Acme (Hive Bee)
10-24-01 06:01
No 228214
      J Med Chem Paper with DOB-like phenethylamines     

J Med Chem 2001, 44, 3283-3291

Compound 6 looks very accessible

and with a Ki of 13 nM in an 5-HT2A

where DOB is 32 nM.

They also mention compound 2, whose work is in press, that is 8nM.

And what the hell are these sarpogrelate and SR46349B chemical entities all about?
(Hive Bee)
10-24-01 07:59
No 228228
      Re: J Med Chem Paper with DOB-like phethylamines     

In response to:
Poster: Acme
Subject: J Med Chem Paper with DOB-like phethylamines
[snip] And what the hell are these sarpogrelate and SR46349B chemical entities all about?

They are 5HT antagonists at the receptor level.  (as opposed to the reuptake level)
(Hive Bee)
10-24-01 08:52
No 228245
      Re: J Med Chem Paper with DOB-like phethylamines     

antagonism at the receptor level sounds like a bummer

but do they have any interesting properties or uses is more the question, i've never heard of them.

(Hive Bee)
10-24-01 11:20
No 228277
      Re: J Med Chem Paper with DOB-like phenethylamine
(Rated as: excellent)

Okay, so here's the deal (as I know it):

They found that the 2,5-Dimethoxy substituent pattern was not required for high receptor binding affinity in 5HT2A ligands, but the catch being that they exibit antagonistic character. Sarpogrelate and SR46349B are just standard 5-HT2 antagonists that these novel antagonists are being compared to. Like how novel 5-HT1A,2A&2C agonists are compared to DOI, LSD, or LY293284.

Out of the Phenylisopropylamines, the DOB and DOTFM analouges with the Benzodifuran1,2, and Tetrahydrobenzodifuran3 moieties seem to be the most potent agonists (=fun).

I still find DOTFM interesting, as it is easily accessable through DOI or DOB, although still being about equipotent. It's effects in humans is still largely unknown, unless you are inclined to believe Drone's rumors in Post 122784 (dormouse: "Bromo-benzodifuranyl-isopropylamine  -Lilienthal", Serious Chemistry). I know that humans are virtually unable to metabolize Trifluoromethyl groups, apperently it just won't leave the receptor? Its ridiculously electronegative, And still very hydrophobic -- it CAN'T hydrogen bond to anything. No enzyme can bind to it. As Dr. Shulgin put it "its the world's shortest length of teflon", and essentially that is what it is. (To borrow a few word's from Drone)

On a similar note, does anyone know why the 4-Cyano or Isocyano compounds have not been explored? These are also easily accessable from the aromatic halogens. I remember Assholium talked of 2-C 4-thiocyanate, and gave conformation that it was indeed active (and fun!).laugh


1) J. Med. Chem. 44, 2001, 1003-1010 (../rhodium/pdf /nichols/nichols-dragonfly-2.pdf)
2) J. Med. Chem. 41, 1998, 5148-5149 (../rhodium/pdf /nichols/nichols-dragonfly-1.pdf)
3) J. Med. Chem. 39, 1996, 2953-2961 (../rhodium/pdf /nichols/nichols-dihydrobenzofuran-3-fly.pdf)

All by the Nichols group of course.wink
(Chief Bee)
10-24-01 12:42
No 228290
      Re: J Med Chem Paper with DOB-like phenethylamine     

How do you make the Cyano or Isocyano from the halogenated PEA?
(Hive Bee)
10-24-01 13:45
No 228313
      Re: J Med Chem Paper with DOB-like phenethylamine     

Post 108811 (dormouse: "Thiocyanation of 2C-H  -Rhodium", Novel Discourse)
(Chief Bee)
10-24-01 19:22
No 228385
      Re: J Med Chem Paper with DOB-like phenethylamine     

That is a procedure for the thiocyanate - that shouldn't work with cyanide... And besides, the procedure does not start with the halo PEA.
(Hive Bee)
10-24-01 20:08
No 228392
      Re: J Med Chem Paper with DOB-like phenethylamine     

The cyano compound could be made by preparing the 4-carboxylic PEA, then converting it to the nitrile in the last step. the carboxylate could be prepared by coverting 4-bromo-2,5-dimethoxybenzaldehyde to its corresponding dioxolane, then treating with magnesium to form the Grignard reeagent. The grignard intermediate is then treated with dry ice, and there you have it.
(Chief Bee)
10-24-01 22:01
No 228417
      Re: J Med Chem Paper with DOB-like phenethylamine     

I think I'd rather do a sandmeyer on a 4-amino-PEA. I have found quite a few references on such reactions where the aliphatic amine is left untouched.

