I would really like it to come in the beginning of the Human-Covenant War, just to show the brutally and hopelessness that humanity faced in the beginning. Reach showed that too, but you knew the Covenant would lose and you were successful in your mission to deliver Cortana. But I would LOVE a heart-wrenching game where you fail in everything. Even your last mission, the most important one. You fail in that too. It'd be a depressing game, but that's honestly what I would enjoy playing.
Ngl though, to have a game set in between 3 and 4 would be cool because then 343 could really flesh out the conflicts between the new Spartan 4s and the ODSTs. The Spartan Handbook hinted that some ODSTs think that new Spartan IV's have "switched sides" and now dislike them. That'd be really interesting to see play out in a game, or a book even.