Synthesis of Highly Functionalized Pyridines: A Metal-Free Cascade Process

Article abstract of DOI:10.1021/acs.orglett.1c02234

Herein, we report a new process for the synthesis of highly functionalized pyridines based on a tandem Pummerer-type rearrangement, aza-Prins cyclization, and elimination-induced aromatization. This formal [5+1] cyclization provides pyridines in good yields with easily accessible starting materials. The synthetic potential of our new method is further demonstrated in the modification of the frameworks of BINOL and some natural products.

Full text of DOI:10.1021/acs.orglett.1c02234

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Letter
Synthesis of Highly Functionalized Pyridines: A Metal-Free Cascade
Process
Kai Wei, Yu-Cui Sun, Rui Li, Jing-Feng Zhao, Wen Chen, and Hongbin Zhang*
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ABSTRACT: Herein, we report a new process for the synthesis of
highly functionalized pyridines based on a tandem Pummerer-type
rearrangement, aza-Prins cyclization, and elimination-induced aroma-
tization. This formal [5+1] cyclization provides pyridines in good
yields with easily accessible starting materials. The synthetic potential
of our new method is further demonstrated in the modification of the
frameworks of BINOL and some natural products.
ne of the most important heterocycles in organic
compounds is the family of pyridines. Pyridines are
methods have been documented (Scheme 1).9c,10 Annulation
based on condensation of 1,5-diketones with ammonia
surrogates is straightforward but requires multistep preparation
O
common structural units present in a large number of natural
alkaloids as well as pharmaceuticals (Figure 1).1 In addition to
Scheme 1. [5+1] Cycloadditions for the Synthesis of
Pyridines
Figure 1. Selected pyridine-containing natural products and
pharmaceuticals.
possessing a variety of biological activities, pyridine derivatives
are useful ligands in organic synthesis and scaffolds in material
sciences.2 Due to their ubiquitous aromatic ring and great
utility, the synthesis of highly substituted and functionalized
pyridines remains an important and challenging topic in
organic synthesis.3
In the literature, various synthetic methods have been
documented and can be classified mainly into five categories:
(1) the traditional multicomponent condensations,4 (2)
hetero-[4+2] cycloadditions,5 (3) transition metal-mediated
or organo-mediated cycloadditions,6 (4) 6π-electrocycliza-
tions,7 and (5) pyridine ring C−H functionalizations.8 In
addition to these categories, a few other methods have also
been reported.9
Received: July 3, 2021
Compared to the well-established [3+3], [4+2], and
[2+2+2] cycloadditions for the synthesis of pyridines, [5+1]
approaches have rarely been investigated, and only a few
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of 1,5-diketones and an additional oxidative aromatization step.
Other reported [5+1] cycloadditions require commercially
unavailable starting materials or/and transition metal catalysts
in combination with organohalides.9c,10 Developing versatile
and efficient methods for the construction of functionalized
pyridines would be highly desirable, especially to fuse a
pyridine moiety to a target molecule during a late stage from
readily accessible starting materials. In this paper, we report a
metal-free [5+1] procedure for the synthesis of highly
functionalized pyridines.
Scheme 3. Studies of the [5+1] Cycloadditions
In our previous synthesis of Vinca alkaloids, we have
developed a practical method for accessing 1,3-dioxinone-
derived tert-butanesulfinamides.11 We envisioned that the 1,3-
dioxinone-containing sulfonamides could serve as 4C−1N
building blocks for the synthesis of functionalized pyridines
(Scheme 2). We postulated that the tert-butanesulfinyl group
Scheme 2. Proposed [5+1] Cycloaddition for the Synthesis
of Polysubstituted Pyridines
reactions with amide 10b, obtained from Boc protection of
10a, but failed again to give any pyridine derivatives. These
results suggested that pyridine formation might follow a
different pathway. It was deduced that the tert-butanesulfina-
mide might first experience a Pummerer-type rearrangement13
to yield sulfenimine (14) in the presence of excess Vilsmeier
reagent, and the newly generated sulfenimine would attack the
Vilsmeier reagent followed by aza-Prins cyclization of the 1,3-
dioxinone moiety (Scheme 3). With this in mind, we next
conducted a reaction with 2.0 equiv of Vilsmeier reagent in
DMF. To our delight, sulfenimine 14 was isolated. Under
standard Pummerer-type rearrangement conditions,13 sulfeni-
mine 14 was obtained in 90% yield. Treatment of sulfenimine
with Vilsmeier reagent provided pyridine in 75% yield. It was
clear that sulfenimine 14 was involved as an intermediate in
this cascade process.
