Alkoxyalkylation of Electron-Rich Aromatic Compounds
Abstract
:1. Introduction
2. Hydroxy- and Alkoxyalkylation of Electron-Rich Arenes: Direct and Catalytic Methods
2.1. Hydroxy- and Alkoxymethylation of Monocylic Arenes
2.2. Hydroxy- and Alkoxymethylation of Phenol-Fused Carbocycles
2.3. Hydroxy- and Alkoxymethylation of N-heterocycles
2.3.1. Hydroxy- and Alkoxymethylation of Indoles
2.3.2. Hydroxy- and Alkoxymethylation of Uracil
3. Hydroxy- and Alkoxyalkylation of Electron-Rich Arenes via Aminoalkyl Intermediates
3.1. Transformations of Phenolic Mannich Bases
3.2. Transformations of Semi-Synthetic Phenols and N-heterocycles
3.2.1. Transformations of Phenol-Fused Molecules
3.2.2. Transformations of N-heterocycles
4. Conclusions and Outlook
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
BAM | bisarylmethylene |
BINOL | 1,1′-bi-2-naphthol |
BDMS | bromodimethylsulfonium bromide |
BODIPY | dipyrrometheneboron difluoride |
BPR | boron-modified phenolic resin |
BSA | bovine serum albumin |
DCM | dichloromethane |
EDG | electron donating group |
MOM | methoxymethyl |
MPM | p-methoxybenzyl |
PPTS | pyridinium p-toluenesulfonate |
pTSA | p-toluenesulfonic acid |
QM | quinone methide |
(R)-TRIP | (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate |
TBSO | tert-butyl-dimethylsilyloxy |
TRIS | tris(hydroxymethyl)aminomethane, tromethamine |
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Entry | R1 | R2 | R3 | R4 | Product | Conditions | Yield | Reference |
---|---|---|---|---|---|---|---|---|
1 | H | H | H | H | 2aa | DME/xylene, 135 °C | 66 | [26] |
2 | H | H | H | H | 2aa | NaBO2, H2O, 40 °C | 93 | [27] |
3 | Me | H | H | H | 2ab | DME/xylene, 135 °C | 77 | [26] |
4 | Me | H | H | H | 2ab | NaBO2, H2O, 40 °C | 87 | [27] |
5 | H | H | Me | H | 2ac | DME/xylene, 135 °C | 92 | [26] |
6 | H | H | Me | H | 2ac | NaBO2, H2O, 40 °C | 90 | [27] |
7 | H | H | i-Bu | H | 2ad | DME/xylene, 135 °C | 85 | [26] |
8 | Ph | H | H | H | 2ae | DME/xylene, 135 °C | 65 | [26] |
9 | cyclohexyl | H | H | H | 2af | DME/xylene, 135 °C | 85 | [26] |
10 | Me | H | Me | H | 2ag | DME/xylene, 135 °C | 92 | [26] |
11 | H | Me | Me | H | 2ah | DME/xylene, 135 °C | 95 | [26] |
12 | t-Bu | H | H | Me | 2ai | DME/xylene, 135 °C | 95 | [26] |
13 | H | H | Ph | H | 2aj | NaBO2, H2O, 40 °C | 95 | [27] |
14 | H | H | t-Bu | H | 2ak | NaBO2, H2O, 40 °C | 86 | [27] |
15 | H | H | Et | H | 2al | NaBO2, H2O, 40 °C | 89 | [27] |
16 | F | H | H | H | 2am | NaBO2, H2O, 40 °C | 85 | [27] |
17 | H | H | F | H | 2an | NaBO2, H2O, 40 °C | 90 | [27] |
18 | F | F | H | H | 2ao | NaBO2, H2O, 40 °C | 90 | [27] |
