Tandem dinucleophilic cyclization of cyclohexane-1,3-diones with pyridinium salts

Article abstract of DOI:10.3762/bjoc.9.124

The cyclization of cyclohexane-1,3-diones with various substituted pyridinium salts afforded functionalized 8-oxa-10-aza-tricyclo[7.3.1.0 ^2,7]trideca-2(7),11-dienes. The reaction proceeds by regioselective attack of the central carbon atom of t

Full text of DOI:10.3762/bjoc.9.124

Tandem dinucleophilic cyclization of
cyclohexane-1,3-diones with pyridinium salts
Mostafa Kiamehr1,2,3, Firouz Matloubi Moghaddam*2, Satenik Mkrtchyan1,
Volodymyr Semeniuchenko4, Linda Supe1, Alexander Villinger1,
Peter Langer*1,5 and Viktor O. Iaroshenko*1,4,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1119–1126.
1Institut für Chemie der Universität Rostock, Albert-Einstein-Straße
3a, D-18059 Rostock, Germany, Fax: (+49-381-498-6411),
2Laboratory of Organic Synthesis and Natural Products, Department
of Chemistry, Sharif University of Technology, P. O. Box 11155-9516
Tehran, Iran, 3Department of Chemistry, Faculty of Science,
University of Qom, Qom, Iran, 4National Taras Shevchenko
University, Volodymyrska st 62, Kyiv-33, 01033, Ukraine and 5Leibniz
Institut für Katalyse e.V. an der Universität Rostock,
doi:10.3762/bjoc.9.124
Received: 22 January 2013
Accepted: 07 May 2013
Published: 10 June 2013
Associate Editor: T. J. J. Müller
Albert-Einstein-Straße 29a, D-18059 Rostock, Germany
© 2013 Kiamehr et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Firouz Matloubi Moghaddam* - Matloubi@sharif.edu; Peter Langer* -
peter.langer@uni-rostock.de; Viktor O. Iaroshenko* -
viktor.iaroshenko@uni-rostock.de
* Corresponding author
§ further email address iva108@gmail.com
Keywords:
cyclization; density functional calculations; heterocycles; nucleophilic
addition; pyridinium salt
Abstract
The cyclization of cyclohexane-1,3-diones with various substituted pyridinium salts afforded functionalized 8-oxa-10-aza-
tricyclo[7.3.1.02,7]trideca-2(7),11-dienes. The reaction proceeds by regioselective attack of the central carbon atom of the 1,3-dicar-
bonyl unit to 4-position of the pyridinium salt and subsequent cyclization by base-assisted proton migration and nucleophilic addi-
tion of the oxygen atom to the 2-position, as was elucidated by DFT computations. Fairly extensive screening of bases and addi-
tives revealed that the presence of potassium cations is essential for formation of the product.
Introduction
The nucleophilic addition to pyridinium salts has recently been ates in organic synthesis [5-12], but also interesting compounds
proven to be a powerful method for the construction of various in medicinal [13] and bioorganic chemistry [14-16]. The
dihydropyridines [1-4], which are not only valuable intermedi- tetrahydropyridine ring is an essential building block for
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Beilstein J. Org. Chem. 2013, 9, 1119–1126.
numerous natural products, synthetic pharmaceuticals, and This efficient cycloaddition encouraged us to investigate this
various biologically active compounds [17]. The tetrahydropyri- process, to improve the reaction conditions, and to extend the
dine scaffold is inherent for pharmacologically relevant repre- reaction with other pyridinium salts and diketones. Herein we
sentatives [18-24]. At the same time, heterocyclic systems report the results of that study. First, we studied the reaction of
containing an annulated pyridinium core, such as quinolinium pyridinium salt 2a with dimedone (1a) using various bases in
and isoquinolinium salts, are of considerable importance as different solvents (Table 1). At the same time, different ratios of
building blocks for the synthesis of various alkaloid frame- 1a and 2a were examined. To reach the optimal yields, dime-
works [10,25-35].
