Hi my friends!
If you direct your attention to J. Org. Chem. 42, 1784 (1977), you will
discover the reagent 1-dimethylamino-2-nitroethylene (DMANE), which is easily
prepared from the inexpensive reagents DMF, dimethylsulfate, nitromethane and
sodium ethoxide. The reagent is capable of directly adding the 2-nitrovinyl
(-CH=CH2-NO2) side chain to the 3-position of indole, as well as a variety of
substituted benzenes. Do you have some 4-acetoxyindole lying around, but don't
want to go through the hassle of using oxalyl chloride when making a 4-hydroxy
tryptamine out of it? Then turn to DMANE, which is dissolved in TFAA, and the
4-acetoxyindole dumped right in. Ten minutes later you return, remove the
solvent and let your product 3-(2-Nitrovinyl)-4-acetoxyindole crystallize in
almost 80% yield, ready to become reduced to 4-hydroxytryptamine. We can also
imagine that you are sitting with some 2,5-dimethoxyphenyl propyl sulfide, and
want to turn it into a juicy phenethylamine. You can either subject it to a
vilsmeyer formylation, followed by a Knoevenagel condensation with nitromethane
to give you the nitrostyrene, or - you can simply get it in one step with this
reagent. If you turn down this reagent with the excuse that you don't want any
low potency phenethylamines, I can tell you about the homolog you can use to
create phenylnitropropenes just as easy - 1-Dimethylamino-2-nitropropene.

Below, I have included a few examples of the reagent, applied to various indole
substrates, and even further down, you'll find preparation details of both the
above-mentioned nitro reagents, as well as how to prepare a DMF/Me2SO4 complex
needed for doing it.

There is one downside to the procedure, and that is that the preferred solvent
for the reaction seems to be trifluoroacetic acid. The authors of the above
article mentions some italians who were using the reagent in ethanolic HCl
(but with relatively low yields), so TFAA is at least not ubiquitous.
Do anyone have an educated guess as to what could be a decent substitute for
TFAA as solvent in a reaction like this? And one more thing, could someone
with access to Beilstein or something run a search on these two nitro reagents
for possible later articles dealing with them than the ones I've already found.

3-(2-Nitrovinyl)indole
----------------------
To a stirred solution of 1-dimethylamino-2-nitroethylene in trifluoroacetic
acid (15 mL) at ice-bath temperature was added 3.51 g (30 mmol) of indole and
the mixture was stirred in a nitrogen atmosphere for 10 min. During this time
the color of the solution changed from light yellow to dark. The mixture was
then allowed to warm up to room temperature and was poured into ice water
(300 mL), from which a yellow semisolid precipitated. The aqueous solution was
extracted with ethyl acetate (350 mL) and then twice with the same solvent
(100 mL). The combined organic phases were washed with saturated NaHCO3
solution (150 mL) and with saturated NaCl solution (100 mL) and dried (Na2SO4).
Removal of solvent in vacuo afforded 5.40 g (96%) of a yellow solid.
Recrystallization from hot methanol gave yellow prisms: mp 172°C (lit 171°C).

Ref: JOC 42, 1784 (1977)

3-(2-Nitrovinyl)-5-methoxyindole
--------------------------------
A 15-mL flask equipped with reflux condenser was charged with 580 mg (5 mmol)
of 1-dimethylamino-2-nitroethene and 3 mL of trifluoroacetic acid. To this
stirred solution was added 735 mg (5 mmol) of 5-methoxyindole. The resulting
suspension was heated to 30-45°C for 10 min and the solution was then allowed
to cool. The dark slurry was poured into ice water. Extraction with ethyl
acetate was followed by washing of the organic layer with saturated NaHCO3 and
saturated NaCl solution. After drying (Na2SO4), the solvent was evaporated,
yielding 1.1 g of dark green crystals. Purification by column chromatography
(100 g, silica gel, CH2Cl2) yielded 60 mg (8%) of unreacted5-methoxyindole
and 697 mg (64%) of 3-(2-nitrovinyl)-5-methoxyindole. Recrystallization from
acetone/hexane gave yellow needles: mp 162-165°C (lit 157-158°C).

