Villarreal held by second-tier Celta
Celta's bright start in driving rain at their Balaidos stadium belied their position of 18th out of 22 in the second-tier standings but they were rocked back by a Villarreal goal in the 12th minute.
Cani sent Giuseppe Rossi clear and the Italian striker finished comfortably past goalkeeper Yoel Rodriguez.
Celta battled bravely against their more skilful opponents and were rewarded a minute before halftime when forward Arthuro Bernhardt headed a Roberto Trashorras free kick past Villarreal keeper Diego Lopez.
Holders Barcelona slipped to a 2-1 home defeat by 2007 winners Sevilla in their first leg at the Nou Camp on Tuesday, Alvaro Negredo netting the winner from the penalty spot after Zlatan Ibrahimovic had cancelled out Diego Capel's opener.
Third-tier Alcorcon, who knocked out Real Madrid 4-1 on aggregate in the last round, play Racing Santander later on Wednesday, La Liga heavyweights Valencia and Deportivo La Coruna clash at the Mestalla and second division Recreativo Huelva host Atletico Madrid.
Getafe play at Malaga in Thursday's only top-flight clash and Real Mallorca and Osasuna take on second division sides Rayo Vallecano and Hercules.
The return legs are next week.