Lewis Acid-Promoted Ring-Contraction of 2,4,6,8-Tetrasubstituted 1,5-Diazacyclooctatetraenes to 2,4,6-Trisubstituted Pyridines

Article abstract of DOI:10.1021/acs.orglett.7b03917

Ring-contraction of 2,4,6,8-tetrasubstituted 1,5-diazacyclooctatetraenes was highly efficiently promoted by Lewis acid such as TiCl₄, affording 2,4,6-trisubstituted pyridines in excellent yields, along with release of a nitrile. A reaction mechanism involving a 6π electrocyclic ring-closing followed by a retro [2 + 2] cyclization of an 1-azetine moiety was supported by both experimental observations and density functional theory calculation.

Full text of DOI:10.1021/acs.orglett.7b03917

Letter
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Lewis Acid-Promoted Ring-Contraction of 2,4,6,8-Tetrasubstituted
1,5-Diazacyclooctatetraenes to 2,4,6-Trisubstituted Pyridines
Zhe Huang,† Wen-Xiong Zhang,† and Zhenfeng Xi*,†,‡
†Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Ring-contraction of 2,4,6,8-tetrasubstituted 1,5-
diazacyclooctatetraenes was highly efficiently promoted by
Lewis acid such as TiCl4, affording 2,4,6-trisubstituted
pyridines in excellent yields, along with release of a nitrile. A
reaction mechanism involving a 6π electrocyclic ring-closing
followed by a retro [2 + 2] cyclization of an 1-azetine moiety
was supported by both experimental observations and density
functional theory calculation.
2,4,6,8-tetrasubstituted 1,5-diazacyclooctatetraenes (NCOTs)
to 2,4,6-trisubstituted pyridines with excellent yields under mild
condition by treatment with TiCl4 (Scheme 1c). In this process,
an intramolecular 6π electrocyclic ring-closing of NCOT was
followed by Lewis acid mediated retro [2 + 2] cyclization.
NCOT is interesting analogues of COT, but its reactivity
remains almost entirely unknown except the reduction with
alkali metals.4 We have developed a one-pot synthetic route to
NCOTs from 1,4-dilithio-1,3-dienes and nitriles.5 It is supposed
that the introduction of N atoms into the conjugated system
may bring about new reactivity as Schiff base, so we carried out
reactions of NCOTs with Lewis acids.
As shown in Scheme 2, TiCl4 (1 M in toluene) was added to
the solution of the NCOT 1a at −78 °C, and insoluble oil
appeared as the mixture was allowed to warm up to room
temperature. Then, the reaction mixture was heated at 60 °C
and monitored by GC−MS. The NCOT 1a was completely
converted into the product (m/z = 287) after 5 h. The product
was isolated in 95% yield and characterized as 2,4,6-
trisubstituted pyridine 2a. This transformation could also be
mediated by some other Lewis acids (Scheme 2). Pyridine
derivatives 2b,c could be obtained in excellent isolated yields
from the reaction of their corresponding NCOTs with TiCl4.
NCOT 1d with two different alkyl groups could also undergo
this transformation to generate 2d in 79% yield, along with 2e
as a minor product, which was observed by GC−MS and NMR.
It should be noted that, the lack of more examples is mainly due
to the limitation in the preparation of starting materials
NCOTs. Aryl nitriles such as benzonitrile tend to trimerize to
form triazine derivatives in the presence of dilithio reagents.
Nitriles with other tertiary alkyl groups such as −Cn-Pr3 and −
CMe(Et)2 afforded a mixture of products. It is worthy to note
ing-contraction reactions are synthetically useful methods
Rin organic synthesis for making smaller rings from larger
rings.1 While a number of anion,2a cation,2b and carbenoid2c
ring-contractions have been well documented and applied, ring-
contractions via intramolecular pericyclic protocol are less
explored and often not useful for synthesis.3 For example,
cyclooctatetraene (COT) could undergo ring-contraction to
benzene under photoirradiation condition3a or thermal
condition,3d but isomerization of COT to styrene took place
at the same time and resulted in mixed products (Scheme 1a).
The ring-contraction of 2-methoxy-azacyclooctatetraene in the
presence of base generated benzonitrile in a moderate yield
(Scheme 1b).3b Herein, we report a useful ring-contraction of
Scheme 1. Ring-Contractions of Cyclooctatetraene and
Azacyclooctatetraene Derivatives
Received: December 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03917
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. Reactions of NCOTs with Lewis Acids
Figure 1. ORTEP drawing of 3 with 30% thermal ellipsoids. Hydrogen
atoms, except for H(1), are omitted for clarity.
that pyridine derivatives with bulky substituents (e.g., t-Bu
group) adjacent to the N atom could be used as the base
component of an FLP,6 but efficient synthetic methods are
limited.7
It was assumed that the coordination of the N atom of
NCOTs to TiCl4 might be a key step in this transformation, so
we tried to isolate the intermediate (Scheme 3). After adding
Figure 2. ORTEP drawing of 4 with 30% thermal ellipsoids. Hydrogen
atoms, except for H(1), are omitted for clarity.
Scheme 4. In Situ NMR Experiments
Scheme 3. Formation of the Pyridinium Salts
the solution of TiCl4 at −78 °C, the mixture was kept at room
temperature for 12 h. Then the reaction mixture was dissolved
in a mixed solvent of THF/toluene from which single crystals
of 3 were obtained (Figure 1). We also tried less reactive HfCl4,
and similar crystals of 4 were obtained (Figure 2). Both 3 and 4
contained a trisubstituted pyridinium cation.
In order to figure out whether the proton of the pyridinium
cation came from the t-Bu group of NCOT, in situ NMR
experiments were carried out (Scheme 4). Pure liquid of TiCl4
was added to a solution of 1a in C6D6. Yellow solid precipitated
immediately, and after 5 h at room temperature, the NMR
