Author Topic: aryl halides' sensitivity to metal hydrides -rev drone  (Read 1490 times)

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aryl halides' sensitivity to metal hydrides -rev drone
« on: April 19, 2000, 09:48:00 AM »

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Author  Topic:   aryl halides' sensitivity to metal hydrides 
rev drone
Member   posted 12-14-1999 04:51 AM          
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Howdy y'all,
I wanted to bring up this topic here, since it seems to be the true stuff of serious chemists' debate. This one's real juicy, full of lot's of conflicting opinions and evidense.

Here's the deal: Now it just so happens that some inexpensive brominated nitrostyrenes are hypothetically commercially available to those "in the know". Now the good reverend was taught by more than one world-reknowned professor in organic chemistry that organohalides don't always stand up well against metal hydrides -- in fact, they're supposed to be highly susceptible to reduction. "Oh, okay." I said, and shuffled away, head bowed.

As time passes, I've learned to be skeptical of organic chemistry's dogmatic stances on such issues. After performing a quick Beilstein search, I've found considerable evidense pointing in the opposite direction -- over a hundred examples of halonitroalkenes being successfully reduced to haloaminoalkanes.

At first I said, "Aha! The Dogma of these organo-pseudopriests has been shown to be hollow yet again! I shall vengefully fart in their general direction! For spreading such vile canards, I shall smite them with mercaptans!" But, as my youthful exhuberance gave way to more somber contemplation, I began to realize that capriciously soiling the air of my teachers may be a hastey and rash judgement call, being both an unjust punishment, as well as limiting my future employment oportunities.

Perhaps their is a qualifiying statement that my memory has omitted. Could this be? Something to the order of "Metal hydrides will reduce the living shit out of oganohalides, with the exceptions of ...., which is due to the fact that ...."? Would anyone be willing to venture a thoughtful, educated explaination of this issue? I feel quite certain that a better understanding of this matter would be appreciated by all.

------------------
-the good reverend drone


 
Osmium
Member   posted 12-14-1999 09:06 AM          
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Could you please define the word metal hydride? I guess you are talking about the famous LAH?
As far as I know, reduction of brominated benzene nuclei (and most probably other halogenated versions, too) with LAH removes the halogen nearly every time, especially when using excess LAH. Using stoichometric amounts usually allows the researcher to isolate crappy yields of the desired halogenated amine. Is there any literature out there about other hydrides? Like that Red-Al everybody is talking about right now?
BH3/NaBH4 and all its variants leave the halogen alone. A real alternative IMHO, both cost and yield-wise.
Catalytic hydrogenation is probably out. Not sure about that, but I do know that CTH with formate and Pd/C definitely is a big nono, because this is the most efficient method to remove the halogen. Quantitative yields of the dehalogenated substrate in a very short time. Used to convert Arochlors into baby food (harmless substances).
 
rev drone
Member   posted 12-14-1999 12:51 PM          
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Os,
What do I mean by 'metal hydrides'? Good question. I mean 'metal hydrides' as in metal salts with hydride ligands: NaBH4, LiAlH4, LiBH4, NaH, LiH, LiEt3AlH, etc. Yes, 'borohydride' isn't in and of itself a metal hydride, but since the hydrides act as ligands toward both the metals and the boron moiety, I felt they were worth including on that technical basis.

Now normally I'd agree LiAlH4 would reduce alkyl halides, since that was what I was taught in school. Still, Jerry March seems to imply that LiAlH4 doesn't effectively reduce aromatic halides, though it apparently does a fine job on every other alkyl halide you can throw at it. LiEt3BH, allegedly the strongest Sn2 nucleophile known, won't touch aryl or tertiary halides, though LiAlH(OMe)3 with a dash of CuI will reduce them all.

This is the point at which I go running to the literature like a frightened child. What do I find? As I said, over 115 examples of halonitrostyrenes being reduced to haloarylethylamines -- primarily via LiAlH4. There are even a few catalytic hydrogenations thrown in there for good measure.

