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Determination of the Conformation of Panthotenic Acid and Pantoylamides by Proton Resonance Spectroscopy.

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With increasing quantities of the acidic catalyst the adducts
(fb) take up further isocyanate, even in the presence of excess
formaldehyde dimethylacetal, giving methylenebivarbamic
acid esters like (5). which by selection of stoichiometric
quantities may be obtained in almost quantitative yield.
The Reaction of Isocyanates with Ortho-esters
and Acetals
By Dr. H. v. Brachel and Dr. R. Merten [*]
Wissenschaftliches Hauptlaboratorium
der Farbenfabriken Bayer AG., Leverkusen (Germany)
-+[
I-+
G3
+-
RO-CH-OR
XI
OR8
x
RNCO
I
R-N-COOR
X-CH-OR
I
b.p. lS5-157°C/0.1 mm. Hg
n f j = 1.5102
ng=
1.5172
[Z 3211148 IEI
[*] Dedicated to Prof. Otto Bayer on his 60th birthday.
[I] See Houben- Weyl: Methoden der organischen Chemie. G.
Thieme, Stuttgart 1952, vol. 8, p. 130.
[2] German Patent 1072385 (1959), by R. Merten.
[3] German Patent 1072386 (1959), by R. Merten.
IR
CH3
n-ClH7
CsHs
94-96/12-14
108-1 11/19
95-96/0.02
I .4202
1.4224
1.4917
CH3
3,4-ClzC6Hl 2,6-(CzHs)1GHlCl-CH2CHz-
53-55/13
134-136/0.2
117-1 18/0.35
100- 102/16
1.4246
1.5484
1.5114
1.4564
Determination of the Conformation of
Panthotenic Acid and Pantoylamides by Proton
Resonance Spectroscopy
By Doz. Dr. H. Fritz and Dip].-Chem. W. Lowe
fnstitut fur Organische Chemie
der Universitat Frankfurt (Germany)
Comparison of the structures of pantoylamide (a,y-dihydroxy-@,@-dimethylbutyramide) (I) and panthothenic acid
(II) with that of pantolactone (111)
C3H7-N-COOCzHs
HO-CH~-C(CHI)Z-CH(OH)-CO-NHR
I
CH=C-C-COOCzHs
o"0
iI
(2)
b.p. 131 "C/14 mm. Hg
n v = 1.4440
(7)
(6)
b.p. 132-134"C/O.l mm. Hg
Received, August 2nd, 1962
The ortho-ester adducts ( l a ) are dissociated above 150 "C in
the aliphatic series and above 100 *C in the aromatic series.
The acetal grouping of the adducts (fa) can undergo exchange reactions in the presence of non-aqueous acid, e.g.
with ethylene qlycol giving the 1.3-dioxolane (2), or it may be
condensed with active methylene compounds, e.g. with cyanoacetic acid ester to form the unsaturated ester (3). In the
aliphatic series, N-formyl carbamic acid esters (4) can be
obtained by saponification.
I
I
CHI
The addition can be extended to numerous other ortho-esters,
acetals [2], a-chloroalkylethers [3], and isocyanates, and also
to the analogous sulphur compounds. Thus, the adducts (6)
and (7) are formed from methyl isocyanate and formaldehyde
dibutylmercaptal.
X = OR; R = CzHs
(Ib): X = H; R = CHI
CBH~-N--COOCZHS
+ CH~(-N-CO-S-C4Hg)z
CHI
(ZU):
Ix I R
-+
C4Hg-S-CHz-N-CO-S-CdHs
The reactions of isocyanates with ortho-esters or acetals indicate that addition reactions of the isocyanate group are not
confined to the transfer of reactive hydrogen atoms [l]. In
the presence of Lewis acids (BF;, ZnClz, AlC13), formic acid
ortho ethyl ester or formaldehyde dimethylacetal adds to the
isocyanate group at 30-70 "C, giving carbamic acid esters
(fa)or (Ib) in 70-90 % yields. Carbeniumoxonium ions are
probably formed as intermediates.