19 | F | H | H | F | 2ap | NaBO2, H2O, 40 °C | 92 | [27] |
20 | H | H | Cl | H | 2aq | NaBO2, H2O, 40 °C | 80 | [27] |
21 | H | H | Cl | H | 2aq | DME/xylene, 135 °C | 67 | [26] |
22 | H | Cl | H | H | 2ar | NaBO2, H2O, 40 °C | 90 | [27] |
23 | H | H | Br | H | 2as | DME/xylene, 135 °C | 69 | [26] |
24 | H | H | Br | H | 2as | NaBO2, H2O, 40 °C | 83 | [27] |
25 | H | Br | H | H | 2at | NaBO2, H2O, 40 °C | 91 | [27] |
26 | H | H | I | H | 2au | DME/xylene, 135 °C | 70 | [26] |
27 | H | H | OMe | H | 2av | DME/xylene, 135 °C | 66 | [26] |
28 | H | H | OMe | H | 2av | NaBO2, H2O, 40 °C | 90 | [27] |
29 | OMe | H | H | H | 2aw | NaBO2, H2O, 40 °C | 88 | [27] |
30 | OMe | H | H | H | 2ax | H-mordenite, 80 °C, water/methanol | 70 | [28] |
31 | H | H | OBn | H | 2ay | NaBO2, H2O, 40 °C | 83 | [27] |
32 | H | H | OH | H | 2az | DME/xylene, 135 °C | 59 | [26] |
33 | i-pentyl | H | OH | H | 2ba | DME/xylene, 135 °C | 61 | [26] |
Entry | R | R1 | R2 | R3 | R4 | Product | Conditions | Yield | Reference |
---|---|---|---|---|---|---|---|---|---|
1 | Bu | Me | OH | H | H | 17a | DME/xylene, 135 °C | 66 | [38] |
2 | -CCl3 | H | H | H | H | 17b | Toluene, 4 h, 15 °C | 96 | [39] |
3 | -CCl3 | H | H | Me | H | 17c | Toluene, 4 h, 15 °C | 97 | [39] |
4 | -CCl3 | H | H | t-Bu | H | 17d | Toluene, 4 h, 15 °C | 97 | [39] |
5 | -CCl3 | Me | H | H | H | 17e | Toluene, 4 h, 15 °C | 65 | [39] |
6 | -CCl3 | i-Pr | H | H | H | 17f | Toluene, 4 h, 15 °C | 78 | [39] |
7 | -CCl3 | t-Bu | H | H | H | 17g | Toluene, 4 h, 15 °C | 53 | [39] |
8 | -CCl3 | Me | H | H | Me | 17h | Toluene, 4 h, 15 °C | 55 | [39] |
9 | -CCl3 | Br | H | H | H | 17i | Toluene, 4 h, 15 °C | 51 | [39] |
10 | -COOEt | H | H | t-Bu | H | 17j | Yb(OTf)3/CH2Cl2, 10 h, rt | 88 | [40] |
11 | -COOEt | H | t-Bu | H | H | 17k | Yb(OTf)3/CH2Cl2, 10 h, rt | 90 | [40] |
12 | -COOEt | H | H | OH | H | 17l | Yb(OTf)3/CH2Cl2, 10 h, rt | 80 | [40] |
13 | -COOEt | H | Et2N | H | H | 17m | Yb(OTf)3/CH2Cl2, 10 h, rt | 68 | [40] |
14 | -COOEt | H | H | F | H | 17n | Yb(OTf)3/CH2Cl2, 10 h, rt | 81 | [40] |
Entry | R1 | R2 | Product | Conditions | Conversion | Reference |
---|---|---|---|---|---|---|
1 | H | i-Pr | 19a | 17 h, 80–90 °C | 12 | [41] |
2 | H | i-Pr | 19a | 54 h, 120 °C | 46 | [42] |
3 | H | i-Bu | 19b | 65 h, 75 °C | 25 | [42] |
4 | H | t-Bu | 19c | 90 h, 70 °C | 24 | [42] |
5 | H | OMe | 19d | 6 h, 95 °C | 24 | [42] |
6 | OMe | OH | 19e | 3 h, 95 °C | 15 | [42] |
7 | OMe | OMe | 19f | 64 h, 95 °C | 25 | [42] |
8 | H | OH | 19g | 6 h, 95 °C | 24 | [42] |
X | R2 | Compound | Yield (%) |
