Hydrazones of
Acylcyclohexenes for the Synthesis of Cyclohexeno[c]-
a,b
Fused Pyridines
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Pd-PEPPSI-IPr
(15 mol %), NaOAc (1.0 equiv), and Cu2O (2.0 equiv) in toluene (4
mL) stirred at 110 °C for 16 h under an air atmosphere, unless
b
c
otherwise noted. Isolated yield. With 1.0 mmol of 1a.
2a (0.3 mmol), Pd-PEPPSI-IPr (15 mol %), NaOAc (1.0
equiv), and Cu2O (2.0 equiv) in toluene (4 mL) stirred at 110
°C for 16 h (see the Supporting Information for details).
With the optimized synthetic condition in hand, we
examined the generality of this reaction. A cyclohexane[c]-
fused pyridine scaffold was frequently used as a valuable
pharmacophore in drug design and discovery.18 For this
reason, we explored the reaction scope of the synthesis for
cyclohexane[c]-fused pyridine first. Various N-acetyl hydra-
zones of acylcycloalkenes 1a−1i were subjected to the reaction
with 2a under the standard condition (Scheme 2). We found
that the steric effects played an important role in this
transformation. The substrates bearing position 5 and position
4 methyl groups on the cyclohexenyl ring proceeded well,
converting to the corresponding products smoothly (3ba and
3ca, respectively), while the position 6 methyl-substituted
substrate failed to afford desired product 3da. Other substrates
bearing an alkyl group (Et, t-Bu, n-propylcyclohexyl, and gem-
dimethyl) or a phenyl group at position 4 reacted smoothly,
and the desired products were delivered in moderate to good
yields (3ea−3ia).
Meanwhile, we investigated the substrate scope of vinyl
azides 2 in the reaction with the N-acetyl hydrazone of
acylcyclohexene 1a (Scheme 3). Diverse aryl vinyl azides
containing an electron-donating (Me, OMe, or Ph) or an
electron-withdrawing (F, Br, Cl, CF3, or NO2) group on the
benzene ring reacted smoothly and gave the target products in
moderate to good yields (3ab−3ak). The structure of 3af was
confirmed by single-crystal X-ray analysis (CCDC: 2005772).
Presumably, due to the steric hindrance, ortho-methyl-
substituted substrate 3ad worked less efficiently than the
meta- and para-substituted analogues (3ab and 3ac,
respectively). Additionally, 1-naphthyl vinyl azide could be
converted to the corresponding product in 65% yield. In
contrast with aryl azides described above, the alkyl and esteryl
vinyl azide could also be transformed in this reaction, giving
3am and 3an, respectively, in low yields, which might be due
to the instability of the azide starting material.
cyclization of cycloalkenes to build a fused pyridine ring on the
cycloalkene structure. In view of synthetic chemistry, the latter
route is considered more challenging.12 Nevertheless, few
methods have been reported for the synthesis of cycloalkeno-
[c]-fused pyridines from α,β-unsaturated oximes and alkynes
(Scheme 1C)13a−e or electron-withdrawing group (EWG)-
substituted alkenes (Scheme 1D)13f,g by Rh-catalyzed C−H
bond activation. Among these reactions, only the C−H bond
of small (five- six-membered) cycloalkanes has been activated,
and a few targeted pyridines were obtained, usually
accompanied by low regioselectivities. As vinyl azides can be
easily obtained14 and have special chemical reactivity,15 vinyl
azides have become an important synthon for the synthesis of
various N-heterocyclic skeletons.16 On the basis of our
previous work on Pd-catalyzed C−H bond activation
reaction,17 we envisioned using a palladium catalytic system
and vinyl azides as coupling partners to construct fused
pyridines, especially medium and large cycloalkeno[c]-fused
pyridines, might be a feasible approach. Herein, we report a
novel approach for accessing cycloalkeno[c]-fused pyridines
with a broad scope via Pd(II)-catalyzed C(sp2)−H activation
and cyclization of N-acetyl hydrazones of acylcycloalkenes with
vinyl azides (Scheme 1E).
According to our previous work,17a the NNHAc was found
to be the most suitable functional group for the directed C−H
activation process. For example, the substrate with cheaper 
NNHTs was partly decomposed to the corresponding ketone.
