*This is the 4th post of the helicene series*
Yeah, asymmetric synthesis of carbon-sulfur helicene was great! But with the iterative synthetic scheme, it seemed we could keep going and going…forever….ha ha ha,…on paper, of course. It was kinda fun… plugging away the connection/annelation sequences…go on and on in many different ways. Different routes were on the drawing board, but which ones to go after? A-ha, another fun game of pick and choose!
At a glance, it may seem easy to get to the helicenes with the connection/annelation sequence of those helicenes we just prepared. Yep, we have been trying to do just that, but….easy said than done…. Well, the retrosynthetic scheme for helicene looked pretty good too. Have a look!
Route A seemed straightforward…we already had in hands the annelated trithiophenes…. We could try di-connection—forming two β-β linkages between the annelated trithiophenes—by Suzuki and/or Negishi cross-couplings, followed by di-annelation, to give helicene. But that didn’t work, even with the use of very active Pd-catalytic systems at mild conditions.
We moved on to consider Route B, which looked like a win-win strategy…. at least we should be able to get to helicene! At this point, we also thought about how to introduce solubilizing groups…’cause…long carbon-sulfur annelated thiophene oligomers would likely to be very insoluble, as rock…. Having the alkyl chains at the terminal α-positions were the only possibility. We thought also that the β-β cross-couplings might be more favorable for the coupling between the relatively less hindered monothiophene and the annelated trithiophenes, as well as the coupling of those thiophenes functionalized with more robust alkyl chains, rather than with labile TMS-groups. Great! We went after Route B and started working on the synthesis of the helicene.
The connection step, the Negishi cross-coupling between functionalized monothiophene and annleated trithiophene, went rather smoothly. Once again, the annelation step gave us some headache!!!…the yields of helicene were highly variable. What was going on? To understand this problem, we monitored the formation of the α,α’-dilithiated intermediate using 1H NMR spectroscopy with double solvent suppression, in which 2% of benzene-d6 was added to the reaction mixture in ether. This allowed us to optimize the formation of the dilithiated intermediate before the addition of (PhSO2)2S. With this procedure, we got ~40% isolated yields of the TMS-protected helicene; deprotection of the TMS by treatment with trifluoroacetic acid (TFA), underwent in a nearly quantitative yield, to give helicene.
The win-win strategy paid off, we got the new helicene functionalized with the alkyl chains, the n-octyl groups, at the terminal α-positions. The synthesis was published in Synlett.
At this point, we thought….good chance to get to helicene. So we went ahead and continued Route B, mono-annelation route; we tried Cu(II)-mediated oxidative homo-coupling of helicenes. Unfortunately, the yields of the homocoupling product were not so good (35-40%); it might be that the β-thienyllithium intermediate of the Br/Li exchange on the helicenes was highly unstable. We then tried different methodologies and found that Pd-catalyzed reductive CC-homocoupling was an efficient approach to the formation of sterically hindered β-β thiophenes linkage under mild conditions. It turned out that this approach to the connection step worked well for both Route B (mono-annelation) and Route C (tri-annelation) for the synthesis of helicene. Here is the synthetic scheme.
We were quite surprised with the results…. Route B synthesis, mono-annelation route, lead to (-)-helicene, plus byproduct (-)-Dimer….. Route C synthesis, tri-annelation route, gave us the tri-annelations product (+)-helicene and the di-annelations product dimer of helicene. Interesting…..mono-annelation and tri-annelation lead to helicene with opposite configurations!!!…..read the JACS communication for detail… But here is the beautiful structure….
Just a brief note…. evidence of cross-conjugation nature of the π-systems in  and  helicenes was provided by the nearly identical electronic absorption onsets and near convergence of the first oxidation potentials. This result was confirmed by FT-Raman/IR studies on helicene, helicene, and annelated trithiophenes, a collaborative work with Professor J. T. Lopez Navarrete group at the University of Málaga and Professor Rainer Glaser at the University of Missouri-Columbia, who carried out the density functional theory (DFT) computations on these structures. This was published in J. Phys. Chem. C. On the basis of the absorption onsets at 355-356 nm, the optical band gap (Eg) of approximately 3.5 eV was estimated for the (C2S)n helix polymer.
Can you believe? These helicenes were mostly synthesized by one man, Dr. Makoto Miyasaka….talent, hardworking, dedicated postdoc. Ah, he basically put to rest the argument about the definition of “hardworking” habit in our lab….simply by his example…. Thanks, Mako, and we wish you the best in your new research frontier at Kanagawa U and in your future career.
OK, definitely there are more interesting helicenes but we will take a break from this subject….I’m a bit tired…of the same….
Read more about Carbon-Sulfur Helicenes…
- Makoto Miyasaka, Andrzej Rajca, Maren Pink, Suchada Rajca, “Cross-Conjugated Oligothiophenes Derived from The (C2S)n Helix: Asymmetric Synthesis and Structure of Carbon-Sulfur Helicene“, J. Am. Chem. Soc., 2005, 127, 13806-13807 (Web Release Date: September 20, 2005), DOI:10.1021/ja55414c.
- Makoto Miyasaka and Andrzej Rajca, “Synthesis of a Short Carbon-Sulfur Helicene: Pd-Catalyzed Cross-Coupling at the β-Positions of Thiophenes”, Synlett (Cluster Issue, invited) 2004.177-182. [Abstract]
- Reyes Malavé Osuna, Rocío Ponce Ortiz, Víctor Hernández, Juan Teodomiro López Navarrete, Makoto Miyasaka, Suchada Rajca, Andrzej Rajca, Rainer Glaser, “Helically Annelated and Cross-Conjugated β-Oligothiophenes: An FT-Raman Spectroscopic and Quantum Chemical DFT Study“, J. Phys. Chem. C., 2007, 111, 4854 – 4860 (Web Release Date: January 18, 2007), DOI:10.1021/jp0677344. [animation]