Substituted Dihydropyridine Synthesis by Dearomatization of Pyridines

Article abstract of DOI:10.1002/anie.202104115

Dearomatization is an effective method to transform readily available N-heterocycles into partially saturated motifs. Manipulation of dihydro-derivatives holds great potential and provides access to a variety of semi-saturated N-heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N-substituted 1,4- and 1,2-dihydropyridines by very mild and selective reduction with amine borane for the first time.

Full text of DOI:10.1002/anie.202104115

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How to cite:
International Edition: doi.org/10.1002/anie.202104115
German Edition: doi.org/10.1002/ange.202104115
Synthetic Methods
Hot Paper
Substituted Dihydropyridine Synthesis by Dearomatization of
Pyridines
Arne Heusler+, Julian Fliege+, Tobias Wagener, and Frank Glorius*
Dedicated to Professor Robert H. Morris
Abstract: Dearomatization is an effective method to transform
readily available N-heterocycles into partially saturated motifs.
Manipulation of dihydro-derivatives holds great potential and
provides access to a variety of semi-saturated N-heterocyclic
building blocks. However, current strategies are limited in
scope and the use of sensitive reagents restricts the applicability
in synthetic laboratories. Herein, we report the synthesis of
a broad variety of N-substituted 1,4- and 1,2-dihydropyridines
by very mild and selective reduction with amine borane for the
first time.
D
ihydropyridines (DHPs) are potent motifs in natural
product synthesis, and constitute backbones of a variety of
active ingredients in the pharmaceutical industry.[1] Especially
1,4-DHPs offer a wide range of interesting applications in
synthetic chemistry, medicinal chemistry, and drug discovery
due to their structural similarity to nicotinamide adenine
dinucleotide (NADH, Scheme 1A).[2] The well-known
Hantzsch esters are analogues of NADH modeled on
nature and are nowadays widely used as a hydride source in
numerous electron transfer reactions.[3] The use of 1,4-DHPs
in medical applications was significantly influenced by the
pioneering work of Bossert and Vater in the development of
Nifepidine.[4]
Scheme 1. Regioselective synthesis of versatile N-substituted dihydro-
pyridine-type motifs by dearomatization of pyridines.
Without doubt, there is high demand for this highly
reactive class of substrates.[5] Besides the widespread synthesis
approaches by condensation in the Hantzsch ester synthesis,
access to DHP motifs with a more versatile substitution
pattern is challenging.[6] An alternative synthetic strategy is
the direct formation from the unsaturated precursors by
dearomatization.[7] The common use and ready accessibility of
pyridines makes this method a powerful and flexible tool for
accessing DHPs. However, this approach is complicated by
the necessity of breaking the aromaticity of the substrates, but
at the same time preventing the commonly known full
reduction to the piperidine (Scheme 1B).[8,9] In 1972, Fowler
described a method in which N-substituted 1,2-DHPs were
afforded with low selectivity by reduction of activated
pyridines with sodium borohydride (Scheme 1C).[10] Despite
the selectivity issue and a limited substrate scope due to the
reactive borohydride species, the Fowler Reduction is
a widely used method for accessing N-substituted 1,2-DHPs
in very recent studies that exploited the potential of these
interesting motifs.[11]
[*] M. Sc. A. Heusler,[+] M. Sc. J. Fliege,[+] M. Sc. T. Wagener,
Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Besides the dearomatization using metal-containing
hydrides, hydroborylation is a common strategy for dearoma-
tization of N-heteroarenes. Several metal-catalyzed and
metal-free hydroboration protocols for the dearomatization
of N-heterocycles by established hydridic boron reagents
have been reported.[12] Mainly, all these reactions were carried
out under strict inert conditions and are limited by their
tedious handling. Recently, our group reported a rhodium-
catalyzed transfer hydrogenation of various (hetero-)arenes
utilizing ammonia borane as hydrogen donor resulting in very
mild reducing conditions.[9] Moreover, the group of Berke
reported a concerted double hydrogen transfer of ammonia
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202104115.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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borane for the reduction of imines and olefins, demonstrating
the catalyst-free reducing potential of amine borane
adducts.[13]
entries 2 and 3). Investigating the influence of the temper-
ature revealed that addition of amine borane to the reaction
mixture at À208C led to the highest regioselectivity (Table S8,
entry 10). With the optimized reaction conditions in hand, we
conducted a reaction-condition-based sensitivity screen and
investigated the scope of the presented method (Table 1, see
the Supporting Information for more details).[14] Due to the
inherent instability and tendency to decompose under re-
aromatization to the starting material, the isolation of the
DHPs is challenging. Therefore, purification was carried out
by flash column chromatography over de-activated neutral
alumina (see the Supporting Information for further details).
