Methods for preparing diazonamides

1. A method for the preparation of a compound of the formula (3a):

wherein R 1 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6 aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted;

each R 2 is independently H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted;

R 6 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted; and

Y is H, or halo, —OH, or —OR 10 , where R 10 is optionally fluorinated C1-C4 alkyl, C2-C4 alkenyl, C6-C14 arylalkyl, optionally fluorinated alkylsulfonyl, arylsulfonyl, optionally fluorinated C1-C6 acyl, or C6-C10 aroyl, each of which may be optionally substituted;

said method comprising the steps of:

(a) contacting a compound of formula (2a):

with an indole of the formula:

optionally in the presence of a protic acid, to provide a mixture;

wherein R 1 , R 2 , R 6 , and Y are as defined for formula (3a);

(b) adding an activating reagent to said mixture; and

(c) optionally heating said mixture to provide the compound of formula (3a).

2. The method according to claim 1 , comprising the steps of:

(a) contacting the compound of formula (2a) with the indole in a protic acid which is acetic acid, to provide a mixture;

(b) adding an activating reagent which is acetic anhydride to said mixture; and

(c) heating said mixture at about 80° C. to provide the compound of formula (3a).

3. A compound having the structure:

R 4 is H, or C1-C4 alkyl;

R 5 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted; or

R 4 and R 5 may be taken together with nitrogen to form an imine, or an optionally substituted 3-8 membered monocyclic azacyclic ring or 8-12 membered bicyclic fused azacyclic ring, each of which may contain 0-2 additional heteroatoms selected from N, O, and S as ring members;

R 6 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted;

R 8 is H, or C1-C8 alkyl, C2-C8 alkenyl, C5-C6 aryl, C6-C14 arylalkyl, or trialkylsilyl;

each of Y and Y′ is independently H, or halo, —OH, or —OR 10 , where R 10 is optionally fluorinated C1-C4 alkyl, C2-C4 alkenyl, C6-C14 arylalkyl, optionally fluorinated alkylsulfonyl, arylsulfonyl, optionally fluorinated C1-C6 acyl, or C6-C10 aroyl, each of which may be optionally substituted; and

n is 1 or 2.

4. The compound of claim 3 wherein R 5 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, arylsulfonyl, or trialkylsilyl, or each of which may be optionally substituted.

5. The compound of claim 3 wherein R 5 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, arylsulfonyl, or trialkylsilyl.

6. The compound of claim 3 wherein R 5 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl.

7. A method for the preparation of a compound of formula (I):

or a salt thereof;

wherein R 1 is H, or C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C6 aryl, C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted;

R 2 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted; or

R 1 and R 2 may be taken together with the atoms to which they are attached to form a 5-or 6-member ring containing one nitrogen atom;

R 3 is H, or —NR 4 R 5 ;

R 4 is H, or C1-C4 alkyl;

R 5 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted; or —C(═X)R′ where X is O, S, or NH, and R′ is optionally fluorinated C1-C8 alkyl, C2-C8 alkenyl, C5-C12 aryl, or C6-C14 arylalkyl, each of which may be optionally substituted; or

R 4 and R 5 may be taken together with nitrogen to form an imine, or an optionally substituted 3-8 membered monocyclic azacyclic ring or 8-12 membered bicyclic fused azacyclic ring, each of which may contain 0-2 additional heteroatoms selected from N, O, and S as ring members;

R 6 is H, or C1-C8 alkyl, C1-C8 heteroalkyl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, optionally fluorinated C1-C6 acyl, C6-C12 aroyl, arylsulfonyl, trialkylsilyl, or alkoxycarbonyl, each of which may be optionally substituted;

R 7 is H, or halo, —CN, optionally substituted C1-C6 acyl, —COOR 8 , or —C(O)NR 9 2 ;

R 8 is H, or C1-C8 alkyl, C2-C8 alkenyl, C5-C6 aryl, C6-C14 arylalkyl, or trialkylsilyl; and

each R 9 is independently H, or C1-C8 alkyl, C2-C8 alkenyl, C5-C6 aryl, C6-C14 arylalkyl, C6-C14 heteroarylalkyl, —OH, or C1-C4 alkoxy, each of which may be optionally substituted; or two R 9 on the same N can optionally cyclize to form a ring; and

each of Y and Y′ is independently H, or halo, —OH, or —OR 10 , where R 10 is optionally fluorinated C1-C4 alkyl, C2-C4 alkenyl, C6-C14 arylalkyl, optionally fluorinated alkylsulfonyl, arylsulfonyl, optionally fluorinated C1-C6 acyl, or C6-C10 aroyl, each of which may be optionally substituted;

said method comprising electrochemical oxidation of a compound of formula (II):

in which the radicals R 1 , R 2 , R 3 , R 6 , R 7 , Y, and Y′ are as defined for formula (I),

and optionally further comprising a step of converting the compound of formula (I) to a diazonamide analog also of formula (I) except that R7 and Y are further reacted and linked.

8. The method of claim 7 wherein R7 and Y of the diazonamide analog form a linkage comprising an oxazole-linked indole.

9. The method of claim 7 , wherein R7 and Y are further reacted to form an oxazole-linked indole, and the diazonamide analog is of formula 16b: