Could you please mention the device you are using?
I actually found the problem after way to mutch time.
When the debugging session is active, the debugger adds some delay to the start of the software.
This is really minor but it was enought, that the I2C didn't work without that extra delay. (The Bus-Busy flag was always set)
Now i added a delay in software between the start of the I2C initialization and the first data transmission and it works perfectly fine.
Device in use: MB9BF164KPMC