Note Cite This: J. Org. Chem. 2019, 84, 8788−8795
pubs.acs.org/joc
One-Pot Conversion of Aldehydes and Aryl Halides to Disubstituted Alkynes via Tandem Seyferth−Gilbert Homologation/Copper-Free Sonogashira Coupling Alexander Sapegin and Mikhail Krasavin* Saint Petersburg State University, Saint Petersburg 199034, Russia
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S Supporting Information *
ABSTRACT: A practically convenient protocol has been developed to convert a mixture of an aldehyde, aryl halide, and the Bestmann−Ohira reagent into disubstituted acetylene via a successive addition of base (Cs2CO3) and a Pd(II) catalyst, allowing sufficient time after addition of each of these reagents for the tandem processes (Seyferth−Gilbert homologation and Sonogashira coupling) to occur. Notably, for the latter reaction, no copper catalyst was required.
D
annelation of o-unsubstituted aromatic methyl hydroxamate to deliver an isoquinolone nucleus,13 the “heptagon” annelation of 1-iodo-8-phenyl naphthalene,14 and a somewhat analogous annelation involving positions 1 and 7 of isatin.15 Additionally, diaryl alkynes are prominent starting materials for the oxidation to benzils (1,2-diaryl ethan-1,2-diones)16 and can be involved in various transition metal catalyzed arylation reactions,17 sometimes accompanied by alkyne dimerization18 (Figure 2). Among various recent coupling approaches to the synthesis of diaryl alkynes involving alkynoic acids,19 alkynyl iodonium salts,20 alkynyl organometallic reagents,21 1-haloalkynes,22 and alkynyl sulfones,23 the Sonogashira coupling of terminal alkynes with an aryl halide24 remains perhaps the most popular method. The monoaryl alkyne partner for the Sonogashira reaction can, in turn, be conveniently elaborated from the respective aromatic aldehyde using the Seyferth− Gilbert homologation.24 The latter, especially its version employing the Bestmann−Ohira reagent,25 generally proceeds under relatively mild conditions and conveniently links the diversity of diaryl alkynes thus obtainable to the vast range of commercially available aromatic aldehydes. Considering this, combining the Seyferth−Gilbert protocol with Sonogashira coupling in a one-pot format would provide a practically convenient alternative to other methods of converting aldehydes directly to diaryl alkynes such as addition−double elimination reaction of aldehydes with aryl sulfonylmethane synthons25 which require the use of sensitive organometallic reagents, silyl halides, and a thoroughly controlled dry and inert atmosphere. Even the recently introduced organocatalytic coupling of aldehydes with benzyl chlorides under strongly basic conditions26 suffers from similar inconvenience. It is therefore surprising that such one-pot methods (Figure 3) have not been investigated to date. In our
iaryl alkynes have broad utility in synthetic organic, medicinal, and materials chemistry. In particular, they are employed in the preparation of conducting polymers,1 materials with useful photophysical properties,2 and liquid crystals.3 Despite its inherently high lipophilicity, the rod-like diarene alkyne scaffold can be found embedded in the structure of compounds intended for medicinal use, for example, as follicle-stimulating hormone receptor (FSHR) antagonists (1) for fertility control and prevention of osteoporosis,4 anxiolytic neurokinin NK-1 and NK-2 receptor modulators (2),5 anti-inflammatory cyclooxygenase-2 inhibitors (3),6 and antiproliferative agents (4)7 (Figure 1).
Figure 1. Examples of biologically active compounds based on 1,2diaryl alkyne scaffold.
Perhaps, the most prominent utility of diaryl alkynes in synthetic chemistry is as building blocks in various annelation reactions. These are eloquently exemplified by Asao− Yamomoto annelation of o-formyl diaryl alkynes,8 annelation of 2-pyridones to 2-quinolones,9 annelation of 1,2-arylidene diamines to quinoxalines,10 annelation of anilines11 and oiodoanilines (the Larock heteroannulation) to give indoles,12 © 2019 American Chemical Society
Received: May 23, 2019 Published: June 17, 2019 8788
DOI: 10.1021/acs.joc.9b01367 J. Org. Chem. 2019, 84, 8788−8795
Note
The Journal of Organic Chemistry
methodology void and certain scope and practicality limitations of the known methods to directly convert certain ketones into disubstituted alkynes,28 we set off to investigate the possibility of in situ preparation of a monoaryl alkyne from the respective aromatic aldehyde followed by same-pot Sonogashira coupling of the former with an aryl halide already present in the reaction mixture triggered by the addition of a transition-metal catalyst. Herein, we present the results of these studies. Initial screening of the conditions was performed with benzaldehyde, the Bestmann−Ohira reagents, and phenyl iodide and included variations of the solvent, temperature, catalyst for the Sonogoshira coupling, and reaction time (Table 1). An initial attempt to expose all the reaction components (including 4 equiv of K2CO3) to a palladium(II) catalyst with (entry 1) or without (entry 2) the addition of Cu(I) iodide resulted in no desired product, presumably due to Pd-induced decomposition of the Bestmann−Ohira reagent. Separating the two chemical events (the terminal alkyne