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The Chemistry of the Aminochromes. Part XVI.Proton Magnetic
Resonance Spectro~copyl,~
W . S . POW ELL,^'^ R . A . H E A CO CK ,'D. G . SMITH,'AND A .
G. M C I N N E S ~Chrrnis try Depnr.tmerzt , Dalhousir U ni~ er si
t y , a l i fau, Nova Scot ia , and Atlantic Regional Lab oratory
,National Reaerrrch Co~lncrl f Can ada, Hnli fax , No va Scoria
Received August 21 , 1972The p.m.r. spectra of a number of
aminochromes and aminochrome monosemicarbazones have beenmeasured
and the major features of the spectra discussed. The synthesis of a
new aminochrome, 2-methylnoradrenochrome is described.Les spectres
de r.m.n. d 'un certain nombre d 'aminochromes et de semicarbazones
d 'aminochromes ontetC mesures et leurs principales
caracteristiques sont discutees. La s ynthtse d 'un nouvel
aminochrome,le methyl-2 noradrenochrome est decrite. [Traduit par
le journal]
Robinson (1) in 1965 reported some p.m.r .da ta for adrenochrome
(compound 1, Table 1)which had previously been assigned a
zwitter-ionic mesomeric structure by Harley-Mason (2).Th e spectrum
was recorded in DMSO-d, solu-t ion and resonances at 5.47 and 6.50
6 wereassigned to the hydrogens at C-4 and -7. How-ever in a
personal communication to one of us(R. A. Heacock) in 1966, Dr.
Robinson s ta tedthat the assignments for these hydrogens
shouldhave been reversed. Since his original paper (1)no fur ther p
.m.r . da ta on adrenochrome orrelated aminochromes have been
reported. Tofill this gap in the literature we have recordedthe
p.m.r . spectra of some aminochromes andaminoch rolne mono
sen~icarbazones (see struc-tures listed in Table I ) in DMSO-d, a t
60 MHz.All p.m.r . parameters in Table 2 were obtainedby comparing
the experimental spectra withthose simulated with the Varian
Spectro System100. Because the spectra were comparativelysimple it
was not considered necessary to checkthe results at a second
radiofrequency.In al l of the compounds examined, except 2,2a, a n
d 4, two resonances with chemical shiftscharacteristic of
"aromatic" type hydrog ens (3)were observed for H-4 and -7.
Moreover H-7could be assigned to the resonance at higher
' F o r P a r t XV , see ref. 12.2 N R C C N o . 1 29 32
.3Taken, in part, from the Ph .D. Thesis ofW . S. Powell,Dalhousie
University, 1972.4Holder of NRCC Scholarship, 1967-1971.'Reprint
requests can b e addressed to any of theseau thors a t the At lan
tic Reg ional Laborato ry .
field (5.30-5.47 6) because th e low field signalfor H- 4
(6.42-6.80 6) was absen t from thespectra of 2 a n d 2a which are
of know n structurewith R, = C H , (4). It follows, therefore,
thatthe iodine atom in 4 must be located at C-7since a
characteristic resonance was observedfor H -4 (6.56 6) whereas n o
signal at higher fieldwas observed for H-7. This work
thereforeconfirms that the iodine atom in iodoamino-chromes is at
C-7 (5) rather th an a t C-2 as wasoriginally suggested (6).Th e
"benzylic" type methylene hydrogen s atC-3 in 8 were readily
assigned (3) to the highfield multiplet a t 3.00 6 whereas the
correspond-ing hydrogens at C-2,which also bears a nitrogenato m ,
occurred as expected at lower field at 3.806 (3). Fo r those com
pounds in which there is anhydroxyl or methoxyl group at posit ion
3, thehydrogen at C-3 exhibited a characteristic down -field shift
appearing in the range 4.50-5.00 6. Onthe other hand, replacement
of one of themethylene hydrogens at C-2 with a methylsubstituent as
in 7 did not appreciably affect thechemical shift of the hydrogen
at C-2 whichappeared as expected at 3.76 6. The remainingsignals in
all the spectra were readily identifiedon the basis of their
chemical shifts, multi-plicities, and/or intensities, or their ease
of re-placement with deuterium. Assignments wereconfirmed by
decoupling experiments.C o m p o u n d 7 was synthesized from
1-(3,4-dihydroxypheny1)-2-aminopropan-1-01, he sidechain of which
has an erythro configuration,thus requiring that the methyl and
hydroxyl sub-st i tuents on C-2 and -3, and therefore H-2a
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POWELL ET 4L.: AMIKOCHROhlES. XV ITABLE. Structures of
aminochromes a nd monosemicarbazone derivatives
Compound X RI RZ R3 Rq R7AdrenochromeAdrenochrome
monosemicarbazone4-Methyladrenochrome4-MethyladrenochromemonosemicarbazoneAdrenochrome
methyl ether7-Iodoadrenochrome methyl e
therNoradrenochromeNoradrenochrome