R-O-CH
+ CHZ(-SC~H&
CHI-NCO
H
I
1
0
CN
111
(3)
b.p. 126-13O0C/O.03 mm. Hg
n v = 1.4970
R-N-COOCZHS
I
CHO
(4)
R = CHI ; b.p. 72"C/15 nim. Hg
R = C3H7; b.p. 82"C/15 mm. Hg
,&=O
H&,
I: R = H ; 11: R = CH2-CHz-CO2H
I
HIC
HlC-C-C-OH
suggests that the two hydrogen atoms of the methylene groups
in the open chain compounds should show a larger degree of
equivalence than those in the ring compound owing to their
enhanced freedom of rotation. The proton resonance spectra
of these three compounds, however, disproved this expectation. In Table 1, the positions of the resonance peaks,
the corresponding coupling constants of the various protons,
CHz(-NCOOCHl)z
I
CHI
(5)
b.p. 120°C/13 mm. Hg
m.p. 40°C
Table 1. 60 Mc Proton resonance spectra of compounds I, 11, and I11 in D20. All data in cps. relative to
tetrameth~lsilane= 0 (DOH = 306). Apparatus: Varian A-60.
~
Type of Proton
0-CHzA, B
HlC-C-CHI
C
d
~~
Na-Salt of
D-(+)-Panthothenic
Acid (11)
D-(+)Pantoylamide (I)
AB-"Quartet" [i] centred
at 228
AA B = 7.0
AB-"Quartet" [l]centred
at 230
AA,B = 7.0
AB-Multiplet 121
centred at 269
JA.B = 11
JA,B
JA,B
c: 71,5; d: 73.5
c: 74.5; d: 76.5
'CHI,
ACH~,
'CHI,
e: 262
e : 284
=
11
CHI=^
CHlE2
D-(--)Pantolactone
(111)
AA,B
=2
9.6
c: 81; d: 91
CHI"^
C
I
HO-C-H
I
C1
e : 259
e
RN-CH~-CH~-CO~
I
H
592
f
f : Triplet centred at 226
Jf,g = 7
g : Triplet centred at 164
Angew. Chem. internat. Edit.
Vol. I (1962) No. I 1
and the values of the chemical shifts of the methylene protons
(AA,B) and the methyl groups (AcH,, CHJ for each of the
substances are summarized.
In the case of pantolactone, AA,B = 2 cps. JA,B = 9.6 cps.
and A c H ~ , CH, = 10 cps.; on the other hand, the respective values for both the two open chain compounds I and
11 are AA,B = 7.0 cps., JA,B = 11 CPS. and AcH,, C H =
~ 2 cps.
Since the protons of the methylene groups of compounds I
and I1 lead to only a single sharp AB-multiplet, and since
the possibility of fast rotation of the hydroxy-methylene
groups can practically be ruled out on account of steric
hindrance and in view of the higher AA,B values observed for
the open chain compounds in comparison with that of the ylactone, the results indicate that the open chain compounds
exist mainly in the conformation shown in IV.
Ar- in I
P-
Ib
M.p. [ "Cl
Yield [%I
124-125
45
NO2
Ic
HOOC-C>-
220-221
45
Id.
H z N O z S O -
147
35
H3C-SOz-CH-CH2-CI
I
Ar
-HCI
-+
H~C--SOz-C=CHz
I
The two protons of the methylene group in formula 1V are
nearer to the substituents of the asymmetric C atom than
those in the lactone V; this increases the difference in their
diamagnetic screening. In accordance with the geometry of
conformation IV, in which the distances between the methyl
groups and the unequal substituents at the center of asymmetry are larger than in the lactone, a decrease in the value
of AcH,, CH, is observed from 10 cps. in the lactone to
2 cps. in the open-chain compounds. The interatomic
distances given were measured on molecular models and are
intended to serve only as references for the relative changes in
the interatomic distances.
Received, August 28tl1, 1962.
