Synthesis of N-Heterocycles by Dehydrogenative Annulation of N-Allyl Amides with 1,3-Dicarbonyl Compounds

Article abstract of DOI:10.1002/anie.201807683

Dehydrogenative annulation under oxidizing reagent-free conditions is an ideal strategy to construct cyclic structures. Reported herein is an unprecedented synthesis of pyrrolidine and tetrahydropyridine derivatives through electrochemical dehydrogenative annulation of N-allyl amides with 1,3-dicarbonyl compounds. The electrolytic method employs an organic redox catalyst, which obviates the need for oxidizing reagents and transition-metal catalysts. In these reactions, the N-allyl amides serve as a four-atom donor to react with dimethyl malonate to give pyrrolidines by a (4+1) annulation, or with β-ketoesters to afford tetrahydropyridine derivatives by a (4+2) annulation.

Full text of DOI:10.1002/anie.201807683

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Accepted Article
Title: Synthesis of N-Heterocycles via Dehydrogenative Annulation of
N-Allyl Amides with 1,3-Dicarbonyl Compounds
Authors: Zheng-Jian Wu, Shi-Rui Li, and Hai-Chao Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807683
Angew. Chem. 10.1002/ange.201807683
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10.1002/anie.201807683
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of N-Heterocycles via Dehydrogenative Annulation of
N-Allyl Amides with 1,3-Dicarbonyl Compounds
Zheng-Jian Wu, Shi-Rui Li and Hai-Chao Xu*
Dedicated to Professor Kevin D. Moeller on the occasion of his 60th birthday.
Abstract: Dehydrogenative annulation under oxidizing reagent-free
conditions is an ideal strategy to construct cyclic structures. Herein
we report an unprecedented synthesis of pyrrolidine and
the catalytic system based on Cp2Fe requires a mixture of
MeOH/THF as the solvent,[13,14] which is a good H-atom donor
and limits the application to the facile intramolecular reactions.
Given the importance of pyrrolidine and piperidine rings in
pharmaceuticals and other bioactive compounds[15] and the lack
of dehydrogenative annulation strategies for their synthesis,[16,17]
we report herein the synthesis of pyrrolidine and
tetrahydropyridine
derivatives
through
electrochemical
dehydrogenative annulation of N-allyl amides with 1,3-dicarbonyl
compounds. The electrolytic method employs an organic redox
catalyst, which obviates the need for oxidizing reagents and
transition-metal catalysts. In these reactions, the N-allyl amides
serve as a four-atom donor to react with dimethyl malonate to give
pyrrolidines via (4+1) annulation or with -ketoesters to afford
tetrahydropyridine derivatives via (4+2) annulation.
tetrahydropyridine
derivatives
through
unprecedented,
electrochemical dehydrogenative annulation reactions of N-allyl
amides with 1,3-dicarbonyl compounds (Scheme 1c). The
success is attributable to the discovery of a phenothiazine based
redox catalyst[10b] that is operative in aqueous solution. To our
best knowledge, phenothiazines have not been used as redox
catalysts in organic electrosynthesis.
