US2016039827A1PendingUtilityA1
Activation of carbonyl beta-carbons for chemical transformations
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
C07D 307/36C07C 201/12C07C 2601/10C07D 207/50C07D 207/26C07D 207/28C07D 409/04C07D 333/06C07D 307/33C07D 487/04
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Claims
Abstract
The present invention relates to a method for synthesizing a compound of Formula (I) as defined herein, comprising: (i) activating a compound of Formula (II) as defined herein, by reacting said compound of Formula (II) with a compound of Formula (III) as defined herein, in the presence of a base, to obtain a compound of Formula (IV) as defined herein; and (ii) reacting the compound of Formula (IV) with an electrophile to obtain the compound of Formula (I). The present invention further relates to the organocatalysts used in the described methods and their respective uses.
Claims
exact text as granted — not AI-modified1 . Method for synthesizing a compound of Formula (I)
wherein
is a single or a double bond, wherein if it is a double bond n is 1 and if it is a single bond n is 2;
each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —OH, —OOH, —NH 2 , —NO 2 , —ONO 2 , —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO 2 OH, —CONH 2 , —NH—NH 2 , —NC, —CSH, or any organic moiety;
B is an electrophilic group; and
NHC + is
comprising:
(i) activating a compound of Formula (II)
wherein
LG is a leaving group;
by reacting said compound of Formula (II) with a compound of Formula (III) in the presence of a base
wherein
R 3 , R 4 , and R 5 are independently from each other selected from the group consisting of hydrogen, halogen, —OH, —OOH, —NH 2 , —NO 2 , —ONO 2 , —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO 2 OH, —CONH 2 , —NH—NH 2 , —NC, —CSH, or any organic moiety;
to obtain a compound of Formula (IV)
and
(ii) reacting the compound of Formula (IV) with an electrophile to obtain the compound of Formula (I).
2 . Method according to claim 1 , wherein the organic moiety is independently selected from the group consisting of linear or branched, substituted or unsubstituted C 1 -C x alkyl; linear or branched, substituted or unsubstituted alkenyl with 2 to x carbon atoms; linear or branched, substituted or unsubstituted alkinyl with 2 to x carbon atoms; linear or branched, substituted or unsubstituted alkoxy with 1 to x carbon atoms; substituted or unsubstituted cycloalkyl with 3 to x carbon atoms; substituted or unsubstituted cycloalkenyl with 3 to x carbon atoms; substituted or unsubstituted aryl with 6 to x carbon atoms; and substituted or unsubstituted heteroaryl with 3 to x carbon atoms; with x being any integer of 2 or more, preferably up to 50, more preferably up to 30.
3 . Method according to claim 1 or 2 , wherein R 3 and R 4 combine to form together with the carbon atoms to which they are attached a substituted or unsubstituted 5- to 40-membered cycloalkyl, cycloalkenyl, heteroalicyclic, aryl, or heteroaryl ring.
4 . Method according to claim 3 , wherein compound of Formula (III) is a compound of Formula (V)
wherein
R 6 is hydrogen, halogen, —OH, —OOH, —NH 2 , —NO 2 , —ONO 2 , —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO 2 OH, —CONH 2 , —NH—NH 2 , —NC, —CSH, or any organic moiety.
5 . Method according to claim 4 , wherein R 6 is selected from the group consisting of substituted or unsubstituted, linear or branched alkyl with 1 to 20 carbon atoms; substituted or unsubstituted, linear or branched alkenyl with 1 to 20 carbon atoms; substituted or unsubstituted cycloalkyl with 5 to 20 carbon atoms; substituted or unsubstituted cycloalkenyl with 5 to 20 carbon atoms; substituted or unsubstituted aryl with 5 to 14 carbon atoms; and substituted or unsubstituted heteroaryl with 5 to 14 carbon atoms.
6 . Method according to claim 5 , wherein R 6 is selected from the group consisting of -iso-Pr, -tert-Bu, —CH 2 Ph, —CH 2 -iso-Pr, and —CH 2 -tert-Bu.
7 . Method according to claim 6 , wherein R 6 is selected from the group consisting of —CH 2 -tert-Bu and —CH 2 -iso-Pr.
8 . Method according any one of claims 4 to 7 , wherein R 5 is a substituted or unsubstituted aryl.
9 . Method according to claim 8 , wherein R 5 is selected from the group consisting of phenyl and mesitylene.
10 . Method according to claim 9 , wherein R 5 is phenyl.
11 . Method according to any one of claims 4 to 10 , wherein the compound of Formula (V) is selected from the group consisting of
12 . Method according to any one of claims 1 to 11 , wherein the compound of Formula (III) or (V) is synthesized from a compound of Formula (VI)
wherein
X is any anion.
13 . Method according to claim 12 , wherein X is selected from the group consisting of F − , Cl − , Br − , I − , BF 4 − , OTf − , and acetate.
14 . Method according to claim 12 or 13 , wherein the compound of Formula (VI) is a compound of Formula (VII)
15 . Method according to any one of claims 12 to 14 , wherein the compound of Formula (VII) is selected from the group consisting of
16 . Method according to any one of claims 1 to 15 , wherein the compound of Formula (III) or Formula (V) according to any one of claims 1 to 11 is generated in situ from a compound according to claims 12 to 15 .
17 . Method according to any one of claims 1 to 16 , wherein the leaving group is selected from the group consisting of hydrogen, halogen, —N 2 + , —OR 2 + , —OSO 2 C 4 F 9 , —OSO 2 CF 3 , —OSO 2 F, —OTs, —OMs, —OH 2 + , —OHR + , —ONO 2 , —OPO(OH) 2 , —SR 2 , —NR 3 , —OCOR, —NH 3 + , and —O—C 6 H 4 -para-NO 2 , and R can be any organic residue.