A broad range of 3-substituted pyridines could be converted
to the corresponding 1,4-DHP-type products in high yields
and very good selectivities (1–14). The tolerance of carbonyl
groups was shown by the synthesis of DHPs 3 and 4. When
scaled up to 20 mmol, DHP 4 was obtained in 87% isolated
yield, proving the notable practicality of this protocol.
Fluorine, chlorine, bromine, and iodine substituents were
competent in the reaction (7–10) and the trifluoromethyl
We envisioned that amine boranes would be suitable mild
reducing agents to give access to DHPs when reacted with
pyridines (Scheme 1C). Since pyridine and amine borane
were unreactive, we investigated in situ activated pyridines.
Pleasingly, we found that sufficient activation of the model
substrate methyl nicotinate for the subsequent reduction step
can be achieved by phenyl chloroformate in acetonitrile
within 10 minutes (Table S8, entry 9). While reasonable
selectivity was achieved for the model substrate, the regioiso-
meric ratios dropped significantly when the method was
expanded to most other substrates. Thus, we investigated the
role of the activating reagent further. To our delight, we found
that triflic anhydride enables very high regioselectivity for the
reduction (Table S8, entry 1). In contrast, other common
anhydrides gave only traces or even no conversion to the
desired product (Table S8, entries 6–8). Omission of amine
borane or triflic anhydride prevented reaction (Table S8,
Table 1: Substrate scope for the pyridine dearomatization by amine borane and reaction-condition-based sensitivity screen.[a]
[a] Standard reaction conditions: N-heterocycle (0.5 mmol), triflic anhydride (1.2 equiv) or phenyl chloroformate (1.2 equiv) and trimethylamine
borane (1.2 equiv) in MeCN (0.5 m) at À208C warming up to room temperature. Isomeric ratios were determined by GC–FID analysis. Isolated yields
reported. See Supporting Information for more details.
2
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group (5) could also be tolerated. Sensitive nitrile (6) and
boronic ester (11) groups were compatible and not reduced.
When 2-methylpyridine was used, the product was obtained
with very good selectivity but only in low yield (13). Other
activation methods, including preformed pyridinium species,
were unsuccessful. Furthermore, 4-trifluoromethyl pyridine
could be converted to the DHP with excellent selectivity (14).
Interestingly, it was found that substituents in the 4-position
completely inverted the selectivity to exclusively yield the 1,2-
DHP. Multi-substituted pyridines could also be converted to
DHPs. In the case of 3,5-disubstitution, 1,4-DHPs (15–19) and
in the case of 3,4-disubstitution, the corresponding 1,2-DHPs
(20–23) were obtained. Owing to the better stability of the
higher substituted DHPs, the tolerance of aryl (18, 23),
aldehyde (19), sulfide (22) and silyl (20) groups could be
demonstrated in great yields and very high selectivities. The
reaction could also be applied to other N-heterocycles,
resulting in dihydroquinolines (24–29) and dihydroisoquino-
lines (30–34), among others. The tolerance of functional
groups is consistent with those discussed for the pyridine
dearomatization. Further, nitrile (28, 32) and nitro groups
(33) were compatible and not reduced. Unlike for pyridines,
variation of the substitution pattern did not result in inverted
selectivity (29). When quinazoline and pyrimidine were used,
the corresponding tetrahydro-derivatives 35 and 36 were
obtained in excellent yields. In contrast, only the dihydro-
derivative 37 was obtained, when the conditions were applied
to phthalazine. In almost all cases, the major regioisomer
could be separated in the purification process, providing
access to the pure major DHP. To explain the observed
selectivity, we propose a two-step mechanism for the reaction
of pyridine, triflic anhydride and amine borane: In the first
step, triflic anhydride reacts with the pyridine and forms an
activated pyridinium species. In the second step, a hydride
from the amine borane adds to the most accessible electro-
philic carbon, which reduces the pyridine. The attack takes
place in the 4-position but is shifted to the 2-position, in case
this position is blocked by a substituent. The regioselectivity
of the dearomatization was confirmed by X-ray diffraction
analysis of product S1, when phenyl chloroformate was used
as an activating reagent. Furthermore, the regioisomeric
outcome of the dearomatization was confirmed by NMR
analysis.[15,16]
Scheme 2. Regioselective functionalization of dihydro- and tetrahydro-
type N-heterocycles. Isolated yields reported. R=COOCH3, R’=Tf,
R’’=COOPh. Transfer hydrogenation (A) was carried out in situ after
the dearomatization. For hydrofluorination (B) and difluorination (C)
the isolated dihydro- or tetrahydro-N-heterocycle was used. In the
stepwise saturation of pyridine (D), deuterated reagents were used in
the last step of each sequence.
