Abstract
Conditions have been identified that enable the one-pot double Suzuki coupling of 4,5-dibromothiophene-2-carboxaldehyde to proceed in good yield. The key to success in these reactions is the use of minimal amounts of water to avoid significant amounts of dehalogenation during the first coupling.
Keywords: regioselective, Suzuki coupling, thiophenes, one-pot, dehalogenation
Cross-coupling reactions are a well established family of reactions that find great use in the preparation of substituted aromatic compounds.1 Through these reactions, C-C, C-N, C-O, and even C-S bonds can be formed with a high degree of control and functional group tolerance. As a result, it is hardly surprising that cross-coupling chemistry is one of the main methods employed in the synthesis of substituted aromatics.
At the same time, the use of cross-coupling chemistry to introduce more than one substituent is inherently less than ideal. For each substituent to be installed, a halogenation and a coupling reaction are required. Thus, a minimum of two steps are needed to introduce each new group. If multiple groups are to be installed, this results in a very linear sequence. (Scheme 1)
Scheme 1.
Stepwise versus One-pot Cross-coupling Methods
In an effort to render the use of cross-coupling reactions to introduce multiple substituents more efficient, we have been interested in developing the regioselective, one-pot polycoupling reaction of polyhaloaromatics.2,3 In this case, multiple halogens are introduced in one step and then, in the second step, different substituents are introduced via sequential cross-coupling reactions. The regiocontrol in these cross-coupling reactions is determined by the electronic differences between the different halogenated sites and is highly predictable.4
Our earliest efforts developing the polycoupling route to polysubstituted aromatics focussed on the pyrrole nucleus.2a,b Particularly successful results were obtained with dibromopyrrole aldehyde 1.2a (Scheme 2) Thus, the use of palladium acetate as the catalyst provided excellent selectivity for coupling at C5, with no competing coupling at C4. By simple addition of a phosphine ligand with the second boronic acid, though, coupling at C4 occurred to afford the dicoupled material in good overall yield.
Scheme 2.
Pyrrole Aldehyde 1 Double Couplings
In light of this success, an obvious extension to consider was related heteroaromatic aldehydes. One such system is thiophene aldehyde 3.5 Despite the apparent similarities, application of the conditions used for regioselective couplings of pyrrole aldehyde 1 to aldehyde 3 failed to afford any significant quanities to the desired double coupling product.
In an effort to determine the source of this failure, investigation of just the first coupling at C5 was undertaken. One complication that was quickly noted was the appearance of a significant by-product 4 in many of the reactions. This apparent product of coupling followed by dehalogenation was difficult to separate from the mono-coupled product 5.6,7 As can be seen, variation in solvent when using palladium acetate as the catalyst did not avoid this dehalogenation (Table 1, entries 1 and 4). Curiously, attempts to use anhydrous reaction conditions did shut down the dehalogenation, but resulted in no reaction (Table 1, entry 3).
Table 1.
Catalyst Studies
| Entry | Catalyst | Base | Solvent | Product |
|---|---|---|---|---|
| 1 | Pd(OAc)2 | aq K2CO3 | DMF | 4 (75%) |
| 2 | Pd(OAc)2 | aq Na2CO3 | EtOH/Toluene (1:3 v/v) | Complex mixture |
| 3 | Pd(OAc)2 | K2CO3 | DMF | No rxn |
| 4 | Pd(OAc)2, tBu3P/HBF4 | aq Na2CO3 | EtOH/Toluene (1:3 v/v) | 4 (82%) |
| 5 | Pd(OAc)2, tBu3P/HBF4 | Cs2CO3 | EtOH/Toluene (1:3 v/v) | 5 (42%) |
| 6 | Pd(OAc)2, tBu3P/HBF4 | aq Cs2CO3 | DMF | 5 (58%) 4 (38%) |
| 7 | Pd(OAc)2, tBu3P/HBF4 | Cs2CO3 | Dioxane | No rxn |
Next, more active palladium catalysts were examined, but even bis(tri-tert-butylphosphine)palladium(II) acetate failed to improve the coupling results.8 Choice of base or solvent made little difference, although again attempts to use anhydrous conditions failed to afford any coupling or dehalogenation (Table 1, entry 7).
