For whatever reason, Marvel Studios and Sony Pictures decided to hold off on introducing the Sinister Six in Spider-Man: No Way Home. While Peter Parker, and his Variants, were pitted against five formidable villains, the sixth - Tom Hardy's Venom - was in Mexico getting drunk in a bar.
The most logical choice of bad guy to line up with the Green Goblin, Doctor Octopus, Electro, Sandman, and The Lizard would have been Jake Gyllenhaal's Mysterio. He was responsible for outing Spider-Man's secret identity as Peter Parker to the world and even claimed to be from another universe (while that was a fake story, it could have been retconned as real in this threequel).
In an interview with IGN (via Screen Rant), Spider-Man: No Way Home writer Chris McKenna confirmed that Jake Gyllenhaal was among the actors they reached out to. However, the decision was ultimately made that not everyone could appear here, so Quentin Beck was dropped.
"When it actually started coalescing, when feelers were put out and actors were like 'Yeah, I'm game for that.' Then it became this overwhelming thing because you're like, 'Okay, this is the reality now,'" he explains. "You can't just be swimming in a million characters, you have to be choosing characters wisely and making sure that they don't overwhelm the story and Peter himself."
Looking at Spider-Man: No Way Home, it would have been tough to squeeze Mysterio in there without sacrificing vital screentime for other characters. Sandman and The Lizard were already afterthoughts, and it might be better for Beck to return in a future movie where he can take centre stage. After all, he ruined Peter's life, so we're sure that one final battle between them would be epic.
Heck, if Spider-Man 6 will be all about the Sinister Six, then we'd vote for Mysterio as team leader!