18 . Method according to claim 17 , wherein the leaving group is —O—C 6 H 4 -para-NO 2 .
19 . Method according to claims 1 to 18 , wherein the method is carried out in a solvent selected from the group consisting of tert-Butanol, toluene, THF, CH 3 CN, CH 2 Cl 2 , dioxane, ethyl acetate, and mixtures thereof.
20 . Method according to any one of claims 1 to 19 , wherein the base is present in an amount of 100 to 300 mol-% based on the total amount of the compound of Formula (I).
21 . Method according to claim 20 , wherein the base is present in an amount of 115 to 250 mol-% based on the total amount of the compound of Formula (I).
22 . Method according to claim 20 or 21 , wherein the base is present in an amount of 130 to 200 mol-% based on the total amount of the compound of Formula (I).
23 . Method according to any one of claims 20 to 22 , wherein the base is present in an amount of about 150 mol-% based on the total amount of the compound of Formula (I).
24 . Method according to any one of claims 1 to 23 , wherein the electrophile is selected from the group consisting of F 2 , Cl 2 , Br 2 , I 2 , alkyl-LG, alkenyl-LG, alkoxy-LG, acyl-LG, aryl-LG, heteroaryl-LG, hydrazone, and a carbonyl compound, wherein LG is a leaving group.
25 . Method according to claim 24 , wherein the electrophile is selected from the group of optionally α,β-unsaturated, linear or branched, substituted or unsubstituted ketone; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted aldehyde; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted esters; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted trifluoroketone; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted carboxamide; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted amide; optionally α,β-unsaturated, linear or branched, substituted or unsubstituted nitrile; and optionally α,β-unsaturated, linear or branched, substituted or unsubstituted hydrazone.
26 . Method according to claim 24 or 25 , wherein the electrophile is selected from the group consisting of α,β-unsaturated, linear or branched, substituted or unsubstituted ketone, trifluoroketone, and hydrazone.
27 . Method according to any one of claims 1 to 26 , wherein the base contains one or more nitrogen atom(s).
28 . Method according to claim 27 , wherein the base is selected from the group consisting of pyrrolidine; N(CH 3 ) 3 ; N(CH 2 CH 3 ) 3 ; (iso-Propyl) 2 NH; 2,2,6,6-Tetramethyl-1-piperidin; LDA (Lithium diisopropylamid); LHMDS (Lithium bis(trimethylsilyl)amide); LTMP (Lithium tetramethylpiperidide); and 4-aminopyridine.
29 . Method according to claim 27 , wherein the base is an amidine.
30 . Method according to claim 29 , wherein the amidine is selected from the group consisting of DBU (1,8-Diazabicyclo[5.4.0]undec-7-en), DBN (1,5-Diazobicyclo[3.4.0]non-5-ene); and DABCO (1,4-Diazobicyclo[2.2.2]octan).
31 . Method according to claim 27 , wherein the base is a phosphazine.
32 . Method according to claim 31 , wherein the phosphazine is selected from the group consisting of P 1 -tert-Bu-tris(tetramethylene); 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine; and 1-Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ 5 ,4λ 5 -catenadi(phosphazene).
33 . Method according to any one of claims 1 to 32 , wherein the reaction temperature of steps (i) and (ii) is from 0° C. to 85° C.
34 . Method according to claim 33 , wherein the reaction temperature of steps (i) and (ii) is from 15° C. to 55° C.
35 . Method according to claim 33 or 34 , wherein the reaction temperature of steps (i) and (ii) is about 25° C.
36 . Method according to any one of claims 1 to 35 , wherein the reaction time is from 0.1 hours to 72 hours.
37 . Method according to claim 36 , wherein the reaction time is from 1 hour to 48 hours.
38 . Method according to claim 36 or 37 , wherein the reaction time is from 5 hours to 36 hours.
39 . Method according to any one of claims 36 to 38 , wherein the reaction time is about 24 hours.
40 . Method according to any one of claims 1 to 39 , wherein a molecular sieve is present during the reaction.
41 . Method according to claim 40 , wherein the molecular sieve has apertures of a size of approximately 4 Å.
42 . Method according to any one of claims 1 to 41 , wherein the method comprises further reaction steps selected from catalyst regeneration, michael reaction, aldol reaction, lactonization, and/or decarboxylation.
43 . Compound of Formula (VI)
or Formula (VII)
wherein R 3 , R 4 , R 5 , and R 6 are independently from each other selected from the group consisting of hydrogen, halogen, —OH, —OOH, —NH 2 , —NO 2 , —ONO 2 , —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO 2 OH, —CONH 2 , —NH—NH 2 , —NC, —CSH, or any organic moiety; and
X is any anion.
44 . Compound according to claim 43 , wherein the compound is selected from the group consisting of
wherein
X is any anion.
45 . Compound of claim 43 or 44 , wherein X is selected from the group consisting of F − , Cl − , Br − , I − , BF 4 − , OTf − , and acetate.
46 . Use of a compound of Formula (VI) and (VII) according to any one of claims 43 to 45 for activating a compound of Formula (II)
wherein
is a single or a double bond, wherein if it is a double bond n is 1 and if it is a single bond n is 2;
each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —OH, —OOH, —NH 2 , —NO 2 , —ONO 2 , —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO 2 OH, —CONH 2 , —NH—NH 2 , —NC, —CSH, or any organic moiety; and
LG is a leaving group.Join the waitlist — get patent alerts
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