Therefore, N-acetyl hydrazones acylcyclohexene 1a and vinyl
B
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Encouraged by these results, we further investigated the
possibility of synthesizing other cycloalkeno[c]-fused pyridines
bearing different sized alkane rings: from small (five-
membered) to medium (8−11-membered) to large (12-, 13-,
and 15-membered) (Scheme 4). N-Acetyl hydrazones of
acylcycloalkenes (6−13) containing different kinds of rings
were subjected to this reaction with several diverse vinyl azides
to afford the corresponding products in different yields. The N-
acetyl hydrazones of acylcycloalkenes bearing a medium-sized
(8−10-membered) ring could proceed smoothly and gen-
erated the target products in moderate to good yields (15−
17). Cyclopenta[c]-pyridine 14 and cycloundeca[c]-pyridine
18 were formed in trace yields, perhaps because of the strained
nature of the cyclopalladated intermediate or because
cyclization/elimination to form the pyridine product is
unfavorable. It is noteworthy that the reaction efficiency
dramatically declined, along with the larger cycloalkene
substrates that were used. The N-acetyl hydrazones of
acylcycloalkene substrates bearing large (12-, 13-, and 15-
membered) rings were also compatible in this transformation,
yielding the fused pyridine products 19−21, respectively.
Above all, most of these medium-sized and large ring fused
products 15−21 were all contained in novel fused pyridine
skeletons, which have never before been reported.
Scheme 3. Substrate Scope of Vinyl Azides for the Synthesis
of Cyclohexeno[c]-Fused Pyridines
a,b
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd-PEPPSI-IPr
(15 mol %), NaOAc (1.0 equiv), and Cu2O (2.0 equiv) in toluene (4
mL) stirred at 110 °C for 16 h under an air atmosphere, unless
b
otherwise noted. Isolated yield.
More importantly, this protocol could be applied in natural
product transformation and the formation of new fused
pyridine scaffolds (Scheme 5). Muscone 22 was converted to
Moreover, we explored the feasibility of the synthesis of
seven-membered fused pyridines in the reaction of the N-acetyl
hydrazone of acylcycloheptene 4 with vinyl azides 2 (Scheme
4). Gratifyingly, a series of cyclohepteno[c]-fused pyridines
a,b
Scheme 5. Synthetic Applications
Scheme 4. Synthesis of Other Cycloalkeno[c]-Fused
a,b
Pyridines
a
Reaction conditions: 23 or 26 (0.2 mmol), 2a (0.3 mmol), Pd-
PEPPSI-IPr (15 mol %), NaOAc (1.0 equiv), and Cu2O (2.0 equiv)
in toluene (4 mL) stirred at 110 °C for 16 h under an air atmosphere,
b
unless otherwise noted. Isolated yield.
the corresponding N-acetyl hydrazone of acylcycloalkene 23,
which was reacted with 2a to provide a novel macrocycle fused
pyridine 24 in 21% yield. Interestingly, a new benzopolycyclic
fused pyridine skeleton 27 could be achieved in 68% yield with
3-benzosuberone as the starting material. Furthermore, we
used acyclic olefin substrate 28 to react with vinyl azide 2a
under the standard condition. To our delight, the correspond-
ing pyridine 29 was obtained in 30% yield (Scheme 5, eq 3).
This indicates that this transformation might have a broad
application in the synthesis of substituted pyridines.
a
Reaction conditions: 4 and 6−13 (0.2 mmol), 2 (0.3 mmol), Pd-
PEPPSI-IPr (15 mol %), NaOAc (1.0 equiv), and Cu2O (2.0 equiv)
in toluene (4 mL) stirred at 110 °C for 16 h under an air atmosphere,
b
c
unless otherwise noted. Isolated yield. Run for 24 h.
To explore the mechanism, some control experiments were
conducted (Scheme 6). The reaction of hydrazone 1a with
aryl-2H-azirine 30 delivered desired product 3aa in 64% yield
(Scheme 6, eq 1), suggesting that 2H-azirine might be a key
reaction intermediate in this transformation. When 1a was
replaced with 15N-labeled hydrazone 1a-15N, only non-15N-
labeled product was generated (Scheme 6, eq 2). This reveals
(5a−5i) were afforded in 25−81% yields. Various aryl vinyl
azides with different substituents, including Me, OMe, halide
(F, Br, or Cl), and CF3 groups, were tolerated, smoothly
converting to the desired products in good to excellent yields.
Importantly, the acylated vinyl azide was also compatible in
this reaction and delivered target product 5i in low yield.
C
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HOAc, respectively. Iminyl copper species III was produced
under the H+ condition. The transmetalation between
intermediate II and III led to iminyl palladium species IV.
