[zarhym]

I was doing a 4+3 cyclization reaction using cyclopentadiene(see attachment). Although I followed the procedures on the literature( 10.1021/ja201901d ), the yield was unstable. The best yield I had was about 80%, while the worst about 15%. I have double checked every parameter such as reaction temperature, time, mixing and the purity of reactants and reagents. It seems the yield of this reaction was independent on any of these.

The only difference between the good and bad reactions was the stabilizer of the cyclopentadiene dimer. I was not convinced that the stabilizer in cyclopentadiene dimer made the difference of the reaction since the cyclopentadiene was cracked and then distillated from its dimer. However, after I tried adding trace amount of 4-tert-Butylcatechol as addictive in my reaction, the yield became stable at about 50%.

I have little knowledge to explain this phenomenon. I guess that 4-tert-Butylcatechol was able to quench the radical of cyclopentadiene, stopping it from forming oligomers or even polymers, resulting cleaner reaction. 

Do you guys have any knowledge or experience about this? Is there a better way to avoid the problem and achieve higher yield?

Low yield made my life miserable when I have to work up this reaction.

[TheUnassuming]

Have you been able to characterize any of the side products that are formed?

[pgk]

1). Apart the polymerization, cyclopentadiene also forms cyclopentadienol and cyclopentadienone by allylic oxidation in air, which are further dimerized, trimerized, polymerized, etc., in situ. Cyclopentadiene’s allylic oxidation is slow in air but quite enough to decrease the yield of your reaction.
So, you work in inert atmosphere (N2 or Ar) and you add BHT at 0.5-1% w/w, at least. Note that BHT is more effective antioxidant than the BHA that you have used.
2). Cycloaddition reactions are sensible to steric hindrance. So, don’t expect such high yields as in the cited publication that starts from secondary halide moieties because you have tertiary bromide moieties, as drawn in your post. 

[zarhym]

Have you been able to characterize any of the side products that are formed?

There are two major side products I found in this reaction (see attachment).

The side product 1 has very similar polarity and difficult to remove through flashcolumn. HNMR indicates it has the same aromatic hydrogens as well as the hydrogens in the R groups, but different chemical shift of the alkene hydrogens. (I am not sure whether my boss will allow me to give further information about this structure.) The side product 1 does not have obvious molecular ion peak in our LCMS. (I guess I should blame the decades-old instruments in our department.) Because of this side product, I have to purify the crude through column twice, then a recrystallization to obtain the desired. I guess the yield is reduced significantly due to this painful process.

The side product 2 was found in LCMS. I didn't purify this one since it does not cause problems in purification.

The ratio of my desire product/ side product 1/ side product 2 was about 6:2:1 on HPLC. By the way, the intermediate in the drawing can be monitored through quenching the reaction with MeOH. The a methoxy group can be found attached to the intermediate on LCMS. I used this method to ensure the completion of the reaction.   

[zarhym]

1). Apart the polymerization, cyclopentadiene also forms cyclopentadienol and cyclopentadienone by allylic oxidation in air, which are further dimerized, trimerized, polymerized, etc., in situ. Cyclopentadiene’s allylic oxidation is slow in air but quite enough to decrease the yield of your reaction.
So, you work in inert atmosphere (N2 or Ar) and you add BHT at 0.5-1% w/w, at least. Note that BHT is more effective antioxidant than the BHA that you have used.
2). Cycloaddition reactions are sensible to steric hindrance. So, don’t expect such high yields as in the cited publication that starts from secondary halide moieties because you have tertiary bromide moieties, as drawn in your post.

Thank you for these suggestions. I will keep these in mind and give them a try if possible.

[TheUnassuming]

Hrmm, not sure how you can avoid byproduct 1 other than maybe increasing the equiv of diene to try to speed up the reaction, or trying slightly different conditions to see if you can stabilize the desired intermediate a little.  I've never run one of these, how fast are they usually?