Still, there are also plenty of reductions of aromatic halides with various metal and non-metal hydride species out there. In one instance, they can do no wrong; in another, they can do no good. So what should a dashing young chemist believe? As it stands, I still haven't found anything dealing directly with Red-Al, but that's certainly what's hoped for.

I wouldn't dismiss catalytic hydrogenation so quickly; there are far too many chemoselective catalysts, not to mention ways to modify reaction conditions, to ever exclude this broad class of reduction procedures from doing just about anything.


Thoughts? Opinion's? Strings of incoherent oaths and obscenities?


------------------
-the good reverend drone


 
rev drone
Member   posted 12-14-1999 12:58 PM          
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To clarify, I did find two examples of halonitrostyrenes being reduced to non-halogenated phenethylamines -- both of which involve LiAlH4. However, I found about 7 dozen LiAlH4-based procedures alone that do the same thing without this occuring -- including 3 DOB syntheses. Ref's given upon request.
------------------
-the good reverend drone


 
Teonanacatl
Member   posted 12-14-1999 03:10 PM          
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Rev...I'm sorry that I can't give an opinion either way...I would like to get hold of those refs from you, as this area interests me...by the way, is there any correlation between other substituents on the ring and loss of the halogen?
 
K.C. Nicolaou
Member   posted 12-15-1999 02:24 AM          
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I would think that aryl halides can only be reduced by metal hydrides through a benzyne intermediate or through a SET mechanism. So, in the absence of Cu(+) salts or conditions that would form the benzyne, I would think you'd be okay. Dissolving metals or cat. hydrogenation would be no-no's. So I guess my answer is that you probably wouldn't have problems if you use fairly mild conditions. That would also explain why there are refs indicating both possibilities.
 
rev drone
Member   posted 12-15-1999 06:25 AM          
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K.C.N.,
Once again, you get to the heart of the matter: mechanistically, what is expected?

I'd agree, Cu+ catalyzed nucleophilic substitution-elimination would be the exactly wrong way to go about things. With the relatively acidic protons on the amine, this would be a bad choice all around -- especially considering that LiAl(OMe)3H complexed with CuI is recommended as an unusually strong reducing agent, capable of reducing even the most pernicious organohalide.

As for strong base-promoted benzyne formation, I guess that means we can rule out LiH, NaH, and KH as reducing candidates (not that I seriously considered any of them; I'm trying to get away from LiAlH4 and its pyrophoric ilk.) Their corresponding free metals, as well as magnesium, can be crossed out too.

The other possible thing to avoid may be UV light or Fe3+ salts -- conditions favoring dissociation of halides, promoting Sn1 reactions. But avoiding excessive UV and Fe(NO3)3 shouldn't be much of a problem anyways, since there's no reason for them to be present anyways. I really only mentioned them for the sake of thoroughness.

Pd(BaSO4) catalytic hydrogenation and CTH are certainly, as Os mentioned, not going to do anything but harm.

Thus far, we know a good list of conditions NOT to choose, but what's left? Well, there's at least one set of conditions we don't have to worry about. In the case of aliphatic alkyl halides, one can expect a halide elimination in the presence of LiAlH4 or Red-Al through an Sn2 reaction mechanism; this is straight-forward. With an aromatic halide, Sn2 is not a problem, since a backside attack is not gonna happen. Still, there are always other possibilities. So we can cancel at least one halide elimination scenario. Again, the numerous ref's detailing this as effective are also strong support for this reaction route.

As said before, BH3*THF with NaBH4, BF3*THF with NaBH4, among other borane systems, are supposed to be exceptionally effective mild reducing reagents for this job. That's all good and well, but for some reason I'm not too enthusiastic about them -- especially considering the length of reaction time (6 days). They're worth mentioning, since the price is right, the conditions are clandestinely manageable, and the yields are reported to be good to excellent.

While not technically a metal hydride reagent, what exactly is wrong mechanistically with catalytic hydrogenation that one would dismiss these conditions across the board? Nitrostyrene reductions and aryl halide reductions are certainly chemically different enough that conditions should exist greatly favoring one over another.