I
I1
Ar
Elimination of HCl from these compounds (I) gives the vinyl
sulphone derivatives I1 in high yield:
By boiling Ia for forty hours with sodium acetate in aqueousalcoholic solution, 98 % of IIa (Ar= O z N - o - ) , m.p.
197-200°C is obtained; on boiling I c for four minutes with
0.2N sodium hydroxide solution, f mole of HCI is eliminated
with formation of IIc (Ar = H O O C - C > - ) , yield 80 %,
m.p. 287-297 "C.
Received, September 3rd, 1962 [Z 342/174 IE]
['I Dedicated to Prof. Otto Bayer on his 60th birthday.
[l] H . Meerwein, E. Biichner and K.v. Emster, J. prakt. Chem.
152, 237 (1939).
[2] Measured and interpretedby H. Walz,Ingenieur-AbteilungAP
der Farbenfabriken Bayer AG.
[3] F. G. Burdwell and G. D. Cooper, J. Amer. chem. SOC.73,
5184. (1951).
IZ 3381171 IE]
[l] Actually two sharply defined doublets.
[2] Appears as a triplet, since the two middle peaks are not resolved.
131 Distance between the methyl C and neighboring H.
Synthesis of 3-Hydroxydehydroquinolizinium
Bromide
By Dr. E. Schraufstatter [*I
Pharmazeutisch-wissenschaftlicheAbteilung
der Farbenfabriken Bayer A.G., Werk Elberfeld (Germany)
The Action of Diazonium Halides
on Methyl Vinyl Sulphone
By Dr. E. Siege1 and Prof. Dr. S. Petersen [*]
Wissenschaftliches Hauptlaboratorium der
Farbenfabriken Bayer AG., Leverkusen (Germany)
Diazonium chlorides react with methyl vinyl sulphone in a
type of Meerwein reaction [I] with vigorous evolution of
nitrogen to form crystalline compounds containing chlorine
and sulfur. The great mobility of the chlorine atom in
these reaction products, and also their NMR - spectra [2]
indicate a P-chlorethylsulphone structure (cf. [3]).
[Ar-Nzl+CI-
+ CH,-SOz--CH=CH2
HzO/Acetone
-9
HCl, CuClz
CH3-SO2-CH-CHzCI
I
+ N2
A r I
The diazo solution from 69 g of p-nitraniline (0.5 mole),
300 ml of ice/water, 132 g conc. hydrochloric acid, and 34.5 g
af sodium nitrite is added to 55 g of methyl vinyl sulphone
(0.52 mole) in 450 ml of acetone. A solution of 20 g of
crystalline cuprous chloride in 50 ml of water is then added.
The vigorous evolution of nitrogen which sets in at 28OC
(duration 1 h.) is moderated by cooling (28 "-30 "C). After
evaporation of the acetone, the crude product (90 g) is
Angew. Chem. internat. Edit.
During the course of investigations into cholinesterase inhibitors, we discovered a synthesis of a dehydroquinolizinium
derivative, which is very simple and which leads to good
yields. a-Diethoxymethylpyridine(I) is treated with chloroacetone to give I1 (rn.p. 148 "C, from acetone), which is then
cyclized to 3-hydroxydehydroquinoliziniumbromide, (111,
m.p. 251°C with decomp., from alcohol) by boiling with
hydrobromic acid.
Vol. I (1962) / No.I I
According to its ultraviolet and infrared spectra [l], compound 111 occurs entirely in the hydroxy-form. The ultraviolet spectrum [maxima at 340 mp (log E = 3.92); 330 m p
(log E = 3.90); 246 mp [log E = 4.37); 227 my (log E = 4.39)]
is very similar to that of dehydroquinolizinium iodide.
Direct reaction of pyridine-2-aldehyde with chloro- or
bromoacetone did not occur.
Received, September 3rd, 1962
[Z 341/173 IEI
[*] Dedicated to Prof. Otto Buyer on his 60th birthday.
[I] Thanks are due to Dr. W . Geiger for measuring and interpreting the spectra.
593
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acid, conformational, spectroscopy, determination, proto, resonance, pantoylamides, panthotenic
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