spectra indicated that 1a was completely converted into four
products: two pyridines (2a and 5) and two nitrile−TiCl4
complexes (6 and 7) (Scheme 4). The doublet at 7.58 (J = 1.4
Hz) and 7.48 ppm (J = 1.5 Hz) in 1H NMR could be assigned
to two different 2,4,6-trisubstituted pyridines 2a and 5, which
were also detected by GC−MS. When the isolated 2a was
treated with TiCl4 in C6D6, no change of 2a was observed as
monitored by NMR. The nitrile−TiCl4 complexes 6 and 7 were
confirmed by independent preparation from the corresponding
nitriles and TiCl4 in C6D6 (see Supporting Information (SI)).
The reaction carried out in toluene-d8 produced a similar result,
B
DOI: 10.1021/acs.orglett.7b03917
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but the reaction in CD2Cl2 was messy. In the solution there
might be an equilibrium between 1a and its valence isomers
1a′.4,5 The products 5 and 7 should be generated from the
reaction between 1a′ and TiCl4. When a solution of TiCl4 was
added at −78 °C, only the ring-contraction of 1a occurred, so
2a could be isolated in nearly quantitative yield. This could also
be realized by using a weaker Lewis acid ZrCl4 as indicated by
the in situ NMR, but the reaction was much slower. However,
when pure TiCl4 was added at room temperature, both 1a and
1a′ could undergo this transformation to generate four
COTs and their bicyclo[4.2.0]octatriene isomers has been well
studied,9 a similar bicyclic isomer A might be formed through
the 6π electrocyclic ring-closing of 1a as well. Subsequent
coordination of TiCl4 to the N atom generated the activated
intermediate B, which could undergo a [2 + 2] cycloreversion
to give the final products 2a and 6. Similar mechanism has been
described for the ring-contraction of COT to benzene under
thermal condition,3a photoirradiation condition,3d and on solid
surfaces.3g Compared to these processes, the present Lewis acid
mediated ring-contraction of NCOTs proceeds with higher
selectivity and higher yield under mild condition.
Computation results for this transformation are shown in
Figure 3. The Gaussian09 program package was used,10 and the
optimization structure of all the minima and transition states
were fully calculated at the B3LYP level11 using the
LANL2DZ12 basis set (for Ti) and the 6-31+G(d)13 basis set
(for other elements) in toluene evaluated by SCRF using the
PCM model.14 According to the results shown in Figure 3, the
6π electrocyclic ring-closing of 1a is the rate-determining step
with an activation free energy of 25.1 kcal/mol, which could be
realized under the reaction condition. Another possible
pathway initiated by direct coordination of TiCl4 to 1a requires
36.0 kcal/mol energy and should be disfavored (see SI). The
energy barrier for the [2 + 2] cycloreversion would be much
higher (42.7 kcal/mol) without TiCl4, which indicates that the
coordination of TiCl4 is necessary for this step. Compounds 1a
and 1a′ can be interconverted to each other with a computed
activation free energy of 17.6 kcal/mol, and the 6π electrocyclic
ring-closing of 1a′ requires a higher activation free energy (27.6
kcal/mol) than 1a. Based on the three competing pathways (1a
to 1a′, 1a to 2a, and 1a′ to 5), we can understand that at low
temperature the pathway from 1a′ to 5 cannot take place and
that 1a′ will be converted to 1a and then to 2a, so 2a could be
obtained in nearly quantitative yield. However, at room
1
products. No other products were found in both H NMR
and 13C NMR spectra, indicating that the proton of the
pyridinium cation was not from 1a or 1a′. Thus, we supposed
that the protonation of pyridine might be a result of partial
hydrolysis of TiCl4 and HfCl4 due to their extreme moisture
sensitivity. The hydrolysis of Lewis acid could occur in the
presence of a small amount of moisture to result in the
protonation of a pyridyl ligand.8
Based on these results, we proposed a mechanism for this
transformation (Scheme 5). As the equilibration between
Scheme 5. Proposed Mechanism
Figure 3. DFT-calculated potential energy surfaces of the transformation.
C
DOI: 10.1021/acs.orglett.7b03917
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In summary, a ring-contraction of 2,4,6,8-tetrasubstituted
1,5-diazacyclooctatetraenes (NCOTs) mediated by TiCl4
afforded 2,4,6-trisubstituted pyridines in nearly quantitative
yields under mild condition. This transformation might proceed
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[2 + 2] cyclization.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03917.
■
S
Experiment details, X-ray data for 3 and 4, and scanned
NMR spectra of all new products (PDF)
(10) See Supporting Information for full reference.
Accession Codes
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Molecular Orbital Theory; Wiley: New York, 1986.
CCDC 1570799−1570800 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing 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.
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(14) (a) Cances, M. T.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997,
AUTHOR INFORMATION
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107, 3032. (b) Cossi, M.; Barone, V.; Mennucci, B.; Tomasi, J. Chem.
Phys. Lett. 1998, 286, 253. (c) Mennucci, B.; Tomasi, J. J. Chem. Phys.
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Corresponding Author
*E-mail: zfxi@pku.edu.cn.
ORCID
Wen-Xiong Zhang: 0000-0003-0744-2832
Zhenfeng Xi: 0000-0003-1124-5380
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21690061, 21372012). We thank
Prof. Zhi-Xiang Yu of Peking University for insightful
discussion of the reaction mechanism and DFT calculations.
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