BTW, can you do a sandmeyer with copper(I)azide, or will it explode?
(Hive Bee)
10-24-01 23:05
No 228439
      Re: J Med Chem Paper with DOB-like phenethylamine     

I't might work, but Cu.azide is much less stabel than lead azideblush
(Hive Bee)
10-25-01 03:27
No 228506
      Re: J Med Chem Paper with DOB-like phenethylamine     

No no no...

4-Halo-PEA with Zn(CN)2 or CuCN, in DMF or Dimethylacetamide catalysed by a Pd(0) Complex. Like Pd(PPh3)4, although other ligand complexes give better conversion. High yields (>90%) when the ring is sufficiently activated.

As usual, references available on request.wink
(Hive Bee)
10-25-01 04:01
No 228511
      Re: J Med Chem Paper with DOB-like phenethylamine     

Acid to ester (drop sulf in MeOH), ester to carboxamide (liq NH3, sealed tube cool or aq NH3 reflux), POCl3 reflux strip, very quantitative

maybee Boc or Z here
then you can do a Pinner reaction thereafter 1 eq EtOH, HCl(g) bnezene/DCM
to get the amino imidate salt,
then amidine, cyclic or not or aminooxime in EtOH or AcOH maybee

or tertrazole with Na azide hell might even be able to do that directly from free amine cyano compound

Maybee the oxadiazole too from the Ester

whatever you would want to
but what would you want to do?
of that which remains to be done
this compound 2 from the paper I mentioned
with 2 nM
is a n-propyl-3-phenyl
(Hive Bee)
10-25-01 10:42
No 228629
      Re: J Med Chem Paper with DOB-like phenethylamine     

BTW: I wouldn't be surprised if gamma-2C-T-4 and gamma-DOM
are 5ht2-antagonists too. Would explain why they're `weird' compounds.
(Chief Bee)
10-25-01 11:40
No 228635
      Re: J Med Chem Paper with DOB-like phenethylamine     

Slappy: Refs for that Cyano/Pd reaction, please!

Yellium: What do you mean by "gamma-DOM"?
(Hive Bee)
10-25-01 18:47
No 228715
      Re: J Med Chem Paper with DOB-like phenethylamine     

PiHKAL #69. Compare also TMA-6, which also has no 2,5-substitution pattern.

(Chief Bee)
10-25-01 23:43
No 228786
      Re: J Med Chem Paper with DOB-like phenethylamine     

That's not gamma, it's Psi (Pseudo).
(Hive Bee)
10-25-01 23:49
No 228792
      Pd-catalyzed Cyanation of Aryl Halides
(Rated as: excellent)

All of these routes are very similar. All using either the Aryl Bromide or Chloride. Zn(CN)2 as the CN donor. Catalytic amounts of the Pd(0) complex, like Pd2(dba)3[tris(dibenzylideneacetone)dipalladium] which gives the best results, or Pd(PPh3)4 and dppf [1,10-bis(diphenylphosphino)ferrocene], which is commonly used as a ligand to enhance the reactivity of a palladium complex, in a polar aprotic solvent like MeCN, N,N-Dimethylformamide(DMF), N,N-Dimethylacetamide(DMA), 1-Methyl-2-Pyrrolidinone(NMP) are all suitable solvents. Although wet DMF seemes to give the best results. Mild heat (<150C) and agitation.

Tetrahedron Lett. 40 (1999) 8193-8195
       - Aryl Bromide, Zn(CN)2 and a variety of Palladiu-Phosphine ligand complexes
Tetrahedron Lett. 41 (2000) 3271-3273
       - Aryl Chloride, Zn(CN)2, and catalytic amounts of Pd2(dba)3, dppf, and Zn(dust) in DMA. >90% yields.
Synth.Commun. 24,6 (1994) 887-890
       - ArX + Zn(CN)2+ Pd(PPh3)4, in DMF, 6h @ 80C
Collect.Czech.Chem.Commun. 48,6 (1983) 1765-1773
       - Similar to above, but using Crown Ethers
Can.J.Chem. 63 (1985) 111-120
       - ArX, CuCN, Pd(0) in DMA
J.Org.Chem. 51,24 (1986) 4714-4716
       - ArX, Et3, Pd(PPh3)4
(Hive Bee)
10-26-01 16:03
No 229034
      Re: J Med Chem Paper with DOB-like phenethylamine     

I took it from the online version of pihkal (@erowid). Shulgin himself is also not really clear about gamma and psi tongue.