---|---|---|---|
CH (24a) | p-NO2C6H4 (25a) | 26a | 86 |
CH (24a) | m-NO2C6H4 (25b) | 26b | 82 |
CH (24a) | o-NO2C6H4 (25c) | 26c | 82 |
CH (24a) | p-MeC6H4 (25d) | 26d | 79 |
CH (24a) | p-(O-CH2-Ph)C6H4 (25e) | 26e | 81 |
CH (24a) | p-OMeC6H4 (25f) | 26f | 63 |
CH (24a) | 2-naphthyl (25g) | 26g | 61 |
N (24b) | p-BrC6H4 (25h) | 26h | 73 |
N (24b) | Ph (25i) | 26i | 71 |
N (24b) | p-OMeC6H4 (25j) | 26j | 72 |
Entry | 1 | 2 | 3 | 4 | 6 | 7 |
---|---|---|---|---|---|---|
Catalyst (27, mol%) | 5 | 25 | 50 | 750 | 100 | 150 |
Yield of 28f (%) | Trace | 21 | 42 | 63 | 86 | 87 |
24 | R2 | Product | Yield (%) | ee (%) |
---|---|---|---|---|
2-naphthol (24a) | Ph (28a) | 30a | 64 | 68 |
2-naphthol (24a) | o-MeC6H4 (28b) | 30b | 58 | 55 |
2-naphthol (24a) | m-MeC6H4 (28c) | 30c | 61 | 71 |
2-naphthol (24a) | p-MeC6H4 (28d) | 30d | 54 | 63 |
2-naphthol (24a) | m-MeOC6H4 (28e) | 30e | 68 | 63 |
2-naphthol (24a) | o-ClC6H4 (28f) | 30f | 42 | 40 |
2-naphthol (24a) | p-ClC6H4 (28g) | 30g | 55 | 58 |
2-naphthol (24a) | p-BrC6H4 (28h) | 30h | 51 | 33 |
2-naphthol (24a) | p-FC6H4 (28i) | 30i | 46 | 50 |
2-naphthol (24a) | 2-naphthyl (28j) | 30g | 44 | 66 |
6-bromo-2-naphthol (24c) | Ph (28a) | 30j | 57 | 57 |
6-bromo-2-naphthol (24c) | m-MeC6H4 (28c) | 30k | 58 | 66 |
6-bromo-2-naphthol (24c) | m-MeOC6H4 (28e) | 30l | 54 | 66 |
1-naphthol (24c) | Ph (28a) | 30m | 72 | 20 |
R1 | R2 | Product | Yield (%) | Method |
---|---|---|---|---|
Ph | Et | 32a | 94 | (a) |
Ph | Me | 32b | 90 | |
Ph | n-Pr | 32c | 92 | |
Ph | i-Pr | 32d | 82 | |
Ph | n-Bu | 32e | 88 | |
Ph | Bn | 32f | 84 | |
Ph | CH2CH=CH2 | 32g | 82 | |
Ph | CH2C≡CH | 32h | 80 | |
Ph | (CH2)3CH=CH2 | 32i | 84 | |
Ph | (CH2)4Ph | 32j | 88 | |
Ph | (CH2)2OH | 32k | 81 | |
Ph | (CH2)8OH | 32l | 82 | |
p-NO2-Ph | Me | 32m | 94 | |
p-NO2-Ph | n-Bu | 32n | 88 | |
p-F-Ph | Et | 32o | 94 | |
p-Br-Ph | Me | 32p | 92 | |
2-C10H7 | Me | 32q | 88 | |
p-Me-Ph | Et | 32r | 90 | |
Ph | H | 32s | 84 | (b) |
p-NO2-Ph | H | 32t | 88 | |
p-F-Ph | H | 32u | 86 | |
p-Cl-Ph | H | 32v | 84 | |
p-Me-Ph | H | 32w | 82 |
Products of synthesis route a | |||||||||
R1 | R2 | R3 | Yield (%) | R1 | R2 | R3 | Yield (%) | ||
H | H | Me | 54aa | 89 | 6-Br | H | Me | 54ap | 80 |
2-Ph | H | Me | 54ab | 90 | 7-NO2 | H | Me | 54aq | 92 |
4-F | H | Me | 54ac | 88 | H | Ph | Me | 54ar | 79 |
4-Cl | H | Me | 54ad | 82 | H | C5H4N | Me | 54as | 89 |
4-OMe | H | Me | 54ae | 82 | H | o-NO2C6H4 | Me | 54at | 88 |
4-OCH2Ph | H | Me | 54af | 84 | H | o-MeC6H4 | Me | 54au | 87 |
5-Me | H | Me | 54ag | 85 | H | m- MeC6H4 | Me | 54av | 96 |