------------------
-the good reverend drone


 
rev drone
Member   posted 12-15-1999 07:00 AM          
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Teo,
I might get in trouble for making this thread hard to navigate, but, here you go. The folling are all organohalonitroalkenes being reduced to organohaloethylamines. They're primarily, but not exclusively phenethylamine syntheses; you'll also find thiofuranylethylamines and tryptamines. I trimmed the list as best I could, so that one example represented each journal ref, and I got rid of most of the fluoro examples (I didn't thenk of them as being as pertinant) but I may have made a few mistakes. Enjoy.


Reactant BRN 4868232 1-bromo-2,5-dimethoxy-4-(2-nitro-vinyl)-benzene
Product BRN 4863873 2-(4-bromo-2,5-dimethoxyphenyl)-1-aminoethane
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4, H2SO4
Solvent tetrahydrofuran
Other Conditions Ambient temperature
Ref. 1 5595464; Journal; Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; JMCMAR; J.Med.Chem.; EN; 35; 4; 1992; 734-740;
-------------------------

Reactant BRN 1980835 1-(2,5-dimethoxy-4-bromophenyl)-2-nitropropene
Product BRN 2807278 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 53 percent (BRN=2807278)
Reagent AlH3
Solvent tetrahydrofuran
Time 6 hour(s)
Other Conditions Ambient temperature
Ref. 1 5745593; Journal; Glennon, Richard A.; McKenney, J. D.; Lyon, Robert A.; Titeler, Milt; JMCMAR; J.Med.Chem.; EN; 29; 2; 1986; 194-199;
-------------------------

Reactant BRN 2047928 1-bromo-4-(2-nitro-propenyl)-benzene
Product BRN 3240553 2-(4-bromo-phenyl)-1-methyl-ethylamine
No. of Reaction Details 4
-------------------------

Reaction Details 1 of 4

Reaction Classification Preparation
Yield 85 percent (BRN=3240553)
Reagent BH3*THF, NaBH4
Solvent tetrahydrofuran
Time 6 day(s)
Temperature 25 C
Ref. 1 5524485; Journal; Kabalka, George W.; Guindi, Laila H. M.; Varma, Rajender S.; TETRAB; Tetrahedron; EN; 46; 21; 1990; 7443-7457;
-------------------------

Reaction Details 2 of 4

Reaction Classification Preparation
Reagent LiAlH4
Solvent diethyl ether
Other Conditions 1.) reflux, 6 h, 2.) RT, 16 h
Ref. 1 5595464; Journal; Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; JMCMAR; J.Med.Chem.; EN; 35; 4; 1992; 734-740;
-------------------------

Reaction Details 3 of 4

Reaction Classification Preparation
Reagent 1.) BH3*THF, NaBH4, 2.) 10percent HCl, 3.) NaOH
Other Conditions 1.) 25 deg C, 6 days, 2.) 60 -65 deg C, 2 h, 3.) NaOH
Note 1 Yield given. Multistep reaction
Ref. 1 5737363; Journal; Mourad, M. Soubei; Varma, Rajender S.; Kabalka, George W.; SYNCAV; Synth.Commun.; EN; 14; 12; 1984; 1099-1104;
-------------------------

Reaction Details 4 of 4

Reaction Classification Preparation
Reagent 1.) NaBH4, BF3*Et2O, 2.) 1 N HCl
Other Conditions 1.) THF, reflux, 5.5 h, 2.) heating, 2 h
Note 1 Yield given. Multistep reaction
Ref. 1 5800128; Journal; Varma, Rajender S.; Kabalka, George W.; SYNCAV; Synth.Commun.; EN; 15; 9; 1985; 843-848;