done and pyridinium salt 2a should be used in a ratio of two to
one. In addition, the optimization study showed the essential
During the past decade the reaction of dinucleophiles with role of a non-nucleophilic base as well as that of the potassium
dielectrophiles has been a major research subject in both our cation.
laboratories. For example, we have studied reactions of quino-
linium [36,37], isoquinolinium [38-40], quinazolinium [41,42] This optimization study afforded a general procedure and
and quinoxalinium [43] salts with 1,3-bis(silyl enol ethers), i.e., optimal reaction conditions: 2.0 mmol of diketone, 1.0 mmol of
masked 1,3-dicarbonyl compounds, which provided facile the appropriate pyridinium salt and 1 mmol of K2CO3 in 7 mL
access to a number of bicyclic systems. Some of these reactions, of CH3CN are stirred at room temperature for 24 hours.
such as the cyclization with quinazolinium salts, proceeded as
one-pot cyclizations. Other cyclizations, such as the reaction Reaction scope
with isoquinolinium salts, had to be carried out in two steps Having found the optimal reaction conditions, we concentrated
(formation of open-chained condensation products, which are on studying the scope and limitations of the discovered cyclo-
subsequently cyclized by the addition of acid). In some cases addition. A variety of pyridinium salts with different
the cyclization step failed, e.g., the reaction of 1,3-bis(silyl enol substituents in positions 1, 2, 3 and 4 were prepared by alkyl-
ethers) with pyridine in the presence of methyl chloroformate ation of the parental commercially available pyridines (see
resulted in the formation of 1,4-dihydropyridines, which Supporting Information File 1, Table S1). The results of this
however, could not be cyclized by the addition of acid due to cyclization reaction (Scheme 2) are summarized in Figure 1.
decomposition [36]. Additionally, we have shown a broad Generally the reaction was complete in 24 hours and afforded
application of the quinolinium [44-48] and isoquinolinium [49] the desired products in good to excellent yields. It is worth
salts for the synthesis of a wide variety of alkaloid-like frame- mentioning that only cyclohexanediones were prone to reaction
works.
with the tested pyridinium salts with formation of the corres-
ponding tetracyclic products 3, 4, 6 and 7. In the frame of the
current project a variety of 1,3-diketones and CF3-containing
Results and Discussion
Reaction optimization
During the course of the above-mentioned study we discovered
an interesting reaction that represents an external dinucle-
ophilic addition of the dimedone molecule to the pyridinium
salt 2a, taken as a random example, delivering 8-oxa-10-aza-
tricyclo[7.3.1.02,7]trideca-2(7),11-diene (3a) in modest yield
(Scheme 1). Previously, we have communicated a similar cyclo-
addition reaction using quinolinium salts [45], and recently Li
and Yan [50] reported this reaction with phenanthrolinium salts.
Scheme 2: Synthesis of compounds 3–8. Reagents and conditions: (i):
CH3CN, K2CO3, rt, 24 h. In the case of 3-cyanopyridinium salts,
NaHCO3 (2 equiv) was used as a base and the reaction time was 4
days.
Scheme 1: Reagents and conditions: (i) CH3CN, K2CO3, rt, 24 h.
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Beilstein J. Org. Chem. 2013, 9, 1119–1126.
Table 1: Optimization of the reaction conditions.