formation and the addition of a Pd(II)/Cu(I) catalyst system) led to the formation of the desired diphenylethyne albeit in negligible yield (entry 3). Significant improvement of the yield was achieved by changing the base to cesium carbonate as well as the solvent to methanol and running the two steps of the onepot protocol for 4 and 12 h, at 30 and 40 °C, respectively (entry 7); the latter temperature and time regimen proved to be optimal in subsequent experiments (vide infra). Interestingly, by merely excluding CuI from the catalyst system, the yield was raised nearly 2-fold (entry 8), and therefore, subsequent optimization (entries 8−15) was carried out in a copper-free format29 by varying the Pd(II) catalyst system and the phosphine ligand. The optimal yield (entry 15) was achieved with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) as the ligand. Employing 4 equiv of base (entries 15−17) was proved to be optimal while adding other solvents to the reaction medium (entries 18−23) neither improved nor drastically affected the product yield. One notable exception is the addition of water (entry 19) which led to no product formation at all. With the optimized reaction conditions at hand, we proceeded to investigate the scope of the newly developed one-pot protocol for the conversion of a mixture of an aldehyde and aryl halide into a disubstituted alkyne using a range of halogenated (hetero)arenes and aromatic as well as aliphatic aldehydes (Table 2). As it can be seen from the data presented in Table 1, the reaction generally displayed a broad scope with respect to both the aldehyde (aromatic, heteroaromatic, and aliphatic alike) and (hetero)aryl halide partners and gave the target
Figure 2. Examples of the uses of 1,2-diaryl alkynes as building blocks for synthesis.
current program aimed at screening for novel cocrystallization partners for active pharmaceutical ingredients,27 we required an expedient and convenient access to a wide range of diaryl alkynes from aromatic aldehydes. Considering the above-stated
Figure 3. Approaches to the direct conversion of aldehydes to diaryl alkynes via (a) addition−double elimination and (b) one-pot Seyferth− Gilbert/Sonogashira sequence investigated in this work. 8789
DOI: 10.1021/acs.joc.9b01367 J. Org. Chem. 2019, 84, 8788−8795
Note
The Journal of Organic Chemistry Table 1. Optimization Experiments for the One-Pot Diaryl Alkyne Synthesis
Entry
Solvent
Base (equiv)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
EtOH EtOH EtOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH/H2O (1:1) MeOH/MeCN (1:1) MeOH/THF (1:1) MeOH/DMF (1:1) MeOH/CH2Cl2 (1:1) MeOH/Toluene (1:1)
K2CO3 (4) K2CO3 (4) K2CO3 (4) K2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (3) Cs2CO3 (5) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4) Cs2CO3 (4)
t1 (h)
Catalyst system (mol %) Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2) Pd(PPh3)4 (2) Pd(PPh3)2Cl2 Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (2), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4), Pd(OAc)2 (4),
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3
(4)a
(4), CuI (4)a (4), CuI (4), CuI (4), CuI (4), CuI (4), CuI (4)
(4) (4) (4) (4) (4)
BINAPb (4) Xantphosb (4) Xphos (4) Xphos (8) Xphos (8) Xphos (8) Xphos (8) Xphos (8) Xphos (8) Xphos (8) Xphos (8) Xphos (8)
t2 (h)
T1 (°C)
24 24 12 12 8 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4
12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12 12
T2 (°C)
Yield (%)
40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40
No reaction No reaction 3 8 17 18 24 41 30 45 51 56 63 76 84 62 83 No reaction 70 66 49 80 74
rt rt rt r. t. rt 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
a
The catalyst was added immediately after mixing the starting reagent. bBINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Xantphos: 4,5bis(diphenylphosphino)-9,9-dimethylxanthene.
process is similar to the earlier described direct conversion of aldehydes to disubstituted alkynes using benzyl aryl sulfone anion addition−double-elimination process. However, it does not require strictly anhydrous conditions and the use of low temperature as well as employing a strong lithium amide base, therefore, can be conveniently adopted to the preparation of arrays of disubstituted alkynes in a combinatorial format.
disubstituted alkynes 5 in good to excellent yields. Notable exceptions were provided by the attempts to use unprotected hydroxybenzaldehydes (entries 6−8) and (E)-cinnamaldehyde (entry 14). The latter finding was in line with our analysis of the literature which revealed that cinnamaldehydes are generally transformed into respective alkynes by methods other than Seyferth−Gilbert homologation.30 Luckily, the anticipated enyne core (which in itself is of importance in synthetic organic chemistry29) was accessed by an umpolung approach from p-tolualdehyde and stiryl bromide (entry 33). Similarly notable is the outcome of the reaction with substrates capable of undergoing double Sonogashira coupling (such as 2chloro-3-iodopyridine or 2-amino-3,5-dibromopyridine). In this case, the major product was the product of the double Sonogashira coupling while the monocoupling product was isolated in low yield (entry 23) or was observed in