Furthermore, the tautomerization from species IV to V
occurred, and then to Pd(II) complex VI. Further reductive
elimination of VI to provide VII, which was detected by HR-
MS, was accompanied by the generation of Pd(0) species.
Finally, intramolecular condensation and elimination of
NH2NHAc occurred to generate compound 3. At the same
time, Pd(II) and Cu(I) catalysts were regenerated via redox
reaction of Pd(0) with Cu(II) species, respectively.
Scheme 6. Mechanistic Investigation
In conclusion, we have developed a novel Pd-catalyzed C−H
activation/cyclization cascade strategy for accessing
cycloalkeno[c]-fused pyridines. In contrast with aromatic C−
H bonds, it is more challenging to activate non-aromatic
vinylic C−H bonds.20 Even the open chain alkene is also
compatible with the transformation. Meanwhile, a number of
new medium-sized and large ring-fused pyridines containing
unique scaffolds have been obtained in a one-step reaction.
Furthermore, this reaction was applied for the functionalization
of muscone and 3-benzosuberone to construct more complex
skeletons. Because of the importance of pyridines, this protocol
might provide a valuable application for new drug discoveries.
that the nitrogen source of the pyridine product originated
from vinyl azide 2a. In addition, another directing group such
as oxime has been exploited in this reaction. Interestingly, the
corresponding product was obtained in lower yield (Scheme 6,
eq 3). The result indicated that this protocol might have a
reaction mechanism similar to that of oxime.19b The reaction
did not proceed without a Pd catalyst (Scheme 6, eq 4), which
implied that the C−H activation might be the key step in this
reaction.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02466.
On the basis of previous works17a,19 and the results
presented above, we proposed the reaction mechanism in
Scheme 7. First, the pyrolysis of vinyl azide 2a along with the
Experimental procedure and characterization data for all
of the products (PDF)
Scheme 7. Proposed Reaction Mechanism
Accession Codes
CCDC 2005772 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Huanfeng Jiang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China; State Key Laboratory of Applied
Organic Chemistry, Lanzhou University, Lanzhou 730000,
China; orcid.org/0000-0002-4355-0294; Email: jianghf@
scut.edu.cn
Yingjun Zhang − State Key Laboratory of Anti-Infective Drug
Development (No. 2015DQ780357), Sunshine Lake Pharma
Company, Ltd., Dongguan 523871, China;
Email: zhangyingjun@hec.cn
release of N2 gave the key intermediates 2H-azirines 30
[detected by HR-MS (see the Supporting Information for
details)]. Then, active Cu(II) aza-enolate species I was formed
via Cu(I)-mediated single-electron transfer (SET) with 2H-
azirines 30, which indicated that the Cu(I) acted as a promotor
for the whole reaction process. Meanwhile, the Pd(II) species
that was produced by the precatalyst Pd-PEPPSI-IPr activated
the vinylic C(sp2)−H bond with the assistance of a hydrazone
directing group, affording palladacycle intermediate II and
Authors
Biao Nie − Key Laboratory of Functional Molecular Engineering
of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou
510640, China
Wanqing Wu − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
D
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(9) Jin, Y.; Makida, Y.; Uchida, T.; Kuwano, R. J. Org. Chem. 2018,
83, 3829.
(10) For recent reviews, see: (a) Reen, G. K.; Kumar, A.; Sharma, P.
Beilstein J. Org. Chem. 2019, 15, 1612. (b) Nakao, Y. Synthesis 2011,
2011, 3209. (c) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev.
2015, 115, 1622.
(11) (a) Bartels, F.; Weber, M.; Christmann, M. Org. Lett. 2020, 22,
552. (b) Zhang, W.-B.; Yang, X.-T.; Ma, J.-B.; Su, Z.-M.; Shi, S.-L. J.
Am. Chem. Soc. 2019, 141, 5628.
(12) For reviews, see: (a) Xue, X.-S.; Ji, P.; Zhou, B.; Cheng, J.-P.
Chem. Rev. 2017, 117, 8622. (b) Murakami, K.; Yamada, S.; Kaneda,
T.; Itami, K. Chem. Rev. 2017, 117, 9302. (c) Stephens, D. E.;
Larionov, O. V. Tetrahedron 2015, 71, 8683.
(13) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325. (b) Parthasarathy, K.; Cheng, C.-H. Synthesis 2009,
2009, 1400. (c) Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.; Chiba, S.