Entry
Conditionsa
Yield 3a (%)
1
1a (1 equiv)/CH3CN/K2CO3/rt/24 h
68
85
72
74
0
2
1a (2 equiv)/CH3CN/K2CO3/rt/24 h
3
1a (2 equiv)/CH3CN/K2CO3/rt/12 h
4
1a (2 equiv)/CH3CN/KHCO3/rt/4 h
5
1a (2 equiv)/CH3CN/KF/rt/24 h
6
1a (2 equiv)/CH3CN/K3PO4/rt/24 h
0
7
1a (2 equiv)/AcOH/AcOK/rt/12 h
0
8
1a (2 equiv)/AcOH/AcOK/100 °C/3 h
1a (2 equiv)/CH3CN/NaHCO3/rt/4 d
1a (2 equiv)/CH3CN/Na2CO3/rt/24 h
1a (2 equiv)/CH3CN/Na2CO3/KI (0.5 equiv)
1a (2 equiv)/CH3CN/Na2CO3/KI (1 equiv)
1a (2 equiv)/CH3CN/Na2CO3/KI (2 equiv)
1a (2 equiv)/CH3CN/Na2CO3/LiI (2 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/rt/12 h
1a (2 equiv)/CH3CN/Cs2CO3/KI (0.5 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/KI (1 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/KI (2 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/NaI (0.5 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/NaI (1 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/NaI (2 equiv)
1a (2 equiv)/CH3CN/Cs2CO3/LiI (2 equiv)
1a (2 equiv)/CH3CN/Li2CO3/rt/24 h
0
9
12
17
32
42
68
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
32
34
44
68
8
10
12
0
0
1a (2 equiv)/CH3CN/Li2CO3/KI (0.5 equiv)
1a (2 equiv)/CH3CN/Li2CO3/KI (1 equiv)
1a (2 equiv)/CH3CN/Li2CO3/KI (2 equiv)
1a (2 equiv)/CH3CN/Li2CO3/NaI (0.5 equiv)
1a (2 equiv)/CH3CN/Li2CO3/NaI (1 equiv)
1a (2 equiv)/CH3CN/Li2CO3/NaI (2 equiv)
1a (2 equiv)/CH3CN/organic baseb/rt/24 h
35
40
71
7
10
10
0
1a (2 equiv)/CH3CN/organic baseb (except DIPEA)/KI, KBr, NaI or LiI/rt/24 h
1a (2 equiv)/CH3CN/DIPEA/KI (0.5 equiv)
1a (2 equiv)/CH3CN/DIPEA/KI (1 equiv)
0
45
58
75
68
22
28
34
0
1a (2 equiv)/CH3CN/DIPEA/KI (2 equiv)
1a (2 equiv)/CH3CN/DIPEA/KBr (2 equiv)
1a (2 equiv)/CH3CN/DIPEA/NaI (0.5 equiv)
1a (2 equiv)/CH3CN/DIPEA/NaI (1 equiv)
1a (2 equiv)/CH3CN/DIPEA/NaI (2 equiv)
1a (2 equiv)/CH3CN/DIPEA/LiI (0.5–2 equiv)
aFor screening we used 2 equiv of base; bas organic bases we tested pyridine, 2,4,6-trimethylpyridine, NEt3, DABCO and DIPEA; in all cases 2 equiv
of base were added.
1,3-diketones were investigated, but these failed for all Additionally, the reaction was monitored by HPLC, and for
mentioned cases. For 3-cyanopyridinium salts a departure from most pyridinium salts investigated no byproducts were detected.
the general trend was observed in terms of reaction conditions However, in the case of 3-cyanopyridinium salts the formation
regarding the base used; here the highest efficiency was of additional products, namely the constitutive isomers of type 5
observed for NaHCO3, and the reaction took 4 days to reach and 8, was observed. These compounds were isolated and iden-
completion. In general, the reaction proceeded with high regio- tified by using standard 2D NMR methods and X-ray analysis
and diastereoselectivity.
[51].
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Our ability to calculate the mechanism as well as to make any
further predictions about reaction products is limited by the
obscure structure of the real reaction product. In fact the reac-
tion of pyridinium salt 2a with cyclic 1,3-diketones in the pres-
ence of either K2CO3 or DIPEA/KI yields an orange precipitate
in acetonitrile. Redissolved in DMSO-d6, this precipitate gave
rise to broad peaks in the 1H NMR spectra; thus its structure
was not defined and is supposed to be of polymeric nature.