To gain further insight into the reaction mechanism, several
control experiments were conducted with sulfenimine 14
(Scheme 4). To exclude the possible oxidation by oxygen in
this process, the reaction system was degassed, and the
reaction was carried out under the protection of argon. There
was no difference observed between reactions conducted in
argon and air. Next, sulfenimine 14 was treated with m-CPBA
(1.1 equiv) in dichloromethane to afford sulfinamide 15 and
sulfonamide 16 [existing as a mixture of imine and enamine
forms (see the Supporting Information)]. Treatment of
sulfonamide 16 with Vilsmeier reagent did not give the
desired pyridine. With substrate 15, pyridine 12a was obtained
in only 5% yield, with chloro-pyridine product 12b being
obtained in 36% isolated yield. In this case, a Pummerer-type
rearrangement occurred and resulted in a Michael acceptor;
the chloride anion thus attacked the conjugated system
would be removed under acidic conditions on the way to
generate Vilsmeier reagent, and the resulting primary amine
(10) would act as a nucleophile to attack the Vilsmeier
reagent, the C1 unit in the desired pyridine ring, to form the
aza-Prins cyclization precursor. After Prins cycloaddition of the
1,3-dioxinone moiety followed by late stage oxidative
dehydrogenation of dihydropyridines (11) as in Hantzsch’s
pyridine synthesis, the desired multifunctional pyridines would
be produced [general structure 12 (Scheme 2)].
We initially investigated the proposed reaction in Scheme 2
with tert-butanesulfinylimine 7a derived from condensation of
commercially available benzaldehyde and tert-butanesulfina-
mide.12 Mannich addition of the dioxinone-derived lithium
dienolate to sulfinyl imine 7a provided sulfinamide 9a in 91%
yield according to our previous conditions.11 Next, we
prepared Vilsmeier reagent by addition of phosphoryl
trichloride (6.0 equiv) to DMF. Introduction of sulfinamide
9a to Vilsmeier reagent in DMF resulted in a new compound
(12a) in 70% yield. To our surprise, the NMR spectra of this
new compound clearly indicated that pyridine was formed
rather than dihydropyridine. This result prompted us to ask
whether an air-induced concomitant autoxidative aromatiza-
tion occurred. To answer the question, we decided to carry out
the reactions step by step (Scheme 3). The sulfinyl group in
compound 9a was removed under acidic conditions to give
10a in 82% yield. Treatment of 10a with Vilsmeier reagent in
DMF unfortunately failed to yield the desired dihydropyridine,
with olefin 13 being formed instead. We also conducted the
B
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functional groups. As indicated in Table 1, optimal reaction
conditions (entry 4) are found after a few screenings. Although
Scheme 4. Reactions to Elaborate the Possible Pathway
a
Table 1. Optimization of Reaction Conditions
entry solvent
reagents (equiv)
POCl3 (4)
POCl3 (5)
yields (%) (12a/12c)
b
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DCM
DCM
DCM
DCM
DCM
50/trace
60/trace
b
b
POCl3 (6)
75/10
c
POCl3 (6) and DMF (10)
POCl3 (12) and DMF (15)
ClCOCOCl (6) and DMF (10)
ClCOCOCl (12) and DMF (15)
POCl3 (6) and DMF (10)
76/7
c
79/8
c
50/trace
c
40/trace
d
71/10
a
b
All reactions were conducted at room temperature for 0.5 h. With
c
1.0 mmol of 9a in DMF (10 mL). With 1.0 mmol of 9a in DCM (20
mL). Gram scale: 3.0 mmol of 9a in DCM (60 mL). Yields represent
d
isolated yields.
this procedure required three reaction steps from commercially
available starting materials, it could be integrated into a
consecutive process without purification of intermediates.