Reactant BRN 2139247 1-bromo-4,5-dimethoxy-2-(2-nitro-vinyl)-benzene
Product BRN 2806289 2-bromo-4,5-dimethoxy-phenethylamine
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Preparation
Reagent Zn, HCl
Ref. 1 5661061; Journal; Estevez, Juan C.; Estevez, Ramon J.; Castedo, Luis; TELEAY; Tetrahedron Lett.; EN; 33; 45; 1992; 6883-6884;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Other Conditions Clemmensen reduction
Ref. 1 5939338; Journal; Kihara, Masaru; Itoh, Joji; Iguchi, Seiichiro; Imakura, Yasuhiro; Kobayashi, Shigeru; JRMPDM; J.Chem.Res.Miniprint; EN; 1; 1988; 0157-0177;
-------------------------

Reactant BRN 135664 2-chloro-5-(2-nitro-vinyl)-thiophene
Product BRN 114677 2-(5-chloro-[2]thienyl)-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent lithium alanate
diethyl ether
Ref. 1 947233; Journal; Gilsdorf; Nord; JOCEAH; J.Org.Chem.; 15; 1950; 807, 810;

Reactant BRN 183324 5-chloro-3-(2-nitro-vinyl)-indole
Product BRN 143483 2-(5-chloro-indol-3-yl)-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
diethyl ether
Ref. 1 1093530; Journal; Young; JCSOA9; J.Chem.Soc.; 1958; 3493, 3494;

Reactant BRN 1985755 2-chloro-3,4-dimethoxy-$b-nitro-styrene
Product BRN 2369860 2-chloro-3,4-dimethoxy-phenethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
diethyl ether
Ref. 1 2266075; Journal; Burger; Foggio; JACSAT; J.Amer.Chem.Soc.; 78; 1956; 4419,4421,4422;

Reactant BRN 2087805 3-bromo-$b-nitro-styrene
Product BRN 2716071 3-bromo-(2-amino-ethyl)-benzene
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Chemical behaviour
Other Conditions Electrolysis
Ref. 1 1705597; Journal; Kondo; Ishiwata; CHBEAM; Chem.Ber.; 64; 1931; 1533, 1539;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Other Conditions bei der elektrochemischen Reduktion
Ref. 1 1933457; Journal; Kondo; Ishiwata; CHBEAM; Chem.Ber.; 64; 1931; 1533,1539;
Ref. 2 1933419; Journal; Ishiwata; YKKZAJ; Yakugaku Zasshi; 51; 1931; 755;

Reactant BRN 3287332 4-(4-chloro-phenyl)-3-nitro-but-3-en-2-one
Product BRN 3258056 3-amino-4-(4-chloro-phenyl)-butan-2-ol
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 2263366; Journal; Dornow; Sassenberg; JLACBF; Justus Liebigs Ann. Chem.; 602; 1957; 14,20;
-------------------------

Reactant BRN 1975835 C10H8F3NO2
Product BRN 2694680 2-Amino-1-(2-trifluormethyl-phenyl)-propan
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 79846; Journal; Holland,G.F. et al.; JMCMAR; J.Med.Chem.; EN; 6; 1963; 519-524;
-------------------------

Reactant BRN 2047926 1$x-(4-chloro-phenyl)-2-nitro-propene
Product BRN 2690849 2-(4-chloro-phenyl)-1-methyl-ethylamine
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 293037; Journal; Foye,W.O.; Tovivich,S.; JPMSAE; J.Pharm.Sci.; EN; 68; 1979; 591-595;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Reagent LiAlH4
Solvent diethyl ether
benzene
Ref. 1 80181; Journal; Benington,F. et al.; JMCMAR; J.Med.Chem.; EN; 8; 1965; 100-104;

Reactant BRN 2104227 C8H5F2NO2
Product BRN 2718242 2,6-difluorophenethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 81223; Journal; Roe,A.M. et al.; JMCMAR; J.Med.Chem.; EN; 11; 4; 1968; 814-819;
-------------------------

Reactant BRN 2369742 1$x-(2,4-dichloro-phenyl)-2-nitro-propene
Product BRN 3243754 2-(2,4-dichloro-phenyl)-1-methyl-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 83311; Journal; Aldous,F.A.B. et al.; JMCMAR; J.Med.Chem.; EN; 17; 1974; 1100-1111;
-------------------------