Potassium with a counter-ion (HCO3− or I−) is also included in
the precipitate since that cannot be burned completely and
yields an unburned material. On the other hand the orange
precipitate is quickly decomposed by silica gel liberating the
desired product 3a or 6a, which was finally eluted from silica.
The formation of a precipitate must be a driving force of the
reaction promoted by DIPEA/KI (see Supporting Information
File 2, thermodynamic analysis).
The reaction starts with 1,3-diketone deprotonation and nucle-
ophilic attack of potassium 3-oxocyclohex-1-enolate on pyri-
dinium cation, which yields an intermediate with a new C–C
bond, and this is a key stage in the reaction. The C–O bond for-
mation can be excluded in the initial stage (see Supporting
Information File 2 for the explanation). Bearing this in mind,
we computed the local softness of 3-acetyl-1-methylpyridinium
(2a+), 2-cyano-1-methylpyridinium (2b+) and 3-cyano-1-
methylpyridinium (2e+) cations towards nucleophilic attack.
Figure 1: Synthesized compounds 3, 4, 6, 7.
At the same time, to our great disappointment 4-substituted According to the local softness indexes (see Supporting Infor-
pyridinium salts appeared to be unreactive, and testing different mation File 2) with 2b+ cation we should observe a regioselec-
reaction conditions as well as bases with various combinations tive formation of product 4a or 7a, while for cations 2a+ and
of time and temperature did not deliver any positive results.
2e+ a regioisomeric mixture should be expected (but is really
only observed for 2e+). In reality, regioisomeric mixtures of
During the course of this work we encountered the low stability compounds 3/5 or 6/8 are produced by cation 2e+, while for
of 8-oxa-10-aza-tricyclo[7.3.1.02,7]trideca-2(7),11-dienes; cations 2a+ and 2b+ regioselective reaction is inherent.
decomposition was observed in polar solvents, i.e., in DMSO. Intrigued by this discrepancy, we computed the full reaction
In some cases this had an influence on the quality of the mechanism for cation 2a+ with potassium 3-oxocyclohex-1-
1H NMR spectra. Heating also led to decomposition, which was enolate in the presence of potassium cation and hydrogencar-
observed after 2–3 hours at 60–70 °C.
bonate anion as base. We included HCO3− in our computation,
both because it has only five atoms and because this base is
The constitution of products 3, 4, 6, 7 was proven by 1D and 2D presumed to operate; it is formed from neutral carbonate when
NMR experiments; that of compounds 6d, 7c and 8 was unam- it deprotonates the cyclic diketone. However, the mechanism
biguously corroborated by X-ray [51] diffraction analysis involving any other base should not differ significantly.
(Supporting Information File 1, Figures S2, S3, S4)
A plausible mechanism is presented in Figure 2. After initial
Reaction mechanism
deprotonation of the diketone and formation of the hydrogen-
In order to shed light on the reaction mechanism we used DFT carbonate anion, the latter is exchanged with iodine in the salt
computations at the B3LYP/6-31G(d,p) [52-54] level, as imple- of 2a, and an initial complex consisting of 2a+HCO3− with
mented in the Gaussian 09 program [55], and acetonitrile was potassium 3-oxocyclohex-1-enolate is assembled (intermediate
included implicitly within the IEFPCM method (more details on 9). Nucleophilic attack yields intermediate 11 through TS 10.
inclusion of the solvent can be found in Supporting Information The latter TS was first localized without HCO3− (TS K-S1a-1,
File 2). For simplicity 1,3-cyclohexanedione rather than dime- see Supporting Information File 2); however, an inclusion of
done was included in the computations.
HCO3− resulted in a slight energy drop. Cyclohexanedione ring
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Beilstein J. Org. Chem. 2013, 9, 1119–1126.
