Process for the cycloaddition of a halogenated 1,3-dipole compound with a (hetero)cycloalkyne

A process comprising reacting a halogenated 1,3-dipole compound with a (hetero)cyclooctyne,

• wherein the halogenated 1,3-dipole compound is defined according to Formula (2):
• Z—[Ce(R4)f(R12)(2e-f)]—(W)g-(L′)t(A′)u 2
• wherein:
• t is 1;
• u is 1-4;
• Z is a 1,3-dipole functional group;
• L′ is a linker;
• A′ is a glycoprotein or an, optionally substituted, saccharide moiety;
• R4 is independently selected from the group consisting of F, Cl, Br and I and —CyR13(2y+1), wherein y is 1-6 and R13 is selected from the group consisting of F, Cl, Br and I;
• R12 is independently selected from the group consisting of hydrogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, wherein the alkyl groups, cycloalkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, and wherein the alkyl groups, cycloalkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N;
• e is 1-10;
• f is 1-2e;
• g is 0 or 1;
• and
• W is selected from the group consisting of C1-C24 alkylene groups, C2-C24 alkenylene groups, C3-C24 cycloalkylene groups, C2-C24 (hetero)arylene groups, C3-C24 alkyl(hetero)arylene groups and C3-C24 (hetero)arylalkylene groups, wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally substituted, and wherein the alkylene groups, alkenylene groups, cycloalkylene groups, (hetero)arylene groups, alkyl(hetero)arylene groups and (hetero)arylalkylene groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N,
• wherein the 1,3-dipole functional group is bonded to an sp3 C-atom, and at least one of the one or more substituents R4 is bonded to that same sp3 C-atom;
• and wherein the (hetero)cyclooctyne is according to Formula (1):
• wherein:
• a is 0, 1, 2, 3 or 4;
• a′ is 0, 1, 2, 3 or 4;
• a″ is 0, 1, 2, 3 or 4;
• with the proviso that a+a′+a″=4;
• n is 0-8;
• R1 is independently selected from the group consisting of oxo, halogen, —OR2, —NO2, —CN, —S(O)2R2, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups, wherein the alkyl groups, cycloalkyl groups, (hetero)aryl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally substituted, wherein the alkyl groups, cycloalkyl groups, alkyl(hetero)aryl groups and (hetero)arylalkyl groups are optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and N, and wherein R2 is independently selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C3-C24 cycloalkyl groups, C2-C24 (hetero)aryl groups, C3-C24 alkyl(hetero)aryl groups and C3-C24 (hetero)arylalkyl groups;
• B and B′ are independently selected from the group consisting of O, S, C(O), NR3 and C(R3)2, wherein R3 is independently selected from the group consisting of hydrogen, R1 or (L)p-(A)r;
• optionally, when n is 2 or more, two R1 groups may together form a (hetero)cycloalkyl group, the (hetero)cycloalkyl group optionally being substituted with an (L)p-(A)r substituent;
• optionally, when n is 2 or more, two R1 groups may together form a (hetero)aryl group, the (hetero)aryl group optionally being substituted with an (L)p-(A)r substituent;
• p is 0 or 1;
• r is 1-4;
• L is a linker;
• A is independently selected from the group consisting of D, E or Q, wherein D, E and Q are as defined below;
• q is 0-4;
• with the proviso that if q is 0, then B and/or B′ is NR3 wherein R3 is (L)p-(A)r, and/or B and/or B′ is C(R3)2 wherein one or more R3 is (L)p-(A)r, and/or n is 2 or more and two R1 groups together form a (hetero)cycloalkyl group wherein the (hetero)cycloalkyl group is substituted with an (L)p-(A)r substituent, and/or n is 2 or more and two R1 groups together form a (hetero)aryl group wherein the (hetero)aryl group is substituted with an (L)p-(A)r substituent;
• D is a molecule of interest;
• E is a solid surface;
• and
• Q is a functional group.