With the optimal conditions (entry 4) in hand, a number of
benzaldehyde derivatives were attempted. We successfully
obtained pyridine products 12d−12p in good yields over three
consecutive steps. Substrates containing other aromatic
heterocycles worked equally well in this process and gave
corresponding pyridines in good yields (the [5+1] step in
yields of 40−90%). Substrates with two aldehyde moieties
could be used to prepare ligand-like bis- and tris-pyridines
[12w and 12x, respectively; 12x was confirmed by X-ray
analysis (see the Supporting Information)]. We noticed that
some substrates led to considerable amounts of 3-formyl-
substituted pyridines [12h′, 12r′, and 12u′ from 4-
fluorobenzaldehyde, thiophene-2-carbaldehyde, and furan-3-
carbaldehyde, respectively (see the Supporting Information for
the proposed pathway)].
We next conducted experiments with alkyl aldehydes. A
number of highly functionalized pyridines (Scheme 5) were
also obtained in three consecutive steps with good yields (the
[5+1] step in yields of 45−91%). Substrates bearing acid
sensitive Boc protecting groups are compatible, leading to
useful scaffolds for further manipulation. 2-Deuterated pyridine
(24h) was also prepared using deuterated DMF. Finally, a few
interesting pyridines were synthesized on the basis of our new
process. (S)-1,1′-Bi-2-naphthol (BINOL)-derived aldehyde
2515 was transformed into pyridine 27 in 40% overall yield
over three steps [Scheme 6; confirmed by X-ray analysis (see
the Supporting Information)]. Attaching our pyridine scaffold
to a natural product was also feasible; in addition to pyridine
24p, steroid-derived pyridine 29 (Scheme 6) was obtained in
74% yield under our optimal conditions.
In conclusion, we have developed a new [5+1] cyclization to
synthesize highly functionalized pyridines from readily
available tert-butanesulfinamide, aldehydes, and 1,3-dioxinones.
This process features a cascade Pummerer-type rearrangement
followed by aza-Prins cyclization and concomitant aromatiza-
tion under mild reaction conditions. The synthesis of highly
(Scheme 4). Therefore, preoxidation before aromatization
could be ruled out in this process.
To elaborate whether the final elimination was a concerted
intramolecular one or assisted by external nucleophiles, the
reaction was then quenched with n-BuLi-pretreated p-
methoxyaniline. We obtained N-p-methoxybenzyl sulfenamide
18 in 52% isolated yield (Scheme 4).14 The reaction mixture
was also analyzed by LC-MS (mobile phases of MeOH and
H2O) before workup. On the basis of mass spectra, we
detected a number of intermediates; however, N,N-dimethyl
sulfenamide 17 was not detected (Scheme 4 and Supporting
Information for details). Those results indicated that the final
elimination might be assisted by external nucleophiles.
Although we are not able to completely exclude the concerted
elimination, external nucleophile-associated elimination is
much more likely.
Having a better understanding of the reaction pathway, we
next investigated the optimal reaction conditions and substrate
scope of this cyclization, aiming to establish a general method
for the synthesis of polysubstituted pyridines bearing tunable
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Scheme 5. Preparation of Substituted Pyridines
Scheme 6. Synthesis of BINOL- and Steroid-Derived
Pyridines
unit in natural products containing aldehyde or other
functional groups that can be transferred to aldehydes.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02234.
Experimental procedures, characterization data, and
spectra of all key intermediates (PDF)
Accession Codes
CCDC 2088618−2088620 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hongbin Zhang − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research and Development of Natural Products,
School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan 650091, P. R. China;
orcid.org/0000-0002-2516-2634; Email: zhanghb@
ynu.edu.cn
Authors
functionalized pyridines for further manipulation remains an
important goal in the synthetic and medicinal chemistry
community. Pyridines prepared by this [5+1] cyclization are
fused with a highly useful dioxinone moiety, enabling further
transformations. This method can also be used to modify
molecules during a late stage, especially to install a pyridine
Kai Wei − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education, Yunnan Provincial Center
for Research and Development of Natural Products, School of
Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
D
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Yu-Cui Sun − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research and Development of Natural Products,
School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan 650091, P. R. China
Rui Li − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education, Yunnan Provincial Center
for Research and Development of Natural Products, School of
Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, P. R. China
Jing-Feng Zhao − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research and Development of Natural Products,
School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan 650091, P. R. China
Wen Chen − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research and Development of Natural Products,
School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan 650091, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02234
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Natural
Science Foundation of China (U1702286, 21572197,
21762047, and 21901224), the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT17R94), Ling-Jun Scholars of Yunnan Province
(202005AB160003), and the Talent Plan of Yunnan Province
(YNWR-QNBJ-2018-025).
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