Reactant BRN 1246310 C10H7BrN2O2
Product BRN 143491 2-(5-bromo-indol-3-yl)-ethylamine
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Preparation
Reagent LiAlH4
Solvent tetrahydrofuran
Ref. 1 5552296; Journal; Still, Ian W. J.; Strautmanis, Juris R.; TELEAY; Tetrahedron Lett.; EN; 30; 9; 1989; 1041-1044;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Yield 83 percent (BRN=143491)
Reagent LiAlH4
Solvent tetrahydrofuran
Time 4 hour(s)
Other Conditions Heating
Ref. 1 5529685; Journal; Still, Ian W. J.; Strautmanis, Juris R.; CJCHAG; Can.J.Chem.; EN; 68; 8; 1990; 1408-1419;

Reactant BRN 2087804 3-chloro-$b-nitro-styrene
Product BRN 774601 3-chloro-phenethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 41 percent (BRN=774601)
Reagent LiAlH4
Solvent tetrahydrofuran
Ref. 1 5672793; Journal; Hocquaux, Michel; Marcot, Bernard; Redeuilh, Gerard; Viel, Claude; Brunaud, Marcel; et al.; EJMCA5; Eur.J.Med.Chem.Chim.Ther.; FR; 18; 4; 1983; 319-329;
-------------------------
Reactant BRN 2090900 2-bromo-$b-nitro-styrene
Product BRN 2802715 $b-(2-bromophenyl)ethylamine
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Preparation
Reagent LiAlH4
Solvent diethyl ether
Time 5 hour(s)
Temperature 0 - 5 C
Note 1 Yield given
Ref. 1 5552806; Journal; Bradsher, Charles K.; Hunt, David A.; JOCEAH; J.Org.Chem.; EN; 46; 2; 1981; 327-330;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 193583; Journal; Mori,M. et al.; JOCEAH; J.Org.Chem.; EN; 43; 9; 1978; 1684-1687;
-------------------------

Reactant BRN 2556909 C9H8BrNO2
Product BRN 3240553 2-(4-bromo-phenyl)-1-methyl-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 94 percent (BRN=3240553)
Reagent BH3,NaBH4
Other Conditions Heating
Ref. 1 5553294; Journal; Kabalka, George W.; Varma, Rajender S.; Gai, Yuan-Zhu; Baldwin, Ronald M.; TELEAY; Tetrahedron Lett.; EN; 27; 33; 1986; 3843-3844;
-------------------------
Reactant BRN 3557016 4-chloro-3-ethoxycarbamido-$b-nitrostyrene
Product BRN 3591629 4-chloro-3-ethoxycarbamido-$b-phenethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent H2, conc. H2SO4
Catalyst 10percent Pd/C
Solvent acetic acid
Time 2 hour(s)
Temperature 70 C
Pressure 60004.8 Torr
Note 1 Yield given
Ref. 1 5501987; Journal; Memetzidis, Georges; Stambach, Jean-Francois; Jung, Louis; HTCYAM; Heterocycles; EN; 31; 2; 1990; 341-351;
-------------------------
Reactant BRN 4501552 $a-(2-trifluoromethyl-4-quinolyl)-$b-nitropropene
Product BRN 6728518 $a-(2-trifluoromethyl-4-quinolyl)-$b-aminopropane
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 55 percent (BRN=6728518)
Reagent hydrogen
Catalyst Raney Ni
Solvent methanol
Other Conditions 1.) 3.6 atm, 4 h, r.t; 2.) 45 deg C, overnight
Ref. 1 5861994; Journal; Monti, D.; Gramatica, P.; Manitto, P.; FRPSAX; Farmaco Ed.Sci.; EN; 36; 6; 1981; 412-418;
-------------------------
Reactant BRN 4603382 C21H18BrNO7S
Product BRN 4588941 toluene-4-sulfonic acid 2-(2-amino-3-furan-2-yl-propyl)-6-bromo-4-methoxy-phenyl ester
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent aluminum hydride
Solvent tetrahydrofuran
Note 1 Yield given
Ref. 1 5547761; Journal; Darlington, W. H.; Szmuszkovicz, J.; TELEAY; Tetrahedron Lett.; EN; 29; 16; 1988; 1883-1886;
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Reactant BRN 4863315 2-(2-nitropropen-1-yl)-5-bromothiophene
Product BRN 4904363 2-[2(RS)-aminopropyl]-5-bromothiophene
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent 1.) 1.0 M borane, sodium borohydride, 2.) 10 percent aq. HCl
Other Conditions 1.) THF, reflux, 26 h, 2.) THF, from 65 deg C to 70 deg C, 2 h
Note 1 Yield given. Multistep reaction
Ref. 1 5596922; Journal; Goodman, Mark M.; Kabalka, George W.; Marks, Ronald C.; Knapp, F.F.; Lee, J.; Liang, Y.; JMCMAR; J.Med.Chem.; EN; 35; 2; 1992; 280-285;
-------------------------
Reactant BRN 4864718 4-bromo-2-methoxy-1-(2-nitro-vinyl)-benzene
Product BRN 4905080 2-(4-bromo-2-methoxyphenyl)aminoethane
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 87 percent (BRN=4905080)
Reagent LiAlH4, H2SO4
Solvent tetrahydrofuran
Other Conditions Ambient temperature
Ref. 1 5595464; Journal; Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; JMCMAR; J.Med.Chem.; EN; 35; 4; 1992; 734-740;
-------------------------