From the TMA-6 entry:

[...] And the first indicators are that, in keeping the 2,6-dimethoxy aspect intact, a completely analogous series could be made, again with modifications of the 4-position. These have been named the psu-series, or psi-series, as an abbreviation for the prefix, pseudo,
and can be differentiated from the 2,4,5-things with the use of the Greek letter "gamma". Thus there is the gamma-DOM (called Z-7 in this book, and certainly an active compound), and gamma-DOB, gamma-DOET, gamma-DOI, and the gamma-ALEPH compounds. And, of course, the gamma-2C-X counterparts. I would expect all of them to be active and, certainly, some of them interesting. They will be considerably more difficult to synthesize. However, some of them, specifically things such as gamma-2C-T-4, have already been prepared, and are being evaluated.

(Chief Bee)
10-26-01 16:25
No 229040
      Re: J Med Chem Paper with DOB-like phenethylamine     

There is the source of confusion. In the real book, the letter Psi is represented, but they have translated it wrong to "gamma" in the online version. Could somebody ask erowid to change that?
(Hive Bee)
10-26-01 18:18
No 229061
      4-cyano-2,5-dimethoxy-PEA (2C-CN) and DOCN
(Rated as: good read)

Just for the record, 4-cyano-2,5-dimethoxy-PEA and its corresponding amphetamine have been synthesized. The experimental details can be found in J. Med. Chem. 27(4), 513-520 (1984) (../rhodium/pdf /2c-c.2c-cn.synthesis.pdf)
(Chief Bee)
10-26-01 18:27
No 229066
      Re: J Med Chem Paper with DOB-like phenethylamine     

Oh, great! Do you know if the -SCN, -OCN, -N3 or other pseudohalogenide derivatives has been made in the open literature?
(Hive Bee)
10-27-01 01:54
No 229163
      Re: J Med Chem Paper with DOB-like phenethylamine
(Rated as: good read)


As far as I can tell, not azido-, cyanato, or thiocyanato-2,5-dialkoxyphenethylamines exist of any kind. In fact, only a handful of phenethylamines bearing cyanates and thiocyanates have been synthesized, and none of them bear either of these groups on the 4-position.

There have, however, been a fiar number of interesting looking 4-azidophenethylamines. One in particular is 4-azido-alpha,alpha-dimethylphenethylamine (J. Biol. Chem.  (1981),  256(22),  11944-50.)
(Chief Bee)
03-15-04 16:17
No 495281
      Dihydrobenzofuran precursor synthesis
(Rated as: excellent)

These compounds are suitable for the preparation of the compounds in Post 228277 (slappy: "Re: J Med Chem Paper  with DOB-like phenethylamine", Methods Discourse)

Synthesis of Dihydrobenzofurans from Phenolic Mannich Bases and their Quaternized Derivatives
By Artur Blade-Font and Teodoro de Mas Rocabayera
J. Chem. Soc. Perkin Trans. 1. 841-848 (1982) (../rhodium/pdf /dihydrobenzofurans.mannich.pdf)

Reaction of dimethylsulphoxonium methylide with quaternized derivatives of phenolic Mannich bases, and in certain cases with the bases themselves, constitutes a useful synthesis of dihydrobenzofurans. On the other hand treatment of those same quaternized derivatives with diazomethane may be a useful alternative procedure for the preparation of coumarans with base-sensitive groups.

The Hive - Clandestine Chemists Without Borders
(Hive Bee)
04-04-04 15:40
No 499013
      Cyanation using CuCN/NMP & MW irradiation
(Rated as: good read)

Efficient Microwave-Assisted Cyanation of Aryl Bromide
Liangzhen Cai; Xin Liu; Xiaochun Tao; Dong Shen

Synthetic Communications 34(7), 1215-1221(2004)

Aryl nitriles were easily prepared from the corresponding bromides and copper cyanide in good yields through microwave-accelerated Rosenmund-von Braun reaction in N-methylpyrrolidinone (NMP) under ambient pressure.


Scheme 1. Cyanation of aryl bromide using MW irradiation.


Microwave-Enhanced Cyanation of Aryl Bromides; General Procedure

A mixture of aryl bromide (10 mmol), CuCN (1.2 g, 13 mmol), and 10 mL of NMP was subjected to microwave irradiation (200 W) under ambient pressure for an optimized time listed in Table 1. The reaction was monitored by TLC. After irradiation, the mixture was cooled to room temperature and then diluted with 20 mL of ice water. The precipitates were collected by filtration and treated with aqueous ammonia. The crude product was taken up into chloroform followed by filtration. After removal of the solvent, the product was further purified by recrystallization from aqueous ethanol.

