NHC-catalyzed cleavage of vicinal diketones and triketones followed by insertion of enones and ynones

Article abstract of DOI:10.3762/bjoc.13.176

Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The diketones gave α,β-double acylation products via unique Breslow intermediates isolable as acid salts, whereas the triketones fo

Full text of DOI:10.3762/bjoc.13.176

NHC-catalyzed cleavage of vicinal diketones and triketones
followed by insertion of enones and ynones
Ken Takaki*, Makoto Hino, Akira Ohno, Kimihiro Komeyama, Hiroto Yoshida
and Hiroshi Fukuoka
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1816–1822.
Department of Applied Chemistry, Graduate School of Engineering,
Hiroshima University, Kagamiyama, Higashi-Hiroshima 739-8527,
Japan
doi:10.3762/bjoc.13.176
Received: 05 May 2017
Accepted: 15 August 2017
Published: 30 August 2017
Email:
Ken Takaki* - ktakaki@hiroshima-u.ac.jp
Associate Editor: M. Rueping
* Corresponding author
© 2017 Takaki et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Breslow intermediate; N-heterocyclic carbene; ring enlargement;
Stetter reaction; vicinal polyketone
Abstract
Thiazolium carbene-catalyzed reactions of 1,2-diketones and 1,2,3-triketones with enones and ynones have been investigated. The
diketones gave α,β-double acylation products via unique Breslow intermediates isolable as acid salts, whereas the triketones formed
stable adducts with the NHC instead of the coupling products.
Introduction
N-Heterocyclic carbenes (NHCs) have been indispensable cata- anion-promoted double acylation of enones with benzils, fol-
lysts for organic synthesis, particularly for umpolung of various lowed by dehydrogenation of the resulting alkanes in one pot
functional groups [1-9]. In the Stetter reaction, NHCs convert [16]. Moreover, if the reaction of cyclic 1,2-diketone I
aldehydes to nucleophilic species, which react with activated (G = C(O)R1) with activated alkenes may take place similarly,
alkenes to yield hydroacylation products [10-14]. When the car- this reaction could be utilized as a ring-enlargement procedure
bonyl compounds I other than aldehyde behave similarly, func- to afford cyclic 1,4-diketones IV.
tionalized 1,4-diketones IV would be produced (Scheme 1).
Previously, we reported that benzils I (G = C(O)R1) reacted With respect to the active species in the Stetter reaction,
with enones III in the presence of thiazolium carbene catalysts aminoenols II (G = H, Breslow intermediates) had been postu-
to give double acylation products IV in good yields [15]. If lated as true nucleophiles for a long time and those generated
enones can be replaced by ynones III in the reaction with from imidazolinium NHC were recently isolated in pure form
benzils, alkenes IV having three acyl moieties would be formed [17,18]. In the reaction of benzils with thiazolium NHC,
directly. Related products were recently obtained by the dimsyl aminoenol esters II (G = C(O)R1) could be formed similarly,
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Scheme 1: Reaction process.
but this active species were found to exist as isolable acid salts 64% yield (Table 1, entry 1). Fortunately possible propargylic
unexpectedly. Moreover, the reactivity of 1,2,3-triketones was alcohols by cross-benzoin reaction were not detected [19]. The
also investigated in comparison with that of 1,2-diketones. We other products of 4 were obtained as inseparable mixtures of
would like to report herein these results.
E- and Z-isomer, except for 4ae and 4ar, but their stereochemis-
try could not be determined by NMR. Only the major isomer of
4ai crystallized from the mixture and thus Z-stereochemistry of
Results and Discussion
The reaction of benzil (1a) with various ynones 2 was carried the two aroyl groups (ClC6H4CO and PhCO) was confirmed by
out by use of thiazolium salt 3 under similar conditions to that X-ray analysis (Figure 1) [20]. Electron-donating substituents of
with enones (Table 1) [15]. In the reaction of 1a with 1-phenyl- ynones 2 gave slightly better yields than electron-withdrawing
prop-2-yn-1-one (2a), tribenzoylethylene (4aa) was formed in ones. The yields and isomer ratios were also affected by the po-
Table 1: Reaction of benzil (1a) with ynones 2a.