Annulation reactions occupy a prominent position in organic
synthesis as they are among the most straightforward and
efficient methods for constructing cyclic structures,[1] which are
subunits of most bioactive compounds and natural products.[2]
Particularly, dehydrogenative annulation under oxidizing
reagent-free conditions represents an ideal strategy because it
uses less functionalized substrates and in the meantime,
minimize steps and waste production. Despite recent significant
progress in dehydrogenative bond-forming reactions, these
oxidative transformations generally employ undesirable chemical
oxidants,[3] which reduce functional group tolerance and bring
safety issues for large-scale applications.[4] In addition, the
synthesis of sp3 center-rich structures, especially saturated N-
heterocycles, via dehydrogenative annulation reactions remains
rare.[5]
1,3-Dicarbonyl compounds are versatile building blocks for
organic synthesis. The 1,3-dicarbonyl moiety can be oxidized to
produce electrophilic C-radicals that can participate in various
C–C bond-forming reactions.[6] Based on this type of reactivity,
β-ketoesters and 1,3-diketones have been shown to undergo
annualtion reactions with alkenes or N-(arylsulfonyl)acrylamides
to produce dihydrofurans[7] (Scheme 1a) or dihydropyridinones[8]
(Scheme 1b) in the presence of chemical oxidants.[9] Organic
electrochemistry, which employs traceless electrons to achieve
redox reactions,[10] has been increasingly studied for promoting
dehydrogenative cross-coupling reactions.[11,12] In this context,
we have recently developed a Cp2Fe-catalyzed electrochemical
method for the generation of C-radicals from 1,3-dicarbonyl
compounds.[13] This method has enabled the synthesis of
oxindoles via dehydrogenative cyclization reactions.[13] However,
Scheme 1. Synthesis of heterocycles via annulation reactions of 1,3-
dicarbonyl compounds.
We began our study by optimizing the electrolysis conditions
for the annulation reaction of N-allyl amide 1 with dimethyl
malonate 2 (Tables 1 and S1). The optimal reaction system was
found to consist of phenothiazine 3 (20 mol %) as the redox
catalyst and HCO2Na (0.3 equiv) as the base additive, in a
mixed solvent of tBuOMe/MeCN/H2O (20:3:1) under reflux (entry
1). Under these conditions, the pyrrolidine derivative 4 was
isolated in 70% yield. Control experiments revealed that
electricity (entry 2), the catalyst (entry 3) and heating (entry 4)
were critical for the formation of 4. Leaving out HCO2Na led to a
reduction in yield (entry 5). Other redox catalysts, such as
phenothiazine derivatives 5 and 6 (entry 6) and triarylamines 7–
9 (entry 7), were less efficient. The composition of the solvent
was also found to be important, as the absence of H2O (entry 8)
or tBuOMe (entry 9) and the substitution of THF (entry 10) or
Et2O (entry 11) for tBuOMe were detrimental to the formation of
[a]
Z.-J. Wu, S.-R. Li, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory for Chemical Biology of Fujian Province, iChEM and
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Web: http://chem.xmu.edu.cn/groupweb/hcxu/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807683
Angewandte Chemie International Edition
COMMUNICATION
4. Moreover, the reaction showed no apparent sensitivity to
oxygen (entry 12) and could be conducted on a decagram scale
(entry 13).
alkyl or aryl groups with different steric properties, such as nBu
(36), cyclohexyl (Cy, 37), tBu (38) and phenyl (39).
When a -ketoester was employed as the coupling partner
(Scheme 3), the resultant (4+2) annulation furnished
a
Table 1. Optimization of reaction conditions.[a]
tetrahydropyridine product and no pyrrolidine derivative was
detected. As the sole exception, the annulation of methyl
acetoacetate with an enyne afforded a small amount of
pyrrolidine 54 (13%) in addition to the main tetrahydropyridine
product 53 (53%). Note that these (4+2) annulation reactions did
not need HCO2Na and benefited from reduced current density.
Dihydrofurans, which are common products for the oxidative
annulation of alkenes with 1,3-dicarbonyl compounds,[7] were not
detected in any of the above reactions. Like what we observed
in the (4+1) annulation reactions, the phenyl rings on the alkene
and the amide nitrogen atom of the N-allyl amide tolerated a
wide range of substituents with diverse electronic properties
(40–51). The N-allyl amide substrate bearing an N-nPr group,
Entry
Deviation from standard conditions
Yield [%][b]
[a] Reaction conditions: RVC anode (100 PPI, 1 cm x 1 cm x 1.2 cm), Pt
cathode, 1 (0.3 mmol), 2 (0.6 mmol), solvent (6 mL), argon, 7.5 mA (janode  0.1
mA cm−2), 4.4 h (4.1 F per mol of 1). [b] Yield determined by 1H-NMR analysis
using 1,3,5-trimethoxybenzene as the internal standard. Unreacted
parenthesis. [c] Isolated yield.