sought-after fluorinated compounds 44–51 and, as it were,
illustrate the high relevance of partially saturated N-hetero-
cycles. To further show the potential of the developed
method, a stepwise saturation of pyridine methyl nicotinate
was carried out. The last step of each saturation sequence was
performed as a deuterium labeling experiment to illustrate
the regioselectivity of the respective process (Scheme 2D).
Following the methods presented earlier, the corresponding
DHP-d 12 and THP-d2 52 were obtained by applying
deuterated amine borane. The remaining THP was success-
fully deuterated with [Rh(COD)Cl]2 in deuterated methanol
to give the corresponding piperidine-d2 53.
In conclusion, we have developed a straightforward
method to access a variety of synthetically highly useful 1,4-
dihydropyridine- and 1,2-dihydropyridine-type motifs from
readily available pyridines through direct dearomatization by
amine borane. The setup is simple and can be carried out
without the use of anhydrous solvent, oxygen exclusion or
special equipment. The valuable building blocks were
obtained in high yield and with high regioselectivity, and
their synthetic utility was highlighted by exemplary stepwise
hydrogenation and (hydro-)fluorination with complete con-
trol of regioselectivity. We envision that this protocol will
greatly simplify access to dihydropyridines and further
advance their use in a variety of applications.
To demonstrate the synthetic utility of our method, we
sought to showcase exemplary follow-up functionalization of
our in situ obtained DHP-type products.[17] Subsequent
palladium-catalyzed transfer hydrogenation furnished the
corresponding tetrahydropyridines (THP) 40–43 selectively
in high yields (Scheme 2A).[18] The position of the remaining
=
C C-double bond was confirmed by X-ray diffraction anal-
ysis of product 40 (see Supporting Information for
details).[16,19] The synthesis of fluorinated piperidine deriva-
tives has been the focus of various studies due to their
application as diverse building blocks.[20] Herein, we present
a hydrofluorination and difluorination of the synthesized
dihydro- or tetrahydro-N-heterocycles with selectfluor, where
the reaction outcome can be controlled by simply varying the
equivalents of the reagents (Scheme 2B,C). The procedures
presented provide access to stereoisomeric mixtures of
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Wiesenfeldt, Z. Nairoukh, T. Dalton, F. Glorius, Angew. Chem.
Int. Ed. 2019, 58, 10460; Angew. Chem. 2019, 131, 10570.
[9] C. Gelis, A. Heusler, Z. Nairoukh, F. Glorius, Chem. Eur. J. 2020,
26, 14090.
[10] a) R. J. Sundberg, G. Hamilton, C. Trindle, J. Org. Chem. 1986,
51, 3672; b) M. J. Wyle, F. W. Fowler, J. Org. Chem. 1984, 49,
4025; c) F. W. Fowler, J. Org. Chem. 1972, 37, 1321.
Acknowledgements
The authors acknowledge generous financial support from the
European Research Council (ERC Advanced Grant Agree-
ment No. 788558), the Deutsche Forschungsgemeinschaft
(Leibniz Award), and the Alfried Krupp von Bohlen und
Halbach Foundation. The authors also thank Karin Voß for
analytical support and Dr. Maximilian Koy, Daniel Moock,
Linda Quach, and Felix Schꢀfers for many helpful discussions
and Dr. Constantin G. Daniliuc for X-ray crystallographic
analysis. Open access funding enabled and organized by
Projekt DEAL.
[11] a) K. Kubota, Y. Watanabe, K. Hayama, H. Ito, J. Am. Chem.
Soc. 2016, 138, 4338; b) T. J. Donohoe, D. J. Johnson, L. H. Mace,
R. E. Thomas, J. Y. K. Chiu, J. S. Rodrigues, R. G. Compton,
C. E. Banks, P. Tomcik, M. J. Bamford, et al., Org. Biomol.
Chem. 2006, 4, 1071; c) G. Zhao, U. C. Deo, B. Ganem, Org. Lett.
2001, 3, 201.