Synlett 2011, 2011, 2789. (d) Hyster, T. K.; Rovis, T. Chem. Commun.
2011, 47, 11846. (e) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J.
Org. Chem. 2012, 77, 2501. (f) Neely, J. M.; Rovis, T. J. Am. Chem.
Soc. 2013, 135, 66. (g) Zhao, D.; Lied, F.; Glorius, F. Chem. Sci. 2014,
5, 2869.
Guangzhou 510640, China; orcid.org/0000-0001-5151-
7788
Qingyun Ren − State Key Laboratory of Anti-Infective Drug
Development (No. 2015DQ780357), Sunshine Lake Pharma
Company, Ltd., Dongguan 523871, China; orcid.org/0000-
0003-0000-0417
Zhongqing Wang − State Key Laboratory of Anti-Infective Drug
Development (No. 2015DQ780357), Sunshine Lake Pharma
Company, Ltd., Dongguan 523871, China; orcid.org/0000-
0001-5194-4157
Ji Zhang − State Key Laboratory of Anti-Infective Drug
Development (No. 2015DQ780357), Sunshine Lake Pharma
Company, Ltd., Dongguan 523871, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02466
Notes
The authors declare no competing financial interest.
(14) (a) Cao, S.; Ji, Q.; Li, H.; Pang, M.; Yuan, H.; Zhang, J.; Bi, X. J.
Am. Chem. Soc. 2020, 142, 7083. (b) Li, X.; Liao, S.; Wang, Z.; Zhang,
ACKNOWLEDGMENTS
■
́
L. Org. Lett. 2017, 19, 3687. (c) L’abbe, G.; Hassner, A. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 98.
The authors gratefully acknowledge the Key-Area Research
and Development Program of Guangdong Province
(2020B010188001) and the grant from State Key Laboratory
of Anti-Infective Drug Development (SKLAID202002) for
financial support.
(15) For a review, see: Fu, J.; Zanoni, G.; Anderson, E. A.; Bi, X.
Chem. Soc. Rev. 2017, 46, 7208.
(16) For reviews, see: (a) Hu, B.; DiMagno, S. G. Org. Biomol. Chem.
2015, 13, 3844. (b) Hayashi, H.; Kaga, A.; Chiba, S. J. Org. Chem.
2017, 82, 11981.
(17) (a) Nie, B.; Wu, W.; Zeng, W.; Ren, Q.; Zhang, J.; Zhang, Y.;
Jiang, H. Adv. Synth. Catal. 2020, 362, 1362. (b) Li, C.; Li, J.; An, Y.;
Peng, J.; Wu, W.; Jiang, H. J. Org. Chem. 2016, 81, 12189. (c) Fang,
S.; Jiang, G.; Li, M.; Liu, Z.; Jiang, H.; Wu, W. Chem. Commun. 2019,
55, 13769. (d) Xu, Y.; Hu, W.; Tang, X.; Zhao, J.; Wu, W.; Jiang, H.
Chem. Commun. 2015, 51, 6843.
REFERENCES
■
(1) (a) Aoyagi, Y.; Inariyama, T.; Arai, Y.; Tsuchida, S.; Matuda, Y.;
Kobayashi, H.; Ohta, A.; Kurihara, T.; Fujihira, S. Tetrahedron 1994,
50, 13575. (b) De Marino, S.; Iorizzi, M.; Zollo, F.; Debitus, C.;
Menou, J.-L.; Ospina, L. F.; Alcaraz, M. J.; Paya, M. J. Nat. Prod. 2000,
63, 322.
́
(18) (a) Pinto, D. J.; Smallheer, J. M.; Corte, J. R.; Austin, E. J.;
Wang, C.; Fang, T.; Smith, L. M., II; Rossi, K. A.; Rendina, A. R.;
Bozarth, J. M.; Zhang, G.; Wei, A.; Ramamurthy, V.; Sheriff, S.;
Myers, J. E., Jr.; Morin, P. E.; Luettgen, J. M.; Seiffert, D. A.; Quan, M.
L.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2015, 25, 1635.
(b) Gudmundsson, K. S.; Sebahar, P. R.; Richardson, L. D.; Miller,
J. F.; Turner, E. M.; Catalano, J. G.; Spaltenstein, A.; Lawrence, W.;
Thomson, M.; Jenkinson, S. Bioorg. Med. Chem. Lett. 2009, 19, 5048.
(19) (a) Jie, L.; Wang, L.; Xiong, D.; Yang, Z.; Zhao, D.; Cui, X. J.