1 in
We then investigated the substrate scope of the reaction by
varying the substituents of the N-allyl amide. The phenyl ring on
the alkenyl carbon (R1) could be substituted with a wide range of
functional groups with diverse electronic properties at its para-
and meta-positions (10−21). However, attaching an OMe
substituent at the ortho-position of the phenyl group (22) led to a
dramatic reduction in yield. The alkenyl position could also be
substituted with a heteroaryl ring, such as 3-thienyl (23) and 3-
furanyl (24), or an alkenyl moiety (25−27). N-allyl amide with a
methyl group at the R1 position exhibited significantly decreased
reactivity and afforded the corresponding product 28 in a low
yield of 15%. On the other hand, the R2 phenyl ring on the amide
nitrogen atom showed a broad tolerance of functional groups
including Me (29), halogens (F, Cl, Br; 30−32), OCF3 (33), as
well as electron-accepting CO2Me (34). However, replacing the
R2 phenyl group with an alkyl substituent abolished product
formation (35). The acyl R3 could be replaced with a variety of
Scheme 2. Scope of pyrrolidine synthesis. Reaction conditions: Table 1, entry
1, 4.1 F per mol of N-allyl amide. [a] 1 equiv of HCO2Na was employed.
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10.1002/anie.201807683
Angewandte Chemie International Edition
COMMUNICATION
any cross-over products (Scheme 4a), suggesting that the
migration of the acyl group occurred intramolecularly. Replacing
the acyl group with a tert-butoxycarbonyl (Boc) group (58)
resulted in the formation of a cyclic carbamate 62 as the only
identifiable product (Scheme 4b). The annulation of 60 with
dimethyl malonate 2 in the presence of H218O afforded 18O-11,
which was reduced by LiAlH4 to generate 18O-free 61 (Scheme
4c). Combined, these experiments provided evidence that the
acyl carbonyl oxygen of the pyrrolidine product originated from
H2O. The reaction of 1 with 2 in H2O-free tBuOMe/MeOH led to
the generation of an uncyclized amine 62 (53% yield), which
cyclized into 4 in 42% yield under the standard electrolysis
conditions. These results strongly suggested that 62 was an
intermediate for the formation of the pyrrolidine product. The
formation of 62 was not observed under the standard conditions,
suggesting that it is preferentially oxidized over the dimethyl
malonate 2 during the preparative electrolysis.
Scheme 3. Scope of tetrahydropyridine synthesis. Reaction conditions: 1 (0.3
mmol), 2 (0.6 mmol), solvent (6 mL), argon, 2.5 F per mol of N-allyl amide. [a]
Reaction for 16 h. [b] 5 equiv of -ketoester. [c] Reaction for 13.9 h.
Scheme 5. Mechanistic proposal.
A possible mechanism has been proposed based on the
findings of this work (Scheme 5).[18] The reaction begins with the
anodic oxidation of 3 (Ep/2 = 0.52 V vs SCE) into the
corresponding radical cation 3•+. Meanwhile, H2O is reduced at
the cathode to produce H2 and HO−, the latter of which then
deprotonates the 1,3-dicarbonyl compound I [Ep/2 (2) > 2.0 V vs
SCE] to generate the more oxidizable anion II (Ep/2 = 0.31 V vs
SCE, R = OMe). The oxidation of II by 3•+ via single-electron
Scheme 4. Mechanistic studies.