Entry
Ynone 2
R
Product 4
Yield (%)b
Isomer ratioc
1
2a
2b
2c
2d
2e
2f
Ph
4aa
4ab
4ac
4ad
4ae
4af
64
54
64
63
32
63
31
49
53
57
44
20
41
54
61
52
50
13
–
2
2-MeC6H4
3-MeC6H4
4-MeC6H4
2,4,6-Me3C6H2
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-MeO2CC6H4
4-NCC6H4
2-furyl
74:26
52:48
52:48
–d
3
4
5
6
53:47
80:20
61:39
60:40e
59:41
59:41
71:29
65:35
67:33
67:33
69:31
53:47
–d
7
2g
2h
2i
4ag
4ah
4ai
8
9
10
11
12
13
14
15
16
17
18
2j
4aj
2k
2l
4ak
4al
2m
2n
2o
2p
2q
2r
4am
4an
4ao
4ap
4aq
4ar
2-thienyl
3-thienyl
1-naphthyl
2-naphthyl
Ph(CH2)2
aEquimolar amounts of 2 were used. bIsolated yields. cEstimated by NMR. dOne stereoisomer was formed. eE/Z = 40:60 determined by
X-ray analysis.
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sition of the substituents on the aroyl groups, i.e., ortho-substit- A reaction mechanism is proposed in Scheme 2, which is simi-
uents decreased the product yields and increased the isomer lar to that with enones [15]. The monoacylated Breslow inter-
ratios (Table 1, entries 2–4 and 7–9). Mesityl and aliphatic mediate C is formed by addition of thiazolium NHC A to benzil
ynones 2e and 2r gave the single isomers 4ae and 4ar in low (1a), followed by migration of the benzoyl group. Then, this
yields (Table 1, entries 5 and 18).
nucleophilic species C reacts with ynones 2 to generate the
intermediate D. The second migration of the benzoyl group to
the α-position of 2 and simultaneous elimination of A affords
product 4.
Figure 1: ORTEP drawing of Z-4ai.
Then, the substituent effect of benzils 1 was investigated
(Table 2). Electron-donating groups decreased the reaction effi-
ciency slightly. The yields were improved by catalytic amounts
of MgCl2 as reported previously [15], whereas the isomer ratios
of 4 were nearly unchanged irrespective of the Lewis acid.
When a mixture of benzils 1b and 1c (0.5 equiv each) was
treated with 2a (1.0 equiv) under similar conditions, the prod-
ucts 4ba and 4ca were formed in 52% and 20% yields, respec-
tively. However, cross products having three different aroyl
groups were not detected at all. Thus, the present reaction was
proved to take place by an intramolecular process.
Scheme 2: Reaction mechanism.
According to the intramolecular mechanism shown in
Scheme 2, the two benzoyl groups of 1a should be delivered to
the ynones 2 from the same side to yield E-products 4 exclu-
sively. However, 4 were obtained as a mixture of E- and
Table 2: Reaction of substituted benzils 1 with ynone 2aa.
Entry
Benzil 1
R
Product 4
Yield (%)b,c
Isomer ratio
1
2
3
4
1b
1c
1d
1e
Me
OMe
Cl
4ba
4ca
4da
4ea
48 (76)
16 (25)
56 (74)
42 (63)
50:50
50:50
53:47
58:42
Br
aEquimolar amounts of 2 were used. bIsolated yields. cYields in parentheses were observed in the presence of MgCl2 (20 mol %).
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Z-isomer in the most cases. Since pure Z-isomer of the product We demonstrated previously the reaction of cyclohexane-1,2-
4ai was exceptionally isolated, its isomerization was tested in dione (5a) with phenyl vinyl ketone (6a) to afford 2-benzoylcy-
order to explain the stereochemistry (Scheme 3). When the clooctane-1,4-dione (7a) in 27% yield [15]. Since this reaction
Z-4ai was dissolved in CDCl3 and monitored by NMR, the ratio would be a unique ring enlargement by two carbons, an
of E/Z changed slowly to 38:62 after 21 days. In contrast, the improvement of the reaction conditions has been tested. Al-
original ratio of 40:60 was quickly attained in the presence of though the yield increased to 45% by the use of diisopropyl-
the NHC catalyst A.
amine instead of DIPEA, the reaction efficiency was much
lower than that of benzil (1a) (Scheme 4). The only isolated
by-product in the reaction of 5a was bicyclo[3.2.1]octanone 8
(ca. 10%), which was formed by competitive tandem
Michael–aldol reaction [21]. Cycloheptane-1,2-dione (5b) and
cyclododecane-1,2-dione (5c) gave the 9- and 14-membered
1,4-diketones 7b and 7c at elevated temperature, respectively.