Byproduct 2 might be cut down a little if you can find conditions to increase the rate of formation of your desired product.  Have you tried adding AgX or similar LA's?  Though, just dawned on me that adding more diene to avoid #1 might increase your #2. 

As pgk mentioned, you do have a fairly sterically hindered substrate, so even after fine-tuning you probably won't get an amazing yield.

Good luck and let us know how it goes!

[pgk]

Diels Alder rection can be accelerated by AlCl3 catalysis. In your case, the synergism of acidic (AlCl3) and basic (TEA) catalysis might favor the formation of the desired product vs. the byproduct 1. Besides, you will not need an excess of cyclopentadiene for the reaction acceleration and thus, the formation of byproduct 2, would be avoided, as TheUnassuming indicated above.
Try this with a little amount of reagents, just in order to check the yield by HPLC. It might work.
1). Acceleration of the Diels-Alder reaction by aluminum chloride, J. Am. Chem. Soc., 1960, 82 (16), pp 4436-4437
http://pubs.acs.org/doi/abs/10.1021/ja01501a085
2). [AlCl3 + 2THF]:  A New and Efficient Catalytic System for Diels-Alder Cycloaddition of α,β-Unsaturated Carbonyl Compounds under Solvent-Free Conditions, Org. Lett., 2006, 8 (12), pp 2487-2489
http://pubs.acs.org/doi/abs/10.1021/ol060569q
3). AlCl3 catalyzed oxa-Diels-Alder reaction of aromatic aldehydes with simple diene, Tetrahedron, 2017, 73 (29), pp 4039-4044
http://www.sciencedirect.com/science/article/pii/S0040402016310936

[rolnor]

Would not the AlCl3 and TEA form adduct?

[pgk]

I have worked with such a kind of catalysis in the past; but not with Diels-Alder reactions. Anyway, synergistic catalysis by Lewis acid/tertiary amine worked perfectly with my chemicals at that time. Probably, AlCl3 and TEA form a “Lewis salt” that exists in equilibrium between adduct and non-adduct form.

[pgk]

Theoretically, there is a risk of Friedel-Crafts alkylation/acylation, as well as cleavage of aromatic alkyl ether groups under AlCl3 catalysis. However, these reactions demand long reaction times and equimolar amounts of catalyst, in contrast to Diels-Alder reaction that is claimed to quickly occur with catalytic amounts of AlCl3. Moreover, “synergistic” catalysis will further accelerate the Diels-Alder reaction to even shorter reaction times.

[rolnor]

I think you need free TEA to pick the HBr from the startingmaterial, the adduct with AlCl3 is not basic enough.

[pgk]

Theoretically, AlCl3 will bind with the carbonyl group and favor the desired dehydrobromination versus the alkene forming one. By its turn, AlCl3 attachment on the carbonyl, will affect the adduct/non-adduct equilibrium and will favor the free TEA form, and so on.
But all above is a hypothesis. Organic chemistry is an experimental science and thus, only the experiment can justify the correctness of hypotheses.

[kriggy]

Also, I think you could use different lewis acids than AlCl3. Might give different results as well

[pgk]

e.g. BBr3:
1). Azetidine based ligands in boron catalyzed asymmetric Diels-Alder reactions, Tetrahedron, (1998), 54(19), 4991-5004
http://www.sciencedirect.com/science/article/pii/S004040209800204X
2). Asymmetric Diels-Alder reaction of 1,3-butadienes with (−)-dimenthyl fumarate in the presence of BBr3 and BBr3·OEt2, Russian Journal of Organic Chemistry, (2007), 43(2), 184-187
https://link.springer.com/article/10.1134/S1070428007020054
3). Enantioselective Formal Aza-Diels–Alder Reactions of Enones with Cyclic Imines Catalyzed by Primary Aminothioureas, J. Am. Chem. Soc., (2013), 135(5), 1891-1894
http://pubs.acs.org/doi/abs/10.1021/ja310718f
etc…
But for the moment, let’s start with AlCl3, if synergistic catalysis is desired.