[12] a) H. Yang, L. Zhang, F.-Y. Zhou, L. Jiao, Chem. Sci. 2020, 11,
742; b) B. Rao, C. C. Chong, R. Kinjo, J. Am. Chem. Soc. 2018,
140, 652; c) S. R. Tamang, A. Singh, D. K. Unruh, M. Findlater,
ACS Catal. 2018, 8, 6186; d) F. Zhang, H. Song, X. Zhuang, C.-H.
Tung, W. Wang, J. Am. Chem. Soc. 2017, 139, 17775; e) E. N.
Keyzer, S. S. Kang, S. Hanf, D. S. Wright, Chem. Commun. 2017,
53, 9434; f) S. Panda, A. Coffin, Q. N. Nguyen, D. J. Tantillo,
J. M. Ready, Angew. Chem. Int. Ed. 2016, 55, 2205; Angew.
Chem. 2016, 128, 2245; g) X. Fan, J. Zheng, Z. H. Li, H. Wang, J.
Am. Chem. Soc. 2015, 137, 4916; h) A. S. Dudnik, V. L. Weidner,
A. Motta, M. Delferro, T. J. Marks, Nat. Chem. 2014, 6, 1100;
i) K. Oshima, T. Ohmura, M. Suginome, J. Am. Chem. Soc. 2012,
134, 3699.
Conflict of interest
The authors declare no conflict of interest.
Keywords: boranes · chemoselectivity · nitrogen heterocycles ·
reduction · synthetic methods
[1] E. Carosati, P. Ioan, M. Micucci, F. Broccatelli, G. Cruciani, B. S.
Zhorov, A. Chiarini, R. Budriesi, Curr. Med. Chem. 2012, 19,
4306.
[2] a) P. Anaikutti, P. Makam, Bioorg. Chem. 2020, 105, 104379;
b) A. P. Mishra, A. Bajpai, A. K. Rai, Mini-Rev. Med. Chem.
2019, 19, 1219; c) V. K. Sharma, S. K. Singh, RSC Adv. 2017, 7,
2682; d) A. Sausin’sh, G. Dubur, Chem. Heterocycl. Compd.
1993, 29, 489.
[13] a) S. Lau, D. Gasperini, R. L. Webster, Angew. Chem. Int. Ed.
2020, https://doi.org/10.1002/anie.202010835 Angew. Chem.
2020, https://doi.org/10.1002/ange.202010835; b) H. C. Brown,
L. T. Murray, Inorg. Chem. 1984, 23, 2746; c) X. Yang, T. Fox, H.
Berke, Chem. Commun. 2011, 47, 2053; d) X. Yang, L. Zhao, T.
Fox, Z.-X. Wang, H. Berke, Angew. Chem. Int. Ed. 2010, 49,
2058; Angew. Chem. 2010, 122, 2102.
[14] L. Pitzer, F. Schꢀfers, F. Glorius, Angew. Chem. Int. Ed. 2019, 58,
8572; Angew. Chem. 2019, 131, 8660.
[3] a) C. Zheng, S.-L. You, Chem. Soc. Rev. 2012, 41, 2498; b) S.-L.
You, Chem. Asian J. 2007, 2, 820.
[15] The structure of dihydropyridine type S1 could be determined by
X-ray crystallography. Dihydropyridines containing triflyl
groups were isolated as liquids and X-ray crystallographic
analysis was not applicable. Instead, the regioselectivity of
dearomatization for the different substitution patterns was
verified by NMR analysis of compounds 6, 14, 17, and 21 as
examples.
[4] F. Bossert, W. Vater, Med. Res. Rev. 1989, 9, 291.
[5] a) E. Silva, P. Varandas, A. Silva, Synthesis 2013, 45, 3053;
b) D. L. Comins, K. Higuchi, D. W. Young, Adv. Heterocycl.
Chem. 2013, 110, 175; c) J. A. Bull, J. J. Mousseau, G. Pelletier,
A. B. Charette, Chem. Rev. 2012, 112, 2642; d) R. Lavilla, J.
Chem. Soc. Perkin Trans. 1 2002, 1141; e) D. M. Stout, A. I.
Meyers, Chem. Rev. 1982, 82, 223.
[6] a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2008, 130, 3645; b) N. M. Evdokimov, I. V. Magedov, A. S.
Kireev, A. Kornienko, Org. Lett. 2006, 8, 899; c) A. Hantzsch,
Ber. Dtsch. Chem. Ges. 1881, 14, 1637.
