Sulfoxide ligand metal catalyzed oxidation of olefins
The enantioselective synthesis of isochroman motifs has been accomplished via Pd(II)-catalyzed allylic C—H oxidation from terminal olefin precursors. Critical to the success of this goal was the development and utilization of a novel chiral aryl sulfoxide-oxazoline (ArSOX) ligand. The allylic C—H oxidation reaction proceeds with the broadest scope and highest levels asymmetric induction reported to date (avg. 92% ee, 13 examples ≥90% ee). Additionally, C(sp 3 )-N fragment coupling reaction between abundant terminal olefins and N-triflyl protected aliphatic and aromatic amines via Pd(II)/sulfoxide (SOX) catalyzed intermolecular allylic C—H amination is disclosed. A range of 52 allylic amines are furnished in good yields (avg. 76%) and excellent regio- and stereoselectivity (avg. >20:1 linear:branched, >20:1 E:Z). For the first time, a variety of singly activated aromatic and aliphatic nitrogen nucleophiles, including ones with stereochemical elements, can be used in fragment coupling stiochiometries for intermolecular C—H amination reactions.
1. A compound of Formula I:
wherein
R a is H, alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
R b is alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
Q is alkyl, heteroalkyl, cycloalkyl, heterocycle, heteroaryl, phenanthryl, 2-naphthyl, 1-naphthyl provided that R 1 , R 2 , R 3 , or R 4 is not H, or Q is the moiety Q1:
R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 4 , and A 5 are each independently H, halo, alkyl, heteroalkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, cycloalkyl, aryl, or heteroaryl;
A 3 is H, halo, (C 3 -C 8 )alkyl, a heteroalkyl, a trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, cycloalkyl, aryl, or heteroaryl; and
each R x is independently H, (C 1 -C 8 )alkyl, or benzyl;
wherein at least one of R a and R b is cycloalkyl, heterocycle, aryl, or heteroaryl.
2. The compound of claim 1 wherein the sulfoxide moiety is in the (S)-configuration and the R a —C—R b moiety is in the (S)-configuration or in the (R)-configuration.
3. The compound of claim 1 wherein the sulfoxide moiety is in the (R)-configuration and the R a —C—R b moiety is in the (S)-configuration, or in the (R)-configuration.
4. The compound of claim 1 wherein:
R a is H, (C 1 -C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
R b is (C 1 -C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
Q is (C 1 -C 8 )alkyl, heteroalkyl, (C 3 -C 8 )cycloalkyl, or Q1;
R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 4 and A 5 are each independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
A 3 is H, halo, (C 3 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J; and
each J is independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, or (C 3 -C 8 )cycloalkyl.
5. The compound of claim 4 wherein:
R a is H, methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, tert-butyl, iso-butyl, cyclopentyl, cyclohexyl, phenyl, p-tolyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, or 4-trifluoromethoxyphenyl; and
R b is methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, tert-butyl, iso-butyl, cyclopentyl, cyclohexyl, phenyl, p-tolyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-tert-butylphenyl, 4-tert-butoxylphenyl, 3,4,5-trimethoxylphenyl, or 3,5-di-tert-butyl-4-methoxyphenyl.
6. The compound of claim 4 wherein Q is isopropyl, cyclohexyl, 4-methylcyclohexyl, phenyl, 4-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-tert-butylphenyl, 4-tert-butoxylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl, or 9-phenanthryl.
7. The compound of claim 4 wherein R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 4 and A 5 are each independently fluoro, chloro, bromo, methyl, ethyl, 2-propyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethoxy, nitro, trifluoromethyl, pentafluoroethyl, OR x , or N(R x ) 2 ;
A 3 is fluoro, chloro, bromo, ethyl, 2-propyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethoxy, nitro, trifluoromethyl, pentafluoroethyl, OR x , or N(R x ) 2 ; and
each R x is independently H, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, or benzyl.
8. The compound of claim 1 wherein the compound of Formula I is a compound of Formula II:
wherein
R b is (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 4 and A 5 are each independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
A 3 is H, halo, (C 3 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
each J is independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, or (C 3 -C 8 )cycloalkyl; and
the H—C—R b moiety is in the (S)-configuration and the sulfoxide moiety is in the (R)-configuration, or the H—C—R b moiety is in the (R)-configuration and the sulfoxide moiety is in the (S)-configuration.
9. The compound of claim 8 wherein the compound of Formula II is a compound of Formula III:
wherein
R 2 , R 3 , A 2 , A 4 , A 6 , A 7 , A 8 , and A 9 are each independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
A 3 is H, halo, (C 3 -C 8 )alkyl, trifluoromethyl, OR x , trifluoromethoxy, N(R x ) 2 , nitro, (C 3 -C 8 )cycloalkyl, or phenyl, wherein phenyl is optionally substituted with 1-5 substituents J;
each J is independently H, halo, (C 1 -C 8 )alkyl, trifluoromethyl, OR x , trifluoromethoxy, N(R x ) 2 , nitro, or (C 3 -C 8 )cycloalkyl; and
the dihydrooxazole moiety is in the (S)-configuration at position-4 and the sulfoxide moiety is in the (R)-configuration, or the dihydrooxazole moiety is in the (R)-configuration at position-4 and the sulfoxide moiety is in the (S)-configuration.
10. The compound of claim 1 wherein the compound is a compound of Formula IIA:
wherein R 9 is methoxy, t-butyl, or trifluoromethoxy.
11. The compound:
12. A compound of Formula IB:
wherein
R a is alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
R b is alkyl, heteroalkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
Q is alkyl, heteroalkyl, cycloalkyl, heterocycle, heteroaryl, phenanthryl, 2-naphthyl, 1-naphthyl provided that R 1 , R 2 , R 3 , or R 4 is not H, or Q is the moiety Q1:
R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , A 4 , and A 5 are each independently H, halo, alkyl, heteroalkyl, trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, cycloalkyl, aryl, or heteroaryl;
A 3 is H, halo, (C 2 -C 8 )alkyl, a heteroalkyl, a trifluoromethyl, trifluoromethoxy, OR x , N(R x ) 2 , nitro, cycloalkyl, aryl, heteroaryl, or methyl; and
each R x is independently H, (C 1 -C 8 )alkyl, or benzyl.
13. The compound of claim 12 wherein the compound of Formula I is a compound of Formula IV:
wherein
R a and R b are each independently methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, tert-butyl, iso-butyl, cyclopentyl, cyclohexyl, phenyl, 4-tolyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, or 4-trifluoromethoxyphenyl;
R 2 , R 3 , A 2 , A 3 , and A 4 are each independently, H, fluoro, chloro, bromo, methyl, ethyl, 2-propyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, trifluoromethoxy, nitro, trifluoromethyl, pentafluoroethyl, OR x , or N(R x ) 2 ; and
each R x is independently H, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, or benzyl.
14. The compound of claim 13 wherein the compound is a compound of Formula IVA:
wherein
R 11 and R 12 are each independently H, methoxy, trifluoromethyl, or trifluoromethoxy;
R 13 is methyl or phenyl; and
R 14 is methyl, methoxy, or phenyl.