5-OMe | H | Me | 54ah | 81 | H | p- MeC6H4 | Me | 54aw | 82 |
5-NO2 | H | Me | 54ai | 65 | H | m-CHOC6H4 | Me | 54ax | 96 |
5-F | H | Me | 54aj | 88 | H | m-OMeC6H4 | Me | 54ay | 79 |
5-Cl | H | Me | 54ak | 85 | H | p-PhC6H4 | Me | 54az | 72 |
5-Br | H | Me | 54al | 83 | H | p-CNC6H4 | Me | 54ba | 89 |
6-COOCH3 | H | Me | 54am | 57 | H | 2,4-Cl2C6H3 | Me | 54ca | 98 |
6-F | H | Me | 54an | 81 | H | CH3CH3C6H3 | Me | 54da | 84 |
6-Cl | H | Me | 54ao | 80 | H | H | CH2CF3 | 54ea | 83 |
Products of synthesis route b | |||||||||
R1 | R2 | R3 | Yield (%) | R1 | R2 | R3 | Yield (%) | ||
H | p-CF3C6H4 | Me | 54fa | 98 | 4-Me | p-BrC6H4 | Me | 54pa | 89 |
H | Ph | Me | 54ga | 96 | 5-Me | p-BrC6H4 | Me | 54qa | 92 |
H | p-BrC6H4 | Me | 54ha | 96 | 6-Me | p-BrC6H4 | Me | 54ea | 94 |
H | p-ClC6H4 | Me | 54ia | 95 | 7-Me | p-BrC6H4 | Me | 54sa | 93 |
H | p-FC6H4 | Me | 54ja | 97 | 5-Cl | p-BrC6H4 | Me | 54ta | 96 |
H | o-ClC6H4 | Me | 54ka | 96 | 5-Br | p-BrC6H4 | Me | 54ua | 98 |
H | 3,4-Cl2C6H4 | Me | 54la | 50 | 5-OMe | p-CF3C6H4 | Me | 54va | 96 |
H | p-NO2C6H4 | Me | 54ma | 65 | 5-CN | p-BrC6H4 | Me | 54wa | 42 |
2-Me | p-BrC6H4 | Me | 54na | 96 | 5-CN | p-CF3C6H4 | Me | 54xa | 56 |
2-Me | p-ClC6H4 | Me | 54oa | 93 |
R1 | R2 | Compound | Yield (%) | R1 | R2 | Compound | Yield (%) | ||
---|---|---|---|---|---|---|---|---|---|
Me | H | 57a | 55 | H | F | 57g | 46 | ||
H | H | 57b | 47 | Me | H | 57h | 56 a | ||
H | OMe | 57c | 56 | H | H | 57i | 54 a | ||
Me | H | 57d | 58 | H | OMe | 57j | 56 a | ||
Me | OMe | 57e | 58 | Me | H | 57k | 36 | ||
H | H | 57f | 56 |
Reaction Scheme | R1 | R2 | Compound | Yield (%) |
---|---|---|---|---|
5-OMe | H | 59a | 74 | |
5-Me | H | 59b | 80 | |
5-F | H | 59c | 86 | |
5-Cl | H | 59d | 66 | |
5-Br | H | 59e | 73 | |
5-I | H | 59f | 77 | |
6-F | H | 59g | 90 | |
6-Cl | H | 59h | 90 | |
6-Br | H | 59i | 76 | |
4-Br | H | 59j | 59 | |
7-Me | H | 59k | 76 | |
H | 2-Me | 59l | 75 |
Ar | |||||
Yield (%) | 74 | 66 | 70 | 64 | 82 |
Compound | 61a | 61b | 61c | 61d | 61e |
Product | Condition | NH2R | Yield (%) | Maximal Yield (%) of 2aa |
---|---|---|---|---|
70a | a (pH = 7, 12 h) | glycine | 27 | 70 |
b (pH = 7, 2 h) | 25 | 75 | ||
70b | a (pH = 6, 15 h) | serine | 60 | 36 |
b (pH = 7, 2 h) | 9 | – | ||
70c,d | a (pH = 5.0, 1 h) | lysine | c: 10 (on ω-NH2), d: 30 (on α-NH2) | 39 |
b (pH = 12, 2 h) | c: 16 (on ω-NH2), d: 64 (on α-NH2) | – | ||
70e, 71a | a (1 h) | tyrosine | e: max. 64 (pH = 10) 71a: max. 18 (pH = 12) | max. 32 (pH = 7) |
71b | a (pH = 7, 0.5 h) | glutathione (on thiol) | 84 | – |
b (pH = 7, 2 h) | 86 | 12 |