Ref: JOC 42, 1784 (1977)

3-(2-Nitrovinyl)-4-acetoxyindole
--------------------------------
To a solution of 175 mg (1.0 mmole) of 4-acetoxyindole in 1 ml of trifluoro-
acetic acid was added 116 mg (1 mmole) of 1-dimethylamino-2-nitroethylene.
The reaction mixture was heated at 55°C under a nitrogen atmosphere for 10
minutes during which time the light yellow solution became dark red. The
reaction was cooled to room temperature and the solvent distilled under
reduced pressure. The resulting red oil was dissolved in 2 ml of chloroform
and the solvent removed in vacuo. This was repeated with 3 ml of dioxane.
Addition of 1 ml of ethyl acetate and scratching induced crystallization of
the residue. Hexane (0.25 ml) was added and the yellow needles collected by
filtration and dried in vacuo to give 191 mg of 3-(2-Nitrovinyl)-4-acetoxy-
indole (78%), mp 200-203°C (dec).

Ref: J. Heterocyclic. Chem. 18, 175 (1981)

N,O-Diacetyl-4-hydroxytryptamine
--------------------------------
3-(2-Nitrovinyl)-4-acetoxyindole (335 mg, 1.36 mmoles) was dissolved in 4 ml
of tetrahydrofuran and added to a stirred suspension of 300 mg (7.89 mmoles)
of lithium aluminum hydride in 5 ml of tetrahydrofuran. After the addition
the reaction was refluxed for 20 minutes, cooled to room temperature, and
water added dropwise until gas evolution ceased. The mixture was filtered
(Celite, dry nitrogen atmosphere) and the filtrate concentrated under
reduced pressure. The resulting clear syrup (slight blue tinge) was dissolved
in a mixture of 5 ml of pyridine and 3 ml of acetic anhydride. After standing
overnight at room temperature the solvents were distilled under reduced
pressure and the residue purified by preparative thin-layer chromatography in
5% methanol in chloroform. The eluted (ethyl acetate) product was crystallized
from ethyl acetate/hexane to give 94 mg (26%), mp 150°C.

Ref: J. Heterocyclic. Chem. 18, 175 (1981)

N,N-dimethylformamide and dimethylsulfate complex
-------------------------------------------------
The reaction between N,N-dimethylformamide and an equimolar amount of dimethyl-
sulfate (which takes two days at room temp, and two hours at 60-80°C, with no
solvent added) furnishes the O-methyl complex of the amide. The formation of the
complex is revealed through a change in viscosity and refraction index. Both DMF
and Me2SO4 are soluble in ether, benzene and ethyl acetate, but their complex
isn't. Upon attempted distillation of the complex, the components are re-formed.

Ref: Angew. Chem. 73, 493 (1961)

1-Dimethylamino-2-nitroethylene
-------------------------------
To a solution of 2.3 grams of sodium metal in 100 ml of absolute ethanol,
20g of DMF/Me2SO4 complex and 6.1 grams of nitromethane is added. The
mixture is heated to a boil for 1-2 minutes, cooled to room temperature,
and the solvent was then evaporated in vacuum. The mixture is then extracted
with methylene chloride, the solvent is again evaporated in vacuum, and the
residue is washed with cold isopropanol, and then recrystallized from the
same solvent. The yield is 60% of melting point 104°C.

Ref: Ber 98, 3847 (1965)

1-Dimethylamino-2-nitropropene
------------------------------
A solution of 10 grams of sodium metal in 500ml of absolute ethanol is cooled
to 10°C and 90 grams of DMF/Me2SO4 complex and 47.5 grams of nitroethane is
added. The solution is shaken with cooling for five minutes, and the solution
takes on a orange-red color. The solvent is removed at 30-35°C in a rotavap,
and the solid yellow residue is extracted with methylene chloride, and the
solvent is again removed under vacuum. The orange-red oily residue is cooled
in the fridge, whereupon it crystallizes. The crystals are washed with a small
amount of cold ether, and are recrystallized from ethanol to give yellow
crystals with a melting point of 78°C in a yield of 73% of theory.

