I have noticed that some people go with the 6 button for players 3 and 4 but I don't remember many games that used then 2 buttons for a 4 player game(X-men being the exception).
Still in the planning stages
For MAME, none use more than 4 buttons and only a couple use 4. I personally would go with three buttons in a row for players 3-4, but many people would say go for four buttons in a 2x2 arrangement.
You might check out other emulators you want to use in your cabinet, some may use more than 4 buttons for players 3-4.