(a) incubation at 100 °C, (b) laser flash photolysis, 266 nm | ||||||
Mannich Base | X | R | R’ | Conditions | oQM | o-HO-benzylalcohol |
79a | 4-morpholinyl | -COOMe | -H | a | 80a | 81a |
79b | 4-morpholinyl | -H | -COOMe | a | 80b | 81b |
79c | 4-morpholinyl | -H | -H | a | 80c | 2aa |
79d | 4-morpholinyl | -H | -OMe | a | 80d | 2aw |
79e | 4-morpholinyl | -OMe | -H | a | 80e | 81c |
79f | -N+Me3 | -H | -H | b | 80c | 2aa |
79g | -N+Me3 | -H | -COOMe | b | 80b | 81b |
79h | -N+Me3 | -H | -OMe | b | 80d | 2aw |
79i | -N+Me3 | -H | -Cl | b | 80f | 2aq |
79j | -N+Me3 | -H | -CN | b | 80g | 81d |
79k | -N+Me3 | -H | -CN | b | 80h | 81e |
Unisolated yields of compounds 89a,b and conditions | |||||
---|---|---|---|---|---|
# | Solvent | Wavelength of irradiation | |||
254 nm | 300 nm | 350 nm | visible, cool white | ||
90a | MeOH | decomposed | 2 | no reaction | |
MeOH/HOH 1:1, pH = 7 | 68 (16 h) | 42 (16 h) | 2 (16 h) | <1 (16 h) | |
MeOH/HOH 1:1, pH = 9 | decomposed | 52 (16 h) | 8 (16 h) | <1 (16 h) | |
90b | MeOH | 30 (9 h) | 12 (12 h) | 1 (16 h) | no reaction |
MeOH/HOH 1:1, pH = 7 | 100 (2 h) | 100 (6 h) | 21 (16 h) | 2 (16 h) | |
MeOH/HOH 1:1, pH = 9 | 94 (4 h) | 100 (6 h) | 19 (16 h) | 2 (16 h) |
Compound | Condition (i) | Compound | Condition (ii) | Compound | Condition (iii) | Compound | Ref. | |
1aa: R1 = R2 = H | 10 equiv. 40% formaldehyde in water, 10 equiv. 50% aqueous Me2NH, 40 °C, 6 h | 82a: 2,4,6-X X = CH2NMe2, R1 = R2 = H | 10 equiv. Ac2O, 100 °C, 4 h | 95a: 2,4,6-X X = CH2OAc, R1 = R2 = H | 10. equiv. K2CO3, EtOH, 80 °C, 2 h | 96a: 2,4,6-X X = CH2OEt | [73] | |
2.0 equiv. 38% formaldehyde in water, 0.98 equiv. morpholine, 50 °C, 15 h | 72: 2,6-X X= morpholino-methyl, R1 = R2 = H (20%) | Ac2O, reflux | 95b: 2,6-X X = CH2OAc, R1 = R2 = H (57%) | From this step, divergent reaction routes were applied | [75] | |||
93a: R1 = 4-Br, R2 = H | 2.2 equiv. 38% formaldehyde in water, 2.2 equiv. morpholine, 80 °C, 6 h, in HOAc | 94a: 2,6-X X = morpholino-methyl, R1 = 4-Br, R2 = H (82%) | Ac2O (2.2 mL to 1 mol) and HOAc (0.15 to 1 mmol), reflux, 24 h | 95c: 2,6-X X = CH2OAc R1 = 4-Br, R2 = H (64%) | [75] | |||
94b was synthesized via different reaction route | 94b: 2,6-X X= morpholino-methyl, R1 = 4-phenylethynyl | Ac2O (11 mL to 1 mmol), HOAc (0.45 to 1 mmol), reflux, 14 h | 95d: 2,6-X X = CH2OAc, R1 = 4-phenyl ethynyl, R2 = H (75%) | 5M H2SO4 in THF, reflux | 96b: 2,6-X X = CH2OH, R1 = 4-phenyl ethynyl, R2 = H (48%) | [75] | ||
Compound | Condition (i) | Compound | Condition (iv) | Compound | Ref. | |||