Ref: Ber 107, 1499 (1974)

Beagle
Member   posted 12-10-98 11:15 AM          
--------------------------------------------------------------------------------
Thanks, Rhodium. I knew about that reagent, but had no idea how easy it was to prepare, nor had I ever thought about its use for nitro-vinylation of dimethoxybenzenes. Do you have any info about its use in the latter instance (or do you say former in Europe?) Did you realize that the synthesis of this reagent as well as its use here in a Michael addition was described in the same paper that led to the development of the Liemgruber-Batcho indole synthesis (Ann Chem 641, 1, '61)? I didn't!
You prob. knew about the use of these similar reagents, but I'll mention them here anyway, because it makes me feel useful.

nitroethyl acetate for indoles to tryptamines:
JMC '79, 22(1) 63-
JMC '85, 28(7) 892- (get this paper! See my comments on it in the DMT BB)

nitropropene and nitrobutene from nitropropanol and nitrobutanol and thier use in tryptamine synth:
JOC '86, 51, 4294-
JOC '80, 45, 1185-

drone 342
Member   posted 12-11-98 07:26 PM          
--------------------------------------------------------------------------------
Rh,
*VERY* intersting. Here's a partial list of stuff from Beilstein, but if you want the super-delux complete list of beilstein stuff, you'll need to give me a hotmail address I can send it to (I use hotmail, but for some reason, hotmail won't allow me to send e-mails to non-hotmail accounts that are larger than 64K.)

I couldn't find *any* exaples of nitrostyrenes being generated this way, it seems it works for indoles, but either it doesn't work for benzenes, or nobody's tried it on benzenes (my guess is the former, since benzenes look like an obvious choice.)

Anyways, for indoles:

Reaction

Reaction ID 1635332
Reactant BRN 111026 1-methyl-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 1245572 1-methyl-3-(2'-nitrovinyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Yield 74. (BRN1245572)
Other conditions 1.) 0 deg C, 1 h, 2.) r.t., 5 h
Ref. 1 5852079; Journal; Mahboobi, Siavosh; Grothus, Goetz; Meindl, Wolfgang; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 327; 2; 1994; 105-114;

Reaction ID 1656814
Reactant BRN 116801 1-ethyl-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 6329927 1-ethyl-3-(2-nitrovinyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Yield 72. (BRN6329927)
Other conditions 1.) 0 deg C, 1 h, 2.) r.t., 5 h
Ref. 1 5852079; Journal; Mahboobi, Siavosh; Grothus, Goetz; Meindl, Wolfgang; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 327; 2; 1994; 105-114;

Reaction

Reaction ID 1735239
Reactant BRN 1282489 1-methoxy-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 1248670 1-methoxy-3-(2-nitro-vinyl)-indole
-------------------------

Reaction Details

Reaction Classification Preparation
Solvent acetonitrile
trifluoroacetic acid
Yield 76. (BRN1248670)
Ref. 1 5698637; Journal; Somei, Masanori; Sato, Haruhiko; Komura, Naoko; Kaneko, Chikara; HTCYAM; Heterocycles; EN; 23; 5; 1985; 1101-1106;

Reaction

Reaction ID 1801413
Reactant BRN 148770 1-methyl-2-phenyl-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 4754071 1-methyl-3-(2-nitrovinyl)-2-phenylindole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Yield 94. (BRN4754071)
Other conditions 1.) 0 deg C, 1 h, 2.) r.t., 5 h
Ref. 1 5852079; Journal; Mahboobi, Siavosh; Grothus, Goetz; Meindl, Wolfgang; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 327; 2; 1994; 105-114;

Reaction

Reaction ID 1843683
Reactant BRN 168910 1-methyl-indole-2-carboxylic acid ethyl ester
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 4515149 1-methyl-2-ethoxycarbonyl-3-(2-nitrovinyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Solvent trifluoroacetic acid
Yield 80. (BRN4515149)
Other conditions 1.) 0 deg C, 15 min; 2.) 0 deg C to room temperature
Ref. 1 5559580; Journal; Vega, A. Monge; Martinez, M. T.; Palop, J. A.; Mateo, J. M.; Fernandez-Alvarez, E.; JHTCAD; J.Heterocycl.Chem.; EN; 18; 1981; 889-892;