transfer (SET) furnishes
a
C-radical III,[13,19,20] which
subsequently adds to the alkenyl moiety of the N-allyl amide IV
(Ep/2 = 1.74 V vs SCE) to generate a tertiary C-radical V. The
intermediate V is oxidized and trapped intramolecularly by the
carbonyl group of its amide moiety instead of that of the 1,3-
dicarbonyl moiety to afford VI. In the case of amide 58 (R′ =
OtBu), the corresponding cationic intermediate VI would lose a
tBu group to afford a cyclic carbamate 59. For other amides, VI
would react with HO− or H2O and proceed with a selective C–N
bond cleavage[21] to produce a secondary amine VIII, which
which exhibited no reactivity toward malonic ester, underwent
annulation with methyl acetoacetate to generate the
corresponding tetrahydropyridine product 52 in 53% yield. The
-ketoester also tolerated variation to include methyl 3-
oxoheptanoate (54) and ethyl acetoacetate (55) as the coupling
partners.
A series of mechanistic studies were carried out to shine
light on the reaction mechanism. The electrolysis of a mixture of
amides 56 and 57 afforded 14 and 37 without the observation of
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10.1002/anie.201807683
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COMMUNICATION
undergoes C(sp3)–H/N–H cross coupling reaction[22] [62 (R =
OMe)] to generate the pyrrolidine product 4 (Ep/2 = 1.07 V vs
SCE) or intramolecular dehydration (R = Me) to afford the
tetrahydropyridine 40 (Ep/2 = 1.15 V vs SCE).[23] When the
[10] Selected recent reviews on organic electrochemistry: a) J. Yoshida, K.
Kataoka, R. Horcajada, A. Nagaki, Chem. Rev. 2008, 108, 2265–2299;
b) R. Francke, R. D. Little, Chem. Soc. Rev. 2014, 43, 2492–2521; M.
Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117, 13230–13319;
c) J. E. Nutting, M. Rafiee, S. S. Stahl, Chem. Rev. 2018, 118, 4834–
4885; d) E. J. Horn, B. R. Rosen, P. S. Baran, ACS Cent. Sci. 2016, 2,
302–308; e) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, R.
Waldvogel Siegfried, Angew. Chem. Int. Ed. 2018, 57, 5594–5619;
Angew. Chem. 2018, 130, 5694–5721; f) Q. L. Yang, P. Fang, T. S. Mei,
Chin. J. Chem. 2018, 36, 338–352; g) K. D. Moeller, Chem. Rev. 2018,
118, 4817–4833; h) S. R. Waldvogel, S. Lips, M. Selt, B. Riehl, C. J.
Kampf, Chem. Rev. 2018, 118, 6706-6765; i) Y. Jiang, K. Xu, C. Zeng,
Chem. Rev. 2018, 118, 4485–4540; j) N. Sauermann, T. H. Meyer, Y.
Qiu, L. Ackermann, ACS Catal. 2018, 8, 7086-7103.
electrochemical reaction of
1 with 2 was conducted in
tBuOMe/MeOH (cf. Scheme 4d), an intermediate with m/z
436.1728 was observed, which was ascribed to IX [Scheme 5,
theoretical m/z for (IX + Na)+ 436.1731]. These results provide
support for the formation of intermediate VIII during the
electrolysis in aqueous solution. Note that the intermediate
amine 62 decomposed quickly in the presence of stoichiometric
nBu4NOH or DBU. Fortunately, under the electrochemical
conditions, HO− is generated in situ and continuously at the
cathode to aid the oxidation steps, allowing the annulation
reactions to proceed under mildly basic conditions (Scheme 2)
or without an external base (Scheme 3).
[11] S. Tang, Y. Liu, A. Lei, Chem 2018, 4, 27–45.
[12] Selected recent examples on electrochemical dehydrogenative
annulation reactions: a) K. Liu, S. Tang, P. Huang, A. Lei, Nat.
Commun. 2017, 8, 775; b) S. Tang, D. Wang, Y. Liu, L. Zeng, A. Lei,
Nat. Commun. 2018, 9, 798; c) C. Tian, L. Massignan, H. Meyer Tjark,
L. Ackermann, Angew. Chem. Int. Ed. 2018, 57, 2383–2387; Angew.
Chem. 2018, 130, 2407–2411; d) Y. Qiu, C. Tian, L. Massignan, T.