Figure 2: Plausible reaction mechanism.
inversion (intermediates 13, 15 and TSs 12, 14) and HCO3− 22a shows only proton displacement, without formation of a
semi-decoordination (TS 16) lead to intermediate 17, which C–O bond. The latter was formed during IRC computation,
undergoes proton abstraction under action of hydrogencar- starting from TS 22a. Previously, Hui Li and Chao-Guo Yan
bonate (TS 18 and intermediate 19). Structural rearrangement of [50] proposed the nucleophilic attack of oxygen onto the carbon
19 through TS 20 shows an intermediate 21. Finally 21 is proto- atom with subsequent protonation. We have explored this
nated by coordinated H2CO3 (highest rate-determining TS 22a) process by decreasing the C–O distance in relaxed scans: the
to yield the final product 23 with a great release of free energy. scan from intermediate 19 showed only a constant rise of
It is worth mentioning that the last reaction is a protonation of energy, while the scan from intermediate 21 showed a
enamine in essence; the imaginary frequency inherent for TS maximum, which was not optimized to any TS. Hence, the
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Beilstein J. Org. Chem. 2013, 9, 1119–1126.
attack by oxygen on the last stage must be excluded. Within the [7.3.1.02,7]trideca-2(7),11-dienes with a wide range of
scope of this mechanism the activation energy is 21.3 kcal/mol substituents. Further studies to extend the scope of the syn-
(energy gap between 22a and 19).
thetic utility of these cyclizations are in progress in both of our
laboratories.
Other TSs (K-S1a-2, K-S1a-3, see Supporting Information
Experimental
File 2), inherent for the initial stage of new C–C bond forma-
tion turned out to be unimportant, because in both cases reac- General Information
tions run again through TS 22a (rate limiting), as was shown by Solvents were purchased from ACROS and directly used
additional computations. On the other hand, we have computed without further purification. Analytical thin-layer chromatog-
four conformers of TS 22: the conformation of the cyclohexane raphy was performed on 0.20 mm 60 Å silica gel plates.
ring and that of the acetyl group were changed. While the cyclo- Column chromatography was performed by using 60 Å silica
hexane-ring conformation has only a negligible effect on the TS gel (60–200 mesh). Pyridinium salts were synthesized
energy (TS 22b, see Supporting Information File 2), the change according to the published procedure [56].
of the acetyl group conformation prevents potassium from coor-
dinating to it and makes the TS energy somewhat higher (TSs The density functional B3LYP [52-54] with 6-31G(d,p) basis
22c and 22d from Supporting Information File 2).
set for all atoms except iodine and solvation by acetonitrile
within the IEFPCM method as implemented in the Gaussian 09
In the proposed mechanism the regioselective formation of pro- package [55], was employed for the calculations. For cases
duct 6a is not explained (see Supporting Information File 2 for when iodine was included, the LANL2DZ basis set and core
discussion). We attribute this to a higher thermodynamic stabi- potential were assigned. All compounds were computed in the
lization of compound 6a by a potassium cation (Scheme 3), as closed-shell singlet state (confirmed by “stable” calculation).
compared with that of regioisomeric 6aa (its formation was not Frequency calculations were performed on all optimized
observed); the energetic distance between 6a-K+ and 6aa-K+ is geometries to ensure only positive eigenvalues for minima and
2.5 kcal/mol at the B3LYP/6-31G(d,p) level and 2.0 kcal/mol at one imaginary frequency for transition states. Free energies at
the B3LYP/6-311++G(d,p)//B3LYP/6-31G(d,p) level. As 298.15 K and 1 bar pressure were calculated according to the
mentioned before, the assumption is hard to prove due to lack of recommendation of Gaussian, Inc. [57,58], and the frequency
information about the real product composition.
scaling factor (0.9608) was applied. For every located tran-
sition state an IRC calculation at the same level of theory
confirmed that this TS connects the corresponding educts/inter-
mediates/products. The methodology of local softness computa-
tion [59,60] uses Fukui functions; for their approximation we
used Mulliken, ESP, NPA and Hirshfeld charges. However,
only the Fukui functions approximated by NPA and Hirshfeld
charges were unambiguous and taken into consideration.