[7] a) C. J. Huck, D. Sarlah, Chem 2020, 6, 1589; b) W. C. Wertjes,
E. H. Southgate, D. Sarlah, Chem. Soc. Rev. 2018, 47, 7996; c) G.
Bertuzzi, L. Bernardi, M. Fochi, Catalysts 2018, 8, 632; d) S.
Park, S. Chang, Angew. Chem. Int. Ed. 2017, 56, 7720; Angew.
Chem. 2017, 129, 7828; e) S. Wꢁbbolt, M. Oestreich, Angew.
Chem. Int. Ed. 2015, 54, 15876; Angew. Chem. 2015, 127, 16103;
f) A. J. Birch, E. A. Karakhanov, J. Chem. Soc. Chem. Commun.
1975, 480.
[8] a) T. Wagener, L. Lꢁckemeier, C. G. Daniliuc, F. Glorius, Angew.
Chem. Int. Ed. 2021, 60, 6425; Angew. Chem. 2021, 133, 6496;
b) T. Wagener, A. Heusler, Z. Nairoukh, K. Bergander, C. G.
Daniliuc, F. Glorius, ACS Catal. 2020, 10, 12052; c) M. Wollen-
burg, A. Heusler, K. Bergander, F. Glorius, ACS Catal. 2020, 10,
11365; d) Z. Nairoukh, M. Wollenburg, C. Schlepphorst, K.
Bergander, F. Glorius, Nat. Chem. 2019, 11, 264; e) J. Mꢂlek,
Org. React. 1988, 249; f) D. S. Grierson, M. Harris, H. P. Husson,
J. Am. Chem. Soc. 1980, 102, 1064; g) Y. Kikugawa, M.
Kuramoto, I. Saito, S. Yamada, Chem. Pharm. Bull. 1973, 21,
1914; h) F. Liberatore, V. Carelli, M. Cardellini, Tetrahedron
Lett. 1968, 9, 4735; i) S. Wawzonek, M. F. Nelson, P. J. Thelen, J.
Am. Chem. Soc. 1952, 74, 2894. For a review, see j) M. P.
[16] Deposition numbers 2063435 (S1) and 2063436 (40) contain the
supplementary crystallographic data for this paper. These data
are provided free of charge by the joint Cambridge Crystallo-
graphic Data Centre and Fachinformationszentrum Karlsruhe
Access Structures service.
[17] a) S. Dongbang, D. N. Confair, J. A. Ellman, Acc. Chem. Res.
2021, 54, 1766; b) S. Chen, B. Q. Mercado, R. G. Bergman, J. A.
Ellman, J. Org. Chem. 2015, 80, 6660; c) S. Duttwyler, S. Chen, C.
Lu, B. Q. Mercado, R. G. Bergman, J. A. Ellman, Angew. Chem.
Int. Ed. 2014, 53, 3877; Angew. Chem. 2014, 126, 3958; d) S.
Duttwyler, C. Lu, A. L. Rheingold, R. G. Bergman, J. A. Ellman,
J. Am. Chem. Soc. 2012, 134, 4064.
[18] If instead benzyl chloroformate was used as the activating
reagent, complete cleavage of the benzyl carboxylate group was
observed during the transfer hydrogenation process. Since these
free tetrahydropyridines, in contrast to the protected variant,
4
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could not be stored for a long time, all applications were
c) P. Jeschke, ChemBioChem 2004, 5, 570; d) B. E. Smart, J.
performed with protective group for strategic reasons.
[19] In contrast to the rhodium-catalyzed transfer hydrogenation of
(hetero-)arenes by ammonia borane, the fully reduced piper-
idine is only a side-product in the described protocol.
Fluorine Chem. 2001, 109, 3.
Manuscript received: March 23, 2021
[20] a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem.
2014, 57, 5845; b) D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071;
Accepted manuscript online: April 8, 2021
Version of record online: && &&, &&&&
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Communications
Synthetic Methods
A. Heusler, J. Fliege, T. Wagener,
F. Glorius*
&&&& — &&&&
Substituted Dihydropyridine Synthesis by
Dearomatization of Pyridines
Metal-free dearomatization of N-hetero-
arenes is a well-known and powerful
method to yield partially saturated N-
heterocyclic building blocks. Yet, the use
of sensitive reagents restricts the applic-
ability in synthetic laboratories. Herein,
we present a very mild and selective
reduction of N-heteroarenes by amine
borane to synthesize a broad variety of N-
substituted 1,4- and 1,2-dihydropyridines.
6
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Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!