Rogge, L. Ackermann, Angew. Chem. Int. Ed. 2018, 57, 5818–5822;
Angew. Chem. 2018, 130, 5920–5924; g) J. Chen, W. Q. Yan, C. M.
Lam, C. C. Zeng, L. M. Hu, R. D. Little, Org. Lett. 2015, 17, 986–989; h)
J. Li, W. Huang, J. Chen, L. He, X. Cheng, G. Li, Angew. Chem. Int. Ed.
2018, 57, 5695–5698; Angew. Chem. 2018, 130, 5797–5800; i) Z.-W.
Hou, H. Yan, J.-S. Song, H.-C. Xu, Chin. J. Chem. 2018, 36, 909-915; j)
Z. W. Hou, Z. Y. Mao, H. B. Zhao, Y. Y. Melcamu, X. Lu, J. Song, H.-C.
Xu, Angew. Chem. Int. Ed. 2016, 55, 9168–9172; Angew. Chem. 2016,
128, 9314–9318; k) Z.-W. Hou, Z.-Y. Mao, Y. Y. Melcamu, X. Lu, H.-C.
Xu, Angew. Chem. Int. Ed. 2018, 57, 1636-1639; Angew. Chem. 2018,
130,1652–1655.
In summary, we have developed an unprecedented
approach
for
the
synthesis
of
pyrrolidines
and
tetrahydropyridines via dehydrogenative annulation reactions of
easily available materials. The use of a phenothiazine-based
redox catalyst enables efficient and selective intermolecular
radical reactions of 1,3-dicarbonyl compounds. The application
of this organocatalyzed electrochemical system in promoting
other oxidative radical reactions of 1,3-dicarbonyl compounds
are under investigation in our laboratory.
Acknowledgements
[13] a) Z.-J. Wu, S.-R. Li, H. Long, H.-C. Xu, Chem. Commun. 2018, 54,
4601–4604; b) Z.-J. Wu, H.-C. Xu, Angew. Chem. Int. Ed. 2017, 56,
4734–4738; Angew. Chem. 2017, 129, 4812–4816.
Financial
support
of
this
research
from
MOST
(2016YFA0204100), NSFC (21672178) and Fundamental
Research Funds for the Central Universities.
[14] L. Zhu, P. Xiong, Z. Y. Mao, Y. H. Wang, X. Yan, X. Lu, H.-C. Xu,
Angew. Chem. Int. Ed. 2016, 55, 2226–2229; Angew. Chem. 2016, 128,
2266–2269.
Keywords: electrochemistry • heterocycles • redox chemistry •
radicals • annulation
[15] R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014, 57,
5845–5859.
[16] a) T. M. Bott, J. A. Vanecko, F. G. West, J. Org. Chem. 2009, 74,
2832–2836; b) L. Q. Lu, J. J. Zhang, F. Li, Y. Cheng, J. An, J. R. Chen,
W. J. Xiao, Angew. Chem. Int. Ed. 2010, 49, 4495–4498; Angew. Chem.
2010, 122, 4597–4600; c) V. Sriramurthy, G. A. Barcan, O. Kwon, J.
Am. Chem. Soc. 2007, 129, 12928–12929.
[1]
[2]
G. A. Molander, Acc. Chem. Res. 1998, 31, 603–609.
a) P. Ertl, S. Jelfs, J. Mühlbacher, A. Schuffenhauer, P. Selzer, J. Med.
Chem. 2006, 49, 4568–4573; b) R. D. Taylor, M. MacCoss, A. D. G.
Lawson, J. Med. Chem. 2014, 57, 5845–5859.