Reactant BRN 1903136 dimethyl-(2-nitro-vinyl)-amine
7144485 2-(4-Acetoxypentyl)-N-benzyl-indol
Product BRN 7150872 (E)-2-(4-Acetoxypentyl)-N-benzyl-3-(2-nitroethenyl)-indol
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Time 5 hour(s)
Yield 94. (BRN7150872)
Temperature 0 øC
Ref. 1 5944741; Journal; Mahboobi, Siavosh; Kuhr, Sabine; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 328; 1; 1995; 45-52;

Reactant BRN 1903136 dimethyl-(2-nitro-vinyl)-amine
7543535 N-benzyl-2-(4-hydroxypentyl)-5-methoxyindole
Product BRN 7552590 (E)-N-benzyl-2-(4-hydroxypentyl)-5-methoxy-3-(2-nitroethenyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Time 5 hour(s)
Yield 70. (BRN7552590)
Temperature 0 øC
Ref. 1 6022955; Journal; Mahboobi, Sioavosh; Kuhr, Sabine; Koller, Markus; TETRAB; Tetrahedron; EN; 52; 18; 1996; 6373-6382;

Reactant BRN 107693 indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 1284476 3-(2-Nitrovinyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent CH2Cl2
Yield 83. (BRN1284476)
Other conditions 1.) 0 deg C, 1 h, 2.) r.t., 5 h
Ref. 1 5852079; Journal; Mahboobi, Siavosh; Grothus, Goetz; Meindl, Wolfgang; ARPMAS; Arch.Pharm.(Weinheim Ger.); GE; 327; 2; 1994; 105-114;

Reactant BRN 112877 5-bromo-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 1246310 5-bromo-3-(2-nitro-vinyl)-indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3CO2H
Solvent CH2Cl2
Time 10 hour(s)
Yield 58. (BRN1246310)
Temperature 0 - 5 øC
Ref. 1 5650837; Journal; Mahboobi, Siavosh; ARPMAS; Arch.Pharm.(Weinheim Ger.); EN; 325; 4; 1992; 249-250;

Reactant BRN 122456 4-methoxy-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 4451310 E-3-(2-nitrovinyl)-4-methoxyindole
-------------------------

Reaction Details

Reaction Classification Preparation
Solvent trifluoroacetic acid
Time 30 min
Yield 56. (BRN4451310)
Other conditions Ambient temperature
Ref. 1 5566103; Journal; Repke, David B.; Ferguson, Wilfred J.; JHTCAD; J.Heterocycl.Chem.; EN; 19; 1982; 845-848;

Reaction ID 1788466
Reactant BRN 143040 4-acetoxy-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 4479870 3-(2-nitrovinyl)-4-acetoxyindole
-------------------------

Reaction Details

Reaction Classification Preparation
Solvent trifluoroacetic acid
Time 10 min
Yield 78. (BRN4479870)
Temperature 55 øC
Ref. 1 5558343; Journal; Repke, David B.; Ferguson, Wilfred J.; Bates, Dallas K.; JHTCAD; J.Heterocycl.Chem.; EN; 18; 1981; 175-179;

Reaction ID 1796480
Reactant BRN 1453805 4-butan-2-one
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 5568438 3-(2-nitrovinyl)-4-(3-oxobutyl)indole
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent CF3COOH
Solvent acetonitrile
Yield 84. (BRN5568438)
Ref. 1 5673140; Journal; Somei, Masanori; Tokutake, Shoichi; Kaneko, Chikara; CPBTAL; Chem.Pharm.Bull.; EN; 31; 6; 1983; 2153-2156;

Reaction ID 1972276
Reactant BRN 183150 4-benzyloxy-indole
1903136 dimethyl-(2-nitro-vinyl)-amine
Product BRN 4512883 E-3-(2-nitrovinyl)-4-benzyloxyindole
-------------------------

Reaction Details

Reaction Classification Preparation
Solvent trifluoroacetic acid
Time 30 min
Yield 76. (BRN4512883)
Other conditions Ambient temperature
Ref. 1 5566103; Journal; Repke, David B.; Ferguson, Wilfred J.; JHTCAD; J.Heterocycl.Chem.; EN; 19; 1982; 845-848;