93b: R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = Me | 50% aqueous Me2NH, paraformaldehyde | 94c: 2-X = CH2NMe2, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = Me | cat. KOH, 5 equiv. paraformaldehyde ethylene glycol, 150 °C, 24 h | 96c: 2-X = CH2O(CH2)2OH, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = Me | [74] | |||
93c: R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = t-Bu | 94d: 2-X = CH2NMe2, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = t-Bu | 96d: 2-X = CH2O(CH2)2OH, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = t-Bu | [74] | |||||
93d: R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2-hydroxy)ethyl | 94e: 2-X = CH2NMe2, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2-hydroxy)ethyl | 96e: 2-X = CH2O(CH2)2OH, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2-hydroxy)ethyl | [74] | |||||
93e: R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2,2,4,4-tetramethyl)butyl | 94f: 2-X = CH2NMe2, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2,2,4,4-tetramethyl)butyl | 96f: 2-X = CH2O(CH2)2OH, R1 = 2-(2H-benzo[d][1,2,3]triazol-2-yl), R2 = 1-(2,2,4,4-tetramethyl)butyl | [74] |
101 | Condition | 102 | Ref. |
---|---|---|---|
a: R1 = Et | 20 equiv. aqueous formaldehyde 37%, HOAc (0.1 mL to 1 mmol), EtOH (10 mL to 1 mmol), 9 equiv. NHR2R3 = TRIS, 1 h R.T., 1–2 h reflux | a: R1 = Et, X = Y = Z = W = CH2OEt (55%) | [77] |
b: R1 = C5H11 | b: R1 = C5H11, X = Y = Z = W = CH2OEt (42–69%) a | [77] | |
c: R1 = C11H23 | c: R1 = C11H23, X = Y = Z = W = CH2OEt (42–69%) a | [77] | |
d: R1 = i-Bu | 5 equiv. aqueous formaldehyde 37%, cat. NHR2R3 = iminodiacetic acid (in water) (9.4 mol%), R4OH as solvent, reflux, 12 h | d: R1 = i-Bu, X = Y = Z = W = CH2OMe (79%) | [78] |
e: R1 = i-Bu, X = Y = Z = W = CH2OEt (66%) | [78] | ||
f: R1 = i-Bu, X = Y = Z = W = CH2OnPr (64%) | [78] | ||
g: R1 = i-Bu, X = Y = Z = W = CH2OnBu (46%) | [78] | ||
h: R1 = i-Bu, X = Y = Z = W = CH2OnPe (40%) | [78] | ||
i: R1 = i-Bu, X = Y = Z = W = CH2OnHx (28%) | [78] | ||
2 equiv. aqueous formaldehyde 37%, cat. NHR2R3 = iminodiacetic acid (10% m/m), R4OH as solvent, reflux (reaction times separately assigned) | j: R1 = i-Bu, X = Y = Z = H, W = CH2OMe (34%, 4 h) | [79] | |
k: R1 = i-Bu, X = Y = Z = H, W = CH2OEt (39%, 135 min) | [79] | ||
l: R1 = i-Bu, X = Y = Z = H, W = CH2OnPr (39%, 90 min) | [79] | ||
m: R1 = i-Bu, X = Y = Z = H, W = CH2OAllyl (43%, 90 min) | [79] | ||
n: R1 = i-Bu, X = Y = Z = H, W = CH2O(2-hydroxyethyl) (37%, 30 min) | [79] | ||
o: R1 = i-Bu, X = Y = H, X = W = CH2OnPr (14%, 160 min) | [79] | ||
p: R1 = i-Bu, X = Y = H, Z = W = CH2OnPr (24%, 160 min) | [79] | ||