Org. Chem. 2018, 83, 10974. (b) Zhu, Z.; Tang, X.; Li, X.; Wu, W.;
Deng, G.; Jiang, H. J. Org. Chem. 2016, 81, 1401. (c) Wang, Y.-F.;
Toh, K. K.; Lee, J.-Y.; Chiba, S. Angew. Chem., Int. Ed. 2011, 50, 5927.
(d) Zhang, Z.-W.; Lin, A.; Yang, J. J. Org. Chem. 2014, 79, 7041.
(e) Donthiri, R. R.; Pappula, V.; Reddy, N. N.; Bairagi, D.;
Adimurthy, S. J. Org. Chem. 2014, 79, 11277. (f) Hou, W.; Zhou,
B.; Yang, Y.; Feng, H.; Li, Y. Org. Lett. 2013, 15, 1814. (g) Fu, J.;
Zanoni, G.; Anderson, E. A.; Bi, X. Chem. Soc. Rev. 2017, 46, 7208.
(20) (a) Wang, K.; Hu, F.; Zhang, Y.; Wang, J. Sci. China: Chem.
(2) (a) Martin, R. E.; Aebi, J. D.; Hornsperger, B.; Krebs, H.-J.;
Kuhn, B.; Kuglstatter, A.; Alker, A. M.; Marki, H. P.; Muller, S.;
Burger, D.; Ottaviani, G.; Riboulet, W.; Verry, P.; Tan, X.; Amrein, K.;
Mayweg, A. V. J. Med. Chem. 2015, 58, 8054. (b) Martin, R. E.;
Lehmann, J.; Alzieu, T.; Lenz, M.; Carnero Corrales, M. A.; Aebi, J.
̈
D.; Marki, H. P.; Kuhn, B.; Amrein, K.; Mayweg, A. V.; Britton, R.
Org. Biomol. Chem. 2016, 14, 5922. (c) Carroll, F. I.; Hu, X.; Navarro,
H. A.; Deschamps, J.; Abdrakhmanova, G. R.; Damaj, M. I.; Martin, B.
R. J. Med. Chem. 2006, 49, 3244.
(3) Pander, P.; Bulmer, R.; Martinscroft, R.; Thompson, S.; Lewis, F.
W.; Penfold, T. J.; Dias, F. B.; Kozhevnikov, V. N. Inorg. Chem. 2018,
57, 3825.
(4) Branowska, D. Synthesis 2003, 13, 2096.
(5) (a) Carroll, F. I.; Navarro, H. A.; Mascarella, S. W.; Castro, A.
H.; Luetje, C. W.; Wageman, C. R.; Marks, M. J.; Jackson, A.; Damaj,
M. I. ACS Chem. Neurosci. 2015, 6, 920. (b) Branowska, D.; Wysocki,
W.; Olender, E.; Ławecka, J.; Chaciak, B.; Led-won, P.; Lapkowski,
M.; Karczmarzyk, Z. New J. Chem. 2015, 39, 9672. (c) Chelucci, G.;
Thummel, R. P. Chem. Rev. 2002, 102, 3129.
(6) (a) Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179.
(b) Boger, D. L. Chem. Rev. 1986, 86, 781. (c) Boger, D. L.; Weinreb,
S. N. Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: New York, 1987; Vol. 47. (d) Barlow, M. G.; Sibous, L.;
Suliman, N. N. E.; Tipping, A. E. J. Chem. Soc., Perkin Trans. 1 1996,
519. (e) Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.;
́
2015, 58, 1252. (b) Saiegh, T. J.; Chedotal, H.; Meyer, C.; Cossy, J.
Org. Lett. 2019, 21, 8364.
́
Taylor, R. J. K. Synlett 2007, 2007, 2217. (f) Fernandez Sainz, Y.;
Raw, S. A.; Taylor, R. J. J. Org. Chem. 2005, 70, 10086.
(7) (a) Saa, C.; Varela, J. Chem. Rev. 2003, 103, 3787. (b) Tanaka,
K.; Suzuki, N.; Nishida, G. Eur. J. Org. Chem. 2006, 2006, 3917.
(8) (a) Sang, Y.; Zhao, J.; Jia, X.; Zhai, H. J. Org. Chem. 2008, 73,
3589. (b) van den Hoogenband, A.; den Hartog, J. A. J.; Faber-
Hilhorst, N.; Lange, J. H. M.; Terpstra, J. W. Tetrahedron Lett. 2009,
50, 5040.
E
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