Next, we investigated the NHC-catalyzed reaction of 1,2,3-
triketone 9 with enone 6a. Since the central carbonyl group of 9
could be more electrophilic than the others at 1- and 3-posi-
tions, nucleophilic addition of NHC followed by migration of
one neighboring acyl group to the central carbonyl oxygen
would generate bisacylated Breslow intermediate 10
(Scheme 5). If this species behaves in a similar manner as the
monoacylated intermediate C derived from 1,2-diketone 1, its
reaction with enone 6a would be expected to yield tetraketone
11. However, when triketone 9 was treated with equimolar
Scheme 3: Isomerization of the stereochemistry of 4ai.
Scheme 4: Reaction of cycloalkane-1,2-diones with phenyl vinyl ketone (6a).
Scheme 5: Preparation and reactivity of the bisacylated Breslow intermediate 10.
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Beilstein J. Org. Chem. 2017, 13, 1816–1822.
amounts of 6a in the presence of 3 and DIPEA (20 mol %,
each), the predicted intermediate 10 was obtained in 19% yield
based on 9, but any coupling products of 9 with 6a such as 11
were not formed. The yield of 10 increased to 83% in the
equimolar reaction of 9 with 3. In addition, the product 10 was
recovered unchanged after treatment with 6a irrespective of
DIPEA. The nucleophilicity of 10 may be canceled by the two
benzoyl groups. The product 10 was fairly stable to air and
moisture, and thus E-structure was confirmed by X-ray analysis
as shown in Figure 2 [20].
Isolation of 10 prompted us to get the monoacylated Breslow
intermediate C also as a stable compound. Treatment of benzil
1d with equimolar amounts of 3 and DIPEA at room tempera-
ture, followed by non-aqueous work-up and column chromatog-
raphy gave crystalline product 12 in 92% yield (Scheme 6). Al-
though 12 did not provide single crystals suitable for X-ray
analysis, its structure was determined by NMR and elemental
analysis. 1H NMR spectra of 12 showed eleven protons in the
aromatic region, i.e., two ClC6H4, Me3C6H2, and one particu-
lar proton at δ 6.68. In 13C NMR spectra, one unknown signal
appeared in the neighborhood of the ester carbon (δ 163.1 and
167.1). Moreover, an unusual signal appeared at δ 71.5. These
Figure 2: ORTEP drawing of 10.
data indicated definitely that the isolated product 12 was differ- After identification of the product 12, we noticed that Massi and
ent from the expected intermediate C. Instead, the iminium salt his group obtained the similar adducts during their study on the
12, that is, the HClO4 salt of C, could account for all unusual multicomponent reaction of thiazolium carbenes, benzils and
signals. Furthermore, elemental analysis of 12 agreed very water to yield 1,4-thiazin-3-ones [22]. Although the initial
closely with its theoretical value and deviated much from process producing the salt 12 was similar, the total mode of the
that of C.
two reactions was quite different, that is, stoichiometric vs cata-
Scheme 6: Preparation of the iminium salt 12 and its reactivity.
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Beilstein J. Org. Chem. 2017, 13, 1816–1822.
lytic reaction with respect to the thiazolium carbenes. In the It was also found that the monoacylated Breslow intermediates
Massi reaction, monoacylated Breslow intermediate C was changed reversibly to the resting state of acid salts.
readily hydrolyzed by hydroxide, whereas Stetter reaction took
place exclusively in our reaction. The difference would be
Supporting Information
caused by the reaction conditions, particularly by the solvent
system.
Supporting Information File 1
Experimental procedure, characterization data and copies of
Since the product 12 was obtained unexpectedly, its reactivity
and role in the catalytic cycle were investigated. The stoichio-
metric reaction of 12 with phenyl vinyl ketone (6a) in the pres-
ence of DIPEA gave the product 13 in 94% yield, while no
product was formed without the base. Moreover, the reaction of
benzil 1d with enone 6a was catalyzed by 12 to give the prod-
uct 13 in good yield, which are comparable results to the use of
3 [15]. These results suggested that compound 12 played a
resting state of the monoacylated Breslow intermediate C as
shown in Scheme 7. Accordingly, when enone 6a was present
in the mixture, facile regeneration of C and its reaction with 6a
took place predominantly. It seems surprising that compound 12
could be quantitatively generated from C and HClO4 regardless
of equimolar amounts of DIPEA, while analogous intermedi-
ates derived from imidazole NHC were protonated by the acid
alone [23].