Reactant BRN 1903136 dimethyl-(2-nitro-vinyl)-amine
5263113 (E)-3-(4-indolyl)propenyl acetate
Product BRN 7039029 (E)-3-<3-<(E)-2-nitroethenyl>-4-indolyl>propenyl acetate
-------------------------

Reaction Details

Reaction Classification Preparation
Reagent TFA
Solvent CH2Cl2
Time 6 hour(s)
Yield 70. (BRN7039029)
Temperature 0 - 20 øC
Ref. 1 5930331; Journal; Kardos, Nathalie; Genet, Jean-Pierre; TASYE3; Tetrahedron: Asymmetry; EN; 5; 8; 1994; 1525-1534;

drone 342
Member   posted 12-11-98 07:33 PM          
--------------------------------------------------------------------------------
BTW, I recently learned how to take advantage of even fancier features of beilstein, so now I can send beilstein outputs including structures, and a bizzilion other goodies.
Adding in all the super-delux features, Beilstein is by far the most ass-kicking piece of chemistry software I've ever seen. The price of it must be obscene (glad I get it free!), but then again, how can you put a pricetag on love?

-drone #342

Labrat
Member   posted 12-12-98 07:58 AM          
--------------------------------------------------------------------------------
The prices are pretty obscene, considering you have to pay around $1000 a year as individual or $500 if you're a university. Searching will cost you $3 per hit, so if you have to pay for this yourself, you'll have to be richer then most of us here. Love don't come cheap!
Hmmm, maybe that our university is interested in getting a subscription to the Beilstein, I'll go check that out! Lr/

drone 342
Member   posted 12-12-98 12:57 PM          
--------------------------------------------------------------------------------
LR,
Now that is a good idea! Imagine if we could half of the college-type bees to convince their universities to buy the Beilstein Crossfire software -- we'd be unstopable! With this kind of powerful database at our disposal, the sophistication and elegance in what we could do would be unreal.

In the end, everybody wins: we get the software we need, the university's get software and databases they should have already, Beilstein makes a lot of money, and a whole lot of really cool clandestine chemistry is produced. Really, if you're studying chemistry, having access to this sort of thing really helps; just don't make any plans to have a social life once you have access to it.

I visisted Beilstein's webpage, but I couldn't find any prices. What was that about $3/hit? Is that in addition to the $1000 subscription? Damn! If that's the case, I'd go through a few million dollars a year in expenses!

Beagle
Member   posted 12-12-98 01:20 PM          
--------------------------------------------------------------------------------
Drone: I run green with envy every time I see you post the output of those Beilstein mining sessions. But don't stop!
Looks like I need to update my stranded on a desert island fantasy to include a computer terminal and a satellite uplink to CAS/Beilstein.

Rhodium
Administrator   posted 12-12-98 02:15 PM          
--------------------------------------------------------------------------------
Drone: Try rhodium45@hotmail.com
In the 1977 JOC article I mention above, they make a few nitrostyrenes from activated benzene substrates. With unactivated ones, their yields drop considerably. But what PEA doesn't contain activating substituents? 

Lilienthal
Member   posted 12-13-98 06:45 AM          
--------------------------------------------------------------------------------
Another paper applying the J. Org. Chem. 51, 4294 1986 nitropropene method: J. Med. Chem. 31, 1406 1988
 
Labrat
Member   posted 12-13-98 11:44 AM          
--------------------------------------------------------------------------------
Yes, it would be really nice to get Beilstein Crossfire at the University! Preferably before I graduate! I'll make sure to check it out.
Don't go to the Beilstein homepage for their pricelist, go to http://www.chemweb.com  . Select their database price list and go to the Beilstein database. You'll see you have to pay $3 per abstract on top of the annual subscription costs of $1000 (for individuals) or $500 (for universities). Lr/

Optimus Prime
Member   posted 12-21-98 08:06 AM          
--------------------------------------------------------------------------------
For a substitution for the TFAA could one use DMF and 1-hydroxybenzotriazole the same way in forming peptides.
OP

Rhodium
Administrator   posted 12-30-98 06:52 AM          
--------------------------------------------------------------------------------
OP: Could you clarify what you wrote? Did you suggest the use of DMF, or did you ask if it could be used?
 
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