[17] a) R. C. Clark, S. S. Pfeiffer, D. L. Boger, J. Am. Chem. Soc. 2006, 128,
2587–2593; b) X.-F. Zhu, J. Lan, O. Kwon, J. Am. Chem. Soc. 2003,
125, 4716–4717; c) B. Han, J. L. Li, C. Ma, S. J. Zhang, Y. C. Chen,
Angew. Chem. Int. Ed. 2008, 47, 9971–9974; Angew. Chem. 2008, 120,
10119–10122; d) J.-F. Zheng, Z.-X. Xie, X. Chen, P.-Q. Huang, Acta
Chim. Sinica 2015, 73, 705–715.
[3]
a) S. A. Girard, T. Knauber, C. J. Li, Angew. Chem. Int. Ed. 2014, 53,
74–100; Angew. Chem. 2014, 126, 76–103; b) M. Gulías, J. L.
Mascareñas, Angew. Chem. Int. Ed. 2016, 55, 11000–11019; Angew.
Chem. 2016, 128, 11164–11184.
[4]
[5]
For the problems associated with the use of oxidants in pharmaceutical
synthesis, see: S. Caron, R. W. Dugger, S. G. Ruggeri, J. A. Ragan, D.
H. B. Ripin, Chem. Rev. 2006, 106, 2943–2989.
[18] See the Supporting Information for more discussion.
[19] Despite the low oxidation potential of II, its direct oxidation on the
electrode did not occur because this species is generated at low
concentration in situ and there is no sufficient amount in the reaction
mixture to sustain the current.
a) J. Li, Y. Ye, Y. Zhang, Org. Chem. Front. 2018, 5, 864–892; b) J.-R.
Chen, X.-Q. Hu, L.-Q. Lu, W.-J. Xiao, Chem. Rev. 2015, 115, 5301–
5365; c) A. Minatti, K. Muniz, Chem. Soc. Rev. 2007, 36, 1142–1152.
B. B. Snider, Chem. Rev. 1996, 96, 339–363.
[6]
[7]
[20] U. Jahn, M. Muller, S. Aussieker, J. Am. Chem. Soc. 2000, 122, 5212–
5213.
a) S. Tang, K. Liu, Y. Long, X. L. Gao, M. Gao, A. W. Lei, Org. Lett.
2015, 17, 2404–2407; b) E.-A. I. Heiba, R. M. Dessau, J. Org. Chem.
1974, 39, 3456–3457; c) G. Savitha, S. K. Niveditha, D. Muralidharan,
P. T. Perumal, Tetrahedron Lett. 2007, 48, 2943–2947.
[21] The origin of this unusual selectivity remains unclear.
[22] This dehydrogenative C–N bond forming strategy is also applicable to
six-membered ring formation (Scheme S1).
[8]
[9]
N. Fuentes, W. Kong, L. Fernandez-Sanchez, E. Merino, C. Nevado, J.
Am. Chem. Soc. 2015, 137, 964–973.
[23] The oxidation potentials of the heterocyclic products and the amine
intermediate VIII are expected to vary with different N-aryl groups.
a) J. Yoshida, K. Sakaguchi, S. Isoe, J. Org. Chem. 1988, 53, 2525–
2533; b) J. Yoshida, K. Sakaguchi, S. Isoe, Tetrahedron Lett. 1986, 27,
6075–6078.
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10.1002/anie.201807683
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Unprecedented dehydrogenative
annulation reactions of N-allyl amides
with 1,3-dicarbonyl compounds have
been developed for the efficient and
modular synthesis of pyrrolidine and
tetrahydropyridine derivatives. These
electricity-powered reactions employ a
phenothiazine based organic redox
catalyst, allowing the reactions to
proceed under transition metal- and
oxidizing reagent-free conditions.
Zheng-Jian Wu, Shi-Rui Li and Hai-
Chao Xu*
Page No. – Page No.
Synthesis of N-Heterocycles via
Dehydrogenative Annulation of N-
Allyl Amides with 1,3-Dicarbonyl
Compounds
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