1H and 13C NMR spectra of the products.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-176-S1.pdf]
References
1. Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T.
Chem. Rev. 2015, 115, 9307–9387. doi:10.1021/acs.chemrev.5b00060
2. Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014,
510, 485–496. doi:10.1038/nature13384
3. Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2012, 51, 11686–11698.
doi:10.1002/anie.201203704
4. Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314–325.
doi:10.1002/anie.201105415
5. Mahatthananchai, J.; Bode, J. W. Chem. Sci. 2012, 3, 192–197.
doi:10.1039/C1SC00397F
6. Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522.
doi:10.1039/c2cs15333e
7. Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.;
Streekumar, V. Chem. Soc. Rev. 2011, 40, 5336–5346.
doi:10.1039/c1cs15139h
8. Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182–1195.
doi:10.1021/ar2000716
9. Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606–5655. doi:10.1021/cr068372z
10.Schedler, M.; Wang, D.-S.; Glorius, F. Angew. Chem., Int. Ed. 2013,
52, 2585–2589. doi:10.1002/anie.201209291
11.Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–2634.
doi:10.1002/anie.200500761
12.Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407–496.
doi:10.1002/0471264180.or040.04
13.Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–647.
doi:10.1002/anie.197606391
14.Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973, 12,
81. doi:10.1002/anie.197300811
15.Takaki, K.; Ohno, A.; Hino, M.; Shitaoka, T.; Komeyama, K.;
Yoshida, H. Chem. Commun. 2014, 50, 12285–12288.
doi:10.1039/c4cc05436a
Scheme 7: Resting state of the monoacylated Breslow intermediate C.
16.Ragno, D.; Bortolini, O.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.;
Massi, A. J. Org. Chem. 2015, 80, 1937–1945. doi:10.1021/jo502582e
17.Berkessel, A.; Yatham, V. R.; Elfert, S.; Neudörft, J.-M.
Angew. Chem., Int. Ed. 2013, 52, 11158–11162.
doi:10.1002/anie.201303107
Conclusion
We have demonstrated the thiazolium NHC-catalyzed reaction
of benzils with ynones to give triacylated alkenes in fairly good
yields. When this reaction was applied to aliphatic cyclic di-
ketones with enones, two carbon ring-enlarged products were
formed, though in low yields. Moreover, aromatic 1,2,3-trike-
tones reacted with NHCs to afford bisacylated Breslow interme-
diates in high yield. However, their nucleophilicity was so weak
that they were recovered unchanged in the reaction with enones.
18.Berkessel, A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.; Schlörer, N. E.;
Teles, J. H. Angew. Chem., Int. Ed. 2012, 51, 12370–12374.
doi:10.1002/anie.201205878
19.Sánchez-Díez, E.; Fernández, M.; Uria, U.; Reyes, E.; Carrillo, L.;
Vicario, J. L. Chem. – Eur. J. 2015, 21, 8384–8388.
doi:10.1002/chem.201501044
1821

Beilstein J. Org. Chem. 2017, 13, 1816–1822.
20.Crystallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 1506357
(4ai) and CCDC 1506358 (10). Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
21.Bortolini, O.; Fantin, G.; Fogagnolo, M.; Giovannini, P. P.; Massi, A.;
Pacifico, S. Org. Biomol. Chem. 2011, 9, 8437–8444.
doi:10.1039/c1ob06480k
22.Bertorasi, V.; Bortolini, O.; Donvito, A.; Fantin, G.; Fogagnolo, M.;
Giovannini, P. P.; Massi, A.; Pacifico, S. Org. Biomol. Chem. 2012, 10,
6579–6586. doi:10.1039/c2ob25928a
23.Pignataro, L.; Papalia, T.; Slawin, A. M. Z.; Goldup, S. M. Org. Lett.
2009, 11, 1643–1646. doi:10.1021/ol900257t
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