q: R1 = i-Bu, X = H, Y = Z = W = CH2OnPr (29%, 180 min) | [79] | ||
r: R1 = i-Bu, X = H, Y = Z = W = CH2OAllyl (30%, 180 min) | [79] | ||
e: R1 = nC11H23 | 5 equiv. aqueous formaldehyde 37%, cat. NHR2R3 = iminodiacetic acid (in water) (9.4 mol%), R4OH as solvent, reflux, 4 h | s: R1 = nC11H23, X = Y = Z = W = CH2OEt (42%) | [78] |
f: R1 = Me | t: R1 = Me, X = Y = Z = W = CH2OEt (65%) | [78] |
conditions | 123 (%) | 124 (%) | |
(a) | 3.0 equiv. 36% aqueous formaldehyde, 3.0 equiv. NH2nBu, MeOH, room temperature, 7 days | 89 | – |
(b) | 3.0 equiv. 36% aqueous formaldehyde, 3.0 equiv. NH2nBu, EtOH, reflux, 20 h | 64 | 21 |
(c) | 3.0 equiv. 36% aqueous formaldehyde, 3.0 equiv. NH2nBu, EtOH, reflux, 6 h then 45 °C, 18 h overnight | ~100 | 0 |
(d) | 3.0 equiv. 36% aqueous formaldehyde, 3.0 equiv. NH2nBu, 1,4-dioxane, reflux, 6 h then 50 °C, 18 h overnight | 60 | – |
(e) | 3.0 equiv. 36% aqueous formaldehyde, 3.0 equiv. NEt3, EtOH, reflux, 2 days (reflux, 6 h then 45 °C, 16 h overnight) | – | 30 |
(f) | 3.0 equiv. 36% aqueous formaldehyde, EtOH, 3 days (reflux, 6 h then 45 °C, 16 h overnight) | – | 0 a |
Conditions | Conversion, Reaction Time (and Isolated Yield) | |||
---|---|---|---|---|
HNR2R3 | Equivalence | R1OH | 131 | 132 |
1.0 | Ethanol | 0% | a: 75% (60 h) | |
1.0 | Ethanol | 0% | b: 98% (60 h) | |
1.0 | Ethanol | a: 4% (8 h) | c: 92% (60 h) | |
1.0 | Ethanol | a: 3% (1–3 h) | a: 56% (28 h) | |
1.0 | Ethanol | a: 5% (1–5 h) | b: 34% (20 h) | |
1.0 | Ethanol | a: 20% (9 h) | c: 60% (9 h) | |
1.0 | Ethanol | a: 5% (6 h) | 0% | |
1.0 | Ethanol | a: 15% (22 h) | 0% | |
1.0 | Ethanol | a: 15% (60 h) | 0% | |
1.0 | Ethanol | 0% | d: isolated 44% (88 h) | |
1.0 | Ethanol | 0% | e: isolated 9% (95 h) | |
0.1 | Ethanol | a: 6% (24 h) | 0% | |
0.5 | Ethanol | a: 39% (40 h, isolated 33%) | 0% | |
1.0 | Ethanol | a: 25% (22 h) | 0% | |
2.0 | Ethanol | a: 48% (40 h) | 0% | |
0.5 | 2-Propanol | b: 21% (26 h, isolated 16%) | 0% |
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Simon, P.; Lőrinczi, B.; Szatmári, I. Alkoxyalkylation of Electron-Rich Aromatic Compounds. Int. J. Mol. Sci. 2024, 25, 6966. https://doi.org/10.3390/ijms25136966
Simon P, Lőrinczi B, Szatmári I. Alkoxyalkylation of Electron-Rich Aromatic Compounds. International Journal of Molecular Sciences. 2024; 25(13):6966. https://doi.org/10.3390/ijms25136966
Chicago/Turabian StyleSimon, Péter, Bálint Lőrinczi, and István Szatmári. 2024. "Alkoxyalkylation of Electron-Rich Aromatic Compounds" International Journal of Molecular Sciences 25, no. 13: 6966. https://doi.org/10.3390/ijms25136966