Table 1. MW-assisted CuCN-mediated synthesis of aryl nitriles in NMP.

Entry Substrates Time (min) Isolated Yield (%) M.p. (obs.) (C) M.p. (lit.) (C)
1 Bromobenzene 20 90 oil ---
2 1-Bromonaphthalene 25 85 37-38 38 (8)
3 4-Phenyl-1-bromobenzene 25 87 83-84 86-87 (9)
4 1-Bromo-4-nitrobenzene 20 56 148-149 148-150 (8)
5 4-Bromobenzonitrile 20 78 223-224 222 (10)
6 4-Bromoanisole 30 75 55-56 56-57 (12)
7 1,4-Dibromobenzene 25 68 224-225 227 (10)
8 5-Bromoindole 30 79 102-104 104-106 (11)


[1] Friedrich K., Waaensfels K. The Chemistry of Cyano Group, Rappoport Z. Wiley-Interscience, New York, 1970.
[2a] Norris J. F., Klemka A. J., J. Am. Chem. Soc., 62 (1940) 14321435.
[2b] Reid W. B., Hunter J. H., J. Am. Chem. Soc., 70 (1948) 3515.
[2c] McElvain S. M., Stevens C. L., J. Am. Chem. Soc., 69 (1947) 26632666.
[2d] Reisner D. B., Horning E. C., Organic Syntheses,  Wiley, New York, 1963, p. 144.  Col. 4.
[2e] Kanaoka Y., Kuga T., Tanizawa K., Chem. Pharm. Bull., 18 (1970) 397399.
[2f] Yamato E., Sugasawa S., Tetrahedron Lett., 50 (1970) 43834384.
[2g] Dennis W. E., J. Org. Chem., 35 (1970) 32533255.
[3a] Rogic M., van Peppen J. F., Klein K. P., Demmin T. R., J. Org. Chem., 39 (1974) 34243426.
[3b] Olah G. A., Vankar Y. D., Synthesis, (1978) 702703.
[3c] Olah G. A., Vankar Y. D., Garcia-Luna A., Synthesis, (1979) 227228.
[3d] Molina P., Alajarin M., Vilaplana M. J., Synthesis, (1982) 1016.
[3e] Arrieta A., Paloma C., Synthesis, (1983) 472474.
[3f] Katrizky A. R., Zhang G. F., Fan W. G., Org. Prep. Proc. Int., 25 (1993) 315319.
[3g] Tamami B., Kiasat A. R., Synth. Commun., 30 (2000) 235242.
[4a] Rosenmund K. W., Struck E., Ber., 52 (1919) 1749.
[4b] von Braun J., Manz G., Ann., 488 (1931) 111126.
[4c] Ito T., Watanabe K., Bull. Chem. Soc. Jpn., 41 (1968) 419423.
[4d] Ellis G. P., Romney-Alexander T. M., Chem. Rev., 87 (1987) 779793.
[4e] Brandsma L., Vasilevsky S. F., Application of Transition Metal Catalysts in Organic Synthesis,  Springer-Verlag, Berlin, 1998, p. 149.
[5a] Varma R. S., Green Chem., 1 (1999) 4355.
[5b] Strauss C. R., Aust. J. Chem., 52 (1999) 8396.
[5c] Varma R. S., Pure Appl. Chem., 73 (2001) 193198.
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[5e] Larhed M., Moberg C., Hallberg A., Acc. Chem. Res., 35 (2002) 717727.
[6] Alterman M., Hallberg A., J. Org. Chem., 65 (2000) 79847989.
[7] Arvela R. K., Leadbeater N. E., Torenius H. M., Tye H., Org. Biomol. Chem., 1 (2003) 11191121.
[8]Cadogan J. I.G., Leg S. V., Pattenden G., Dictionary of Organic Compounds 6th Ed., Chapman and Hall, New York, pp. 46784758.
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[10] Weissberger S., J. Chem. Soc., 1 (1935) 855.
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(Hive Bee)
10-12-04 05:35
No 535521
      Here is a complete article mentioned by ...
(Rated as: good read)

Here is a complete article mentioned by Megamole in Post 229163 (megamole: "Re: J Med Chem Paper  with DOB-like phenethylamine", Methods Discourse). I hope you'll enjoy it.

Photoaffinity Labeling of the beta-Adrenergic Receptor
Thomas N. Lavin, Sarah L. Heald, Peter W. Jeffs, Robert G. L. Shorr, Robert J. Lefkowitz, and Marc G. Caron
Journal of Biological Chemistry, Vol. 256 (22), 11944-11950 (1981)