product 74 , which contains the secondary amine required for coupling with
the other major fragment.
Synthesis of the second heterocyclic fragment begins with the conden-
sation of phenylglyoxal oxime ( 75 ) with guanidine to form the pyrazine
N-oxide ( 76 ). Treatment with triethylphosphine reduces the N-oxide func-
tion leading to pyrazine ( 77 ). The amino group is next treated with nitrous
acid and the resulting diazonium salt reacted with hydrogen bromide to
afford the brominated derivative ( 78 ). Reaction of 78 with ethyl thioglyco-
late in the presence of sodium carbonate arguably begins by displacement
of bromine by sulfur to form the transient thioether ( 79 ). Addition of the
enolate on carbon adjacent to the ester then attacks the cyano group to
form the fused thiophene ring 80. The newly formed amine on the thio-
phene ring is then converted to the corresponding isocyanate ( 81 ), by reac-
tion with phosgene.
O
NOH
75
H 2 N NH 2
NH
N
N
O
CN
NH 2
76
P(OC 2 H 5 ) 3
N
N CN
NH 2
77
HONO
HBr N
N CN
Br
N
N
S
NH 2
CO 2 C 2 H 5
N
N CN
HS
CO 2 C 2 H 5
S
CO 2 C 2 H 5
78
80 79
N
N
S
N=C=O
CO 2 C 2 H 5
81
COCl 2
Na 2 CO 3
There remains the task of joining together the two heterocyclic frag-
ments. To this end the free secondary amino group on the benzoxazine ( 74 )
N
N
S
O=C=N
C 2 H 5 O 2 C
81
O
OCH 3 NH
74
1.Br CN
- Ni
O
OCH 3 N
NH 2
N
N
S
NH
C 2 H 5 O 2 C
O
OCH 3 N
HN
O
83
N
N
S
NH
N
O
O
O
OCH 3
N
84
82
226 POLYCYCLIC FUSED HETEROCYCLES