Reactant BRN 4869621 1-bromo-2,5-dimethoxy-4-(2-nitro-propenyl)-benzene
Product BRN 2807278 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane
No. of Reaction Details 2
-------------------------

Reaction Details 1 of 2

Reaction Classification Preparation
Reagent LiAlH4, H2SO4
Solvent tetrahydrofuran
Other Conditions Ambient temperature
Ref. 1 5595464; Journal; Glennon, Richard A.; Raghupathi, Reva; Bartyzel, Piotr; Teitler, Milt; Leonhardt, Sigrun; JMCMAR; J.Med.Chem.; EN; 35; 4; 1992; 734-740;
-------------------------

Reaction Details 2 of 2

Reaction Classification Preparation
Reagent LiAlH4
Ref. 1 82030; Journal; Barfknecht,C.F.; Nichols,D.E.; JMCMAR; J.Med.Chem.; EN; 14; 1971; 370-372;

Reactant BRN 5557139 1-(2,5-dimethoxy-3-bromophenyl)-2-nitropropene
Product BRN 5741628 (+/-)-1-(2,5-dimethoxy-3-bromophenyl)-2-aminopropane
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent AlH3
Solvent tetrahydrofuran
Time 1 hour(s)
Other Conditions Ambient temperature
Ref. 1 5697427; Journal; Glennon, Richard A.; Liebowitz, Stephen M.; Anderson, George M; JMCMAR; J.Med.Chem.; EN; 23; 3; 1980; 294-299;
-------------------------

Reaction

Reaction ID 3581967
Reactant BRN 6418921 5-Brom-4-O-ethoxycarbonyl-$b-nitrostyrol
Product BRN 6481422 1-(5-Brom-4-O-ethoxycarbonyl-phenyl)-2-aminoethan
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent Zn<Hg>, conc aq. HCl
Solvent tetrahydrofuran
Time 2 min
Other Conditions Heating
Note 1 Yield given
Ref. 1 5806200; Journal; Pachaly, Peter; Schaefer, Michael; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 322; 1989; 477-482;

Reaction

Reaction ID 4099449
Reactant BRN 7139382 C17H13ClN2O2
Product BRN 7168969 2-[1-(4-chloro-benzyl)-1H-indol-3-yl]-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 74 percent (BRN=7168969)
Reagent LiAlH4
Solvent tetrahydrofuran
Time 1.5 hour(s)
Other Conditions Heating
Ref. 1 5946950; Journal; Guengoer, Timur; Malabre, Patrice; Teulon, Jean-Marie; Camborde, Francoise; Meignen, Joelle; et al.; JMCMAR; J.Med.Chem.; EN; 37; 25; 1994; 4307-4316;