From these results, it appeared that the presence of water was both crucial for the coupling but also involved in the dehalogenation. Indeed, using tetrakis(triphenylphosphine) palladium(0) as the catalyst with potassium carbonate as the base in a mixture of dioxane and water supported this hypothesis. (Table 2) Thus, in a 4:1 solvent mixture, dehalogenation was the major product, while in an 8:1 mixture the reaction failed to proceed to completion within 24 hours. Selecting a value between these two (6:1) was a good compromise, affording complete conversion within 5 hours, but minimizing the amount of dehalogenation (<10% as determined by 1H NMR).
Table 2.
Dioxane/Water Studies
| Entry | Ratio(H2O/Dioxane) | % Yield of 5 | % Yield of 4 |
|---|---|---|---|
| 1 | 1:4 | 35 | 55 |
| 2 | 1:6 | 95 | 3 |
| 3 | 1:8 | 35a | 0 |
Remainder was covered starting material.
Fortunately, the second coupling also proceeded under these same conditions, enabling a simple one-pot double coupling method using tetrakis(triphenylphosphine) palladium(0) and potassium carbonate. The catalyst remained active for the second coupling, so only additional base and the second boronic acid needed to be added. Interestingly, no particular care needed to be taken to exclude oxygen and these reactions were performed under a simple atmosphere of air rather than nitrogen or argon.
With reaction conditions in hand, the application to a variety of boronic acids was explored.9.10 (Table 3) Not unexpectedly, the reaction worked best with electron-rich boronic acids. Still, electron-deficient and even alkenyl boronic acids worked at modestly reduced yields (Table 3, entries 2, 3, and 6). Finally, steric hindrance also decreased the efficiency, but an ortho substituted boronic acid did afford the coupled product (Table 3, entry 5).
Table 3.
Double Coupling Results
| Entry | Ar | Ar′ | % Yield |
|---|---|---|---|
| 1 | PMeOC6H4 | Ph | 97 |
| 2 | pFC6H4 | Ph | 82 |
| 3 | Ph | pFC6H4 | 56 |
| 4 | Ph | 3,4-DiMeOC6H4 | 80 |
| 5 | OMeOC6H4 | Ph | 25 |
| 6 | Trans-heptenyl | pMeOC6H5 | 41 |
In short, we have identified conditions that are effective for the regioselective double Suzuki coupling of thiophene aldehyde 3. This sequential, one-pot reaction affords the double coupled products in generally good yield and is expected to be of great utility in the preparation of substituted thiophenes for a variety of applications. Efforts are currently underway to extend these dicoupling conditions to furfural and other thiophenes.
Acknowledgments
Financial support by NIH (GM074662-01) and a gift of boronic acids from Frontier Scientific are gratefully acknowledged.
Footnotes
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References