monosemicarbazone1-Isopropylnoradrenochrome2-MethylnoradrenochromeEpinochrome
0HZNCONHN0HzNCONHN000HzNCONHN
and -3a, have a trans relationship to one another.This follows
because the experimental conditionsfor cyclization preclude
epimerization at thetwo asymmetric carbons (see Experimental).From
Table 2 it can be seen that, apar t from thetypical geminal
coupling constants (7, 8), thespin-spin couplings between hydrogens
on C-2and -3 fall either in the range 1.8-4.0 or 6.2-7.0Hz. The
data for 7, (J,,,,, = J,,,,, = 3.6 Hz),together with known trends
in the behavior ofspin-spin couplings in other similar
five-memberring systems (8), enabled the lower range ofvalues
discussed above to be assigned to trans,and the higher range of
values to cis, spin-spincouplings for the compounds listed. It is
alsoworth noting that for those compounds with amethylene group at
position 2, the hydrogen(H-2a) cis to R, = OH or OCH,, occurred
athighest field and was trans coupled to H-3a. Inthe case of
compound 8 which bore no electro-negative substituent at C-3 the
trans (J,,,,, =J2,,,,= 4.0 Hz) and cis (J2,,,, = J,,,,, = 7.0Hz)
couplings were the largest observed through-out the series of
compounds investigated, aswould be expected (8).For those compounds
in which R, = H long-range coupling (1.5 < J,,, < 2.3 Hz) was
ob-served between this hydrogen and all hydrogensdirectly bonded to
C-3. When R, = CH,, long-range coupling (8) was observed between
H-3aand these methyl hydrogens in 2 but surprisingly
not in 2a . The presence of long-range couplingbetween one of
the aromatic hydrogens (H-4)and H-3a in the iodoaminochrome 4 is of
coursefurther evidence that the iodine atom must beattached to C-7
in this compound.Experimental
AminochromesMethods described in the literature were used to
pre-pare adrenochrome (9), adrenochrome methyl ether
(lo),7-iodoadrenochrome methyl ether (lo) , 4-methyladreno-chrome
(4), 1-isopropylnoradrenochrome (lo), noradren-ochrome (1 I), and
epinochrome (12).2-Methylnoradrenochrome was prepared in a
manneranalogous to that for noradrenochrome (11). The freebase
1-(3,4-dihydroxypheny1)-2-aminopropan-1-01
3,4-dihydroxynorephedrine; 2 g), prepared according to oneof the
standard procedures (cf. ref. 4) from the cor-responding
hydrochloride, was treated with silver oxide(8.3 g) in methanol
(200 ml) for 8 min and the reactionmixture subsequently filtered
through anhydrous sodiumsulfate and then Dowex-1 x 8 (C1-).
Crystallization wasinitiated by adding ethyl acetate (250 ml) and
reducingthe volume to % 30 ml at i 5' in naclto followed by
thefurther addition of ethyl acetate (30 ml) and once againreducing
the volume of the solution to z 2 5 ml. 2-Methylnoradrenochrome
(515 mg; 26% yield) wasobtained as dark red microcrystals which
completelydecomposed without melting by 115"; h,,, (H,O) nm(E): 216
(26 800), 295 (9600), 488 (3690); v,,, (Nujol):3235, 3210, 1667,
1617, 1582, 1543 cm-'.Anal. Calcd. for CyHyN03:C, 60.33; H, 5.06;
N,7.82. Found: C, 59.94; H, 4,86; N,
7.79%.Ami~?ochromeMonosemicarbazonesMethods in the literature were
used to prepare 4-methyladrenochrome and noradrenochrome
monosemi-
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P O W E L L ET AL . : AM I NOC HR OM E S. XV I 77 9carbazones
(4, 11). Adrenochrome monosemicarbazone D A L Y , n d B . WITKO P.
. Am. Chem. Soc . 85, 1825was obtained from the Koch-Light Laborato
ries. (1963).6 . D . R I C H T E R n d H . B L A S C H K O .. Chem.
Soc. 601
The au thors wish to thank M r . J. van lnge n for record-ing
some of the spectra. 7 . R . C A H I L L .R . C . C O O K S O N ,nd
T. A . CRABB . e t-rahedron. 25. 4681 119691.8 . S . STERNHEL L.
uar t . Rev . 23, 236 (1969).1 . B . ROBINS ON.. Pharm. Pharmacol.
17 , 89 (1965). 9 . R . A . H E A C O C K , . N E R E N B E R G ,n
d A . N . P A Y Z A .2. J . H A R L E Y - M A S O N .xper ien t ia
, 4 , 307 (1948). C a n . J . C h e m . 36, 853 (1958).3 . L. M . J
A C K M A Nnd S . STERNH ELL. ppl ica t ions of 10 . R. A. HEACO
CKnd B . D . SCOTT.Can. J . Chem. 38,nuclear magnetlc resonance
spectrosco py in organic 516 (1960).chemistry. Pergamon Press, Ne w
Yo rk. 1969. Part 3. 11 . W. S . PowELLand R. A. HEACOC K.an . J .
C h e m . 49,4. R. A. H E A C O C K ~ ~ ~.H U T Z I N G E R .an . J
. C h e m .43, 341 (1971).2535 (1965). 12 . W. S . POW ELL n d R .
A . H E A C O C K .an . J. C h e m . 50,5 . R . A . H E A C O C K ,
. H U T Z I N G E R ,. D. SCOTT, . W. 3360 (1972).