Reaction

Reaction ID 4304654
Reactant BRN 1986470 C10H10BrNO4
Product BRN 2806297 3-bromo-4,5-dimethoxy-phenethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Other Conditions (electrochemical reduction)
Ref. 1 16508; Journal; Bessho,K.; CPBTAL; Chem.Pharm.Bull.; EN; 11; 1963; 1500-1503;

Reaction

Reaction ID 4309901
Reactant BRN 2535283 C10H10BrNO4
Product BRN 2806296 (2-bromo-3,4-dimethoxyphenyl)ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent aq. HCl, AcOH
Solvent tetrahydrofuran
methanol
Other Conditions (electrochemical reduction)
Ref. 1 16506; Journal; Bessho,K.; CPBTAL; Chem.Pharm.Bull.; EN; 11; 1963; 1491-1494;

Reaction

Reaction ID 4443400
Reactant BRN 7425239 4-bromo-1-methoxy-2-(2-nitro-vinyl)-benzene
Product BRN 7289804 2-(2-methoxy-5-bromophenyl)ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent LAH
Solvent tetrahydrofuran
Ref. 1 6008913; Journal; Bell, Frank W.; Cantrell, Amanda S.; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; JMCMAR; J.Med.Chem.; EN; 38; 25; 1995; 4929-4936;

Reaction

Reaction ID 4696460
Reactant BRN 7702035 1-nitro-2-(2'-chlorothien-3'-yl)ethylene
Product BRN 7700072 2-(2-chloro-thiophen-3-yl)-ethylamine
No. of Reaction Details 1
-------------------------

Reaction Details

Reaction Classification Preparation
Yield 90 percent (BRN=7700072)
Reagent LiAlH4
Solvent diethyl ether
Time 6 hour(s)
Other Conditions Heating
Ref. 1 6054410; Journal; Othman, Mohamed; Pigeon, Pascal; Decroix, Bernard; TETRAB; Tetrahedron; EN; 53; 7; 1997; 2495-2504;

Reaction

Reaction ID 4880729
Reactant BRN 4582971 (E)-5-bromo-3-nitrovinyl-7-(p-toluenesulfonyloxy)indole
Product BRN 7942750 5-bromo-7-(p-toluenesulfonyloxy)tryptamine
No. of Reaction Details 1
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Reaction Details

Reaction Classification Preparation
Yield 72 percent (BRN=7942750)
Reagent LIAlH4
Solvent tetrahydrofuran
Time 2 hour(s)
Other Conditions Ambient temperature
Ref. 1 6091633; Journal; Murakami, Yasuoki; Watanabe, Toshiko; Takahashi, Hiroyuki; Yokoo, Hiroshi; Nakazawa, Yoshie; et al.; TETRAB; Tetrahedron; EN; 54; 1-2; 1998; 45-64;

Reaction

Reaction ID 5022415
Reactant BRN 8057701 (E)-5-bromo-3-(2-nitroethenyl)-1H-indole
Product BRN 143491 2-(5-bromo-indol-3-yl)-ethylamine
No. of Reaction Details 1
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Reaction Details

Reaction Classification Preparation
Reagent LiAlH4
Solvent tetrahydrofuran
Time 5 hour(s)
Other Conditions Ambient temperature
Ref. 1 6128264; Journal; Mor, Marco; Rivara, Silvia; Silva, Claudia; Bordi, Fabrizio; Plazzi, Pier Vincenzo; et al.; JMCMAR; J.Med.Chem.; EN; 41; 20; 1998; 3831-3844;