General procedures for the synthesis of
compounds 3–8
Procedure (A)
In a 25 mL Schlenk flask, under argon flow, 2.0 mmol of dike-
tone, 1.0 mmol of the appropriate pyridinium salt, and 1.0 mmol
(138 mg) of K2CO3 were loaded. The flask was covered with a
septum stopper and 7 mL of absolute CH3CN was added by
syringe. The reaction mixture was left under intensive stirring at
room temperature for 24 hours. Then the solvent was removed
under reduced pressure and the crude material was subjected to
column chromatography.
Scheme 3: The influence of K+ on the product free energy.
Conclusion
In summary, we have studied the dicomponent binucleophilic Procedure (B)
cycloaddition of 1,3-diketones with diverse substituted In the case of the 3-cyanopyridinium salt, NaHCO3 (2.0 mmol,
pyridinium salts. The reaction took place under mild conditions 168 mg) was used as a base, and the reaction mixture was left
and provided an efficient route to 8-oxa-10-aza-tricyclo- over 4 days.
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Beilstein J. Org. Chem. 2013, 9, 1119–1126.
15.Sunkel, C. E.; Fau de Casa-Juana, M.; Santos, L.; Mar Gomes, M.;
Villarroya, M.; Gonzalez-Morales, M. A.; Priego, J. G.; Ortega, M. P.
J. Med. Chem. 1990, 33, 3205–3210. doi:10.1021/jm00174a017
16.Jaing, J.-L.; Li, A.-H.; Jang, S.-Y.; Chang, L.; Melman, N.; Moro, S.;
Ji, X.-d.; Lobkovsky, E.; Clardy, J.; Jacobson, K. A. J. Med. Chem.
1999, 42, 3055–3060. doi:10.1021/jm980688e
Procedure (C)
In the case of 2-cyanopyridinium salts the reaction was
completed within 1 hour.
Supporting Information
17.Mateeva, N. N.; Wineld, L. L.; Redda, K. K. Curr. Med. Chem. 2005,
12, 551–571. doi:10.2174/0929867053362776
Supporting Information File 1
18.Ito, S.; Satoh, A.; Nagatomi, Y.; Hirata, Y.; Suzuki, G.; Kimura, T.;
Satow, A.; Maehara, S.; Hikichi, H.; Hata, M.; Kawamoto, H.; Ohta, H.
Bioorg. Med. Chem. 2008, 16, 9817–9829.
Details on synthetic procedures, list of pyridinium salts,
characterization of new compounds, copies of NMR
spectra, X-ray structures of compounds 6d, 7c and 8.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-124-S1.pdf]
doi:10.1016/j.bmc.2008.09.060
19.Jones, P.; Griffin, A. M.; Gawell, L.; Lavoie, R.; Delorme, D.;
Roberts, E.; Brown, W.; Walpole, C.; Xiao, W.; Boulet, J.; Labarre, M.;
Coupal, M.; Butterworth, J.; St-Onge, S.; Hodzic, L.; Salois, D.
Bioorg. Med. Chem. Lett. 2009, 19, 5994–5998.
Supporting Information File 2
doi:10.1016/j.bmcl.2009.09.072
Computational results, optimized structures (atomic
coordinates as reported by Gaussian 09), charges and local
softness indexes (nucleophilic attack) for cations 2a+, 2b+
and 2e+, additional discussions related to computations.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-124-S2.pdf]
20.Liras, S.; McHardy, S. F.; Allen, M. P.; Segelstein, B. E.; Heck, S. D.;
Bryce, D. K.; Schmidt, A. W.; Vanase-Frawley, M.; Callegari, E.;
McLean, S. Bioorg. Med. Chem. Lett. 2010, 20, 503–507.
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