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- 10.All new compounds exhibited spectral properties consistent with the assigned structures. 5-(4′-methoxyphenyl)-4-phenylthiophene-2-carboxaldehyde: brown oil. IR (cm−1, neat) 2860, 2820, 1665, 1435 1252, 1176, 1043, 831; 1H NMR (360 MHz, CDCl3) 9.89 (s, 1H), 7.77 (s, 1H), 7.34-7.24 (m, 7H), 6.82 (d, J = 6.8 Hz, 2H), 3.81 (s, 3H); 13C NMR (90 MHz, CDCl3) 183.0, 160.2, 149.2, 140.7, 139.6, 138.9, 135.5, 130.6, 129.1, 128.8, 127.7, 125.5, 114.3, 55.4. HRMS (EI) calcd for C18H14O2S 402.0784, found 402.0785. 5-(4′-fluorophenyl)-4-phenylthiophene-2-carboxaldehyde: tan solid. mp = 78-79 °C. IR (cm−1, neat) 2860, 2820, 1645, 1375, 1236, 1159, 1038, 835; 1H NMR (360 MHz, CDCl3) 9.92 (s, 1H), 7.79 (s, 1H), 7.59 (d, J = 6.8 Hz, 2H), 7.44 (t, J = 6.8 Hz, 2H), 7.34-7.24 (m, 3H), 7.00 (t, J = 8.6 Hz, 2H); 13C NMR (90 MHz, CDCl3) 182.9, 166.3, 147.5, 141.5, 139.8, 139.2, 135.0, 131.1 (d, J = 34 Hz), 130.7, 129.1 (d, J = 60 Hz), 128.9, 127.9, 116.0 (d, J = 54 Hz). HRMS (EI) calcd for C17H11OS 390.0515, found 390.0515. 4-(4′-fluorophenyl)-5-phenylthiophene-2-carboxaldehyde: brown oil. IR (cm−1, neat) 2860, 2820, 1650, 1480, 1232, 1162, 1041, 829; 1H NMR (360 MHz, CDCl3) 9.92 (s, 1H), 7.77 (s, 1H), 7.34-7.18 (m, 7H), 7.01 (t, J = 9.2 Hz, 2H); 13C NMR (90 MHz, CDCl3) 182.9, 164.0, 160.7, 148.8, 141.6, 138.9, 138.5, 133.0, 131.2, 130.8 (d, J = 32 Hz), 129.2 (d, J = 100 Hz), 128.8, 115.8 (d, J = 86 Hz). HRMS (EI) calcd for C17H11FOS 390.0515, found 390.0517. 4-(3′,4′-dimethoxyphenyl)-5-phenylthiophene-2-carboxaldehyde: tan solid, mp = 152-155 °C. IR (cm−1, neat) 2860, 2820, 1668, 1513, 1465, 1432, 1251, 1027, 845; 1H NMR (360 MHz, CDCl3) 9.92 (s, 1H), 7.80 (s, 1H), 7.36-7.30 (m, 5H), 6.86 (d, J = 6.8 Hz, 1H), 6.85 (s, 1H), 6.68 (d, J = 6.8 Hz, 1H), 3.89 (s, 3H), 3.63 (s, 3H); 13C NMR (90 MHz, CDCl3) 182.9, 148.8, 141.3, 139.4, 138.9, 129.4, 128.9, 128.8, 127.7, 121.3, 119.2, 112.3, 111.5, 111.2, 110.4, 55.9, 55.7. HRMS (EI) calcd for C19H16O3S 432.0820, found 432.0818. 5-(2′-methoxyphenyl)-4-phenylthiophene-2-carboxaldehyde: tan wax, mp = 77–78 °C. IR (cm−1, neat) 2860, 2820, 1164, 1460, 1248, 1025, 831; 1H NMR (360 MHz, CDCl3) 9.94 (s, 1H), 7.85 (s, 1H), 7.28-7.22 (m, 6H), 7.08-7.00 (m, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.86 (d, J = 6.8 Hz, 1H), 3.49 (s, 3H); 13C NMR (90 MHz, CDCl3) 183.1, 156.7, 142.0, 141.2, 138.1, 136.2, 132.0, 131.5, 130.7, 128.4, 128.0, 127.4, 120.8, 120.6, 111.6, 55.2. HRMS (EI) calcd for C18H14O2S 402.0784, found 402.0783. 5-(trans-heptenyl)-4-(4′-methoxyphenyl)thiophene-2-carboxaldehyde: yellow solid, mp = 74–75 °C. IR (cm−1, neat) 2860, 2820, 1164, 1508, 1437, 1289, 1246, 1177, 835, 741; 1H NMR (360 MHz, CDCl3) 9.83 (s, 1H), 7.63 (s, 1H), 7.30 (d, J = 6.6 Hz, 2H), 6.98 (d, J = 6.6 Hz, 2H), 6.54 (d, J = 14.4 Hz, 1H), 6.36 (dt, J = 6.7, 14.4 Hz, 1H), 3.86 (s, 3H), 2.18 (q, 2H), 1.46-1.24 (m, 6H), 0.89 (t, 3H); 13C NMR (90 MHz, CDCl3) 182.8, 159.3, 147.2, 139.5, 139.2, 139.0, 137.1, 130.2, 128.5, 122.2, 114.2, 55.4, 33.3, 31.5, 28.7, 22.6, 14.1. HRMS (EI) calcd for C19H22OS 406.1391, found 406.1390.