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-the good reverend drone


 
K.C. Nicolaou
Member   posted 12-15-1999 10:56 PM          
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Well Rev, I guess that eliminating the rxn conditions that'll reduce the aryl halide leaves... the other rxn conditions . Seriously though, I would guess that LAH in ether/THF, Red-AL(I was told by a very bright professor of mine that this was almost identical in reactivity in LAH, so until someone tells me he's wrong I'll keep assuming that), superhydride, NaBH4/BH3, and maybe DIBAL-H. I'd try to use a very small excess of reducing agent and keep the temp reasonable as well. With some of those reagents, you may have a situation where dehalogenation will take place at high temps and large excesses of reducing agents but not under milder conditions. I would think that out of all of those, the NaBH4/BH3 reduction would be the most user friendly and least likely to remove the halide.
As for catalytic hydrogenation, I don't think it's necessarily a matter of dismissing it across the board, it's just that all of the catalyst systems(Pd/Pt) that I know of that reduce the nitrostyrene would also reduce the C-X bond as well. As far mechanistic reasons, as far as I know, the current "accepted" mechanism for catalytic hydrogenation is basically an educated guess(although a very likely true one) that has never really been proven. So I'm not even going to mess with guessing at how you would do that reduction selectively with H2.

Also, not to be nitpicky, but I'll point out that NaBH4/BF3 just implies in-situ production of BH3 due to

3NaBH4 + BF3 -> 3NaF + 4BH3

and(I'm pretty sure, but not positive) the Cu(+) aids the LiAl(OMe)3H reduction by promoting a SET mechanism, not a nucleophillic substitution mechanism. Al(OMe)3H(-) would be a pretty shitty nucleophile. Much worse that AlH4(-).


rev drone
Member   posted 12-16-1999 07:47 AM          
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KCN,
Yes, as it turns out, the few nitrostyrene reduction procedures involving dehalogenation involved reaction times of 16 hours under reflux with considerable LAH excess.

Catalytic hydrogenation has one of the most well-studied, well-established mechanisms in organic chemistry. Admittedly, no mechanism can be definatively proven due to the uncertainty inherent the location of the electrons involved, but it still comes as close to certainty as any. Now I understand the overlapping involved between the pi bond and the empty d-orbitals in the catalyst, but if this is the same mechanism responsible for dehalogenation, then it sould be pretty easy to find a catalyst whose empty orbitals are the perfect shape for pi-bonds, but lousy for overlapping with the filled pi-orbitals in halogens -- the geometries are just so different. There's got to be some mild homogeneous caalyst out there that has been designed to do just that industrially -- time to hit the books!

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-the good reverend drone


 
Rhodium
Administrator   posted 12-16-1999 02:53 PM          
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What is a "SET" mechanism?
 
K.C. Nicolaou
Member   posted 12-17-1999 01:20 AM          
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Single Electron Transfer. Often promoted by Cu(+) salts.
 
Rhodium
Administrator   posted 12-18-1999 02:51 PM          
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Oh, so that's why Cu+ is able to bring about all those nifty aryl halide substitutions I have read so much about - it makes a free radical out of the ring carbon... Thanks!
 
rev drone
Member   posted 12-19-1999 08:11 AM          
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Rh,
Well, yes and no. Actually, I know for a fact that nucleophilic substitutions promoted by CuI or CuBr with heat (for example, the replacement of a halide with a perfluoroalkyl group) actually doesn't involve any single electron transfer mechanism, but rather goes through a Cu(III) intermediate. This fascinating and often misunderstood mechanism is a personal favorite, and was part of a undergrad research project of mine. I don't have the paper I wrote on it with me, but I'll send ref's on this unique mechanism shortly.

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-the good reverend drone


 
Rhenium
Member   posted 12-20-1999 07:05 AM          
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Ok, it's late at night, and I haven't had a chance to read all of this especialy Drone's Bielstein cut and paste.
However, reduction of Iodo-benzoic acid methyl ester normally gives low yields of the alcohol with much impurity.
However addition of just one equivalent of AlCl3 gave wonderful product in good yield.
Now maybe this isn't all that relevant, but I have found for that reaction and others of simple halogenated systems to be quite effective. This I think is covered in a few of the references which Drone posted.
Just my tired 2 cents.
Rhenium


chemstu
Junior Member   posted 12-27-1999 10:07 PM          
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                :                                                                    :     ):
 
chemstu
Junior Member   posted 12-27-1999 10:08 PM          
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