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Base-Catalysed Reactions of Ketones with Hydrogen Sulfide.

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In order to determine the degree of racemization, the
method worked out by Anderson [161] may be used.
Carbobenzoxyglycyl-L-phenylalanine is coupled with
the ethyl ester of glycine and the tripeptide formed is
fractionally crystallized from a 2 % solution in alcohol.
I n this way, the m-peptide precipitates first and can be
recognized by its higher melting point. In a less commonly used test for racemization [162], use is made of
the separability of carbobenzoxyglycyl-L-phenylalanylL-alanylglycine and carbobenzoxyglycyl-D-phenylalanyl-L-alanylglycine (synthetized from the dipeptides)
by countercurrent distribution. A third procedure has
been used by Young and coworkers [163] on several
coupling methods under very different conditions. It
entails the coupling of acetyl-L-leucine with the ethyl
ester of glycine. The racemic and the optically pure
dipeptides are not always obtained crystalline, however,
so that the rotation must be measured both before and
after hydrolysis, thus allowing only an approximate
estimate of the degree of racemization. Recent investigations by the same author [163a] of peptides of N-benzoylleucine, which crystallize more readily, have not
been considered in Table 2 The results obtained in tests
for the racemization occuring during the methods of
peptide bonding in general use are summarized in
Table 2. The values given were determined under the
conditions most favorable for retention of configuration.
It has already been indicated that the azide method is
the only one in which the activated peptide component
does not racemize. Table 2 shows that, apart from this
procedure, there appears to be no ideal method of
activation. The deficiency of the azide method lies in
the hydrazinolysis of polypeptide esters, which sometimes proceeds unsatisfactorily. Here the catalytic
acceleration with imidazole outlined above and the
use of a somewhat more reactive ester may be of
assistance. However, on the other hand, the dangers of
racemization during very rapid coupling should not be
exaggerated. Speedy execution of a peptide synthesis
by the anhydride method using ethyl chloroformate
at a low temperature can give good yields of pure
L-peptides by activating dipeptides. A relatively safer,
though more laborious procedure involves progressive
attachment of carbobenzoxyamino acids which are
known to racemize only with difficulty because of their
lack of ability to form azlactones. A final possibility
entails using peptides with glycine or proline at the
carboxyl end. It should be noted that not all L-amino
acids racemize to an equal extent, so that the choice
of racemization resistant oligopeptides which can be
coupled with others in a simple way may be further
increased. Much systematic work is still to be done
here. Enzymatic coupling [175] proceeds in the assurance that there is no racemization of the carboxyl end,
but this will not be considered further here.
Received, October 3rd. 1962
[A 274187 IE]
German version: Angew. Chem. 75, 539 (1963).
[175] See H. Determann, 0. Zipp, and T. Wieland, Liebigs Ann.
Chem. 651, 172 (1962).
Base-Catalysed Reactions of Ketones with Hydrogen Sulfide [11
BY PROF. DR. ROLAND MAYER, G. HILLER, MARGOT NITZSCHKE, AND D1PL.-CHEM. J. JENTZSCH
INSTITUT F’OR ORGANISCHE CHEMIE DER TECHNISCHEN UNIVERSITAT DRESDEN (GERMANY)
Monoketones react with hydrogen sulfide in the presence of basic catalysts to give geminal
dithiols or thioketones. P-Diketones are converted into monothiodiketones. a-Diketones
can be selectively reduced by hydrogen sulfide in the cold in the presence of secondary or
tertiary amines to give hydroxy- or mono-ketones.
Base-catalysed additions of hydrogen sulfide onto
carbonyl groups have been little investigated, although
they form one of the fundamental reactions of organic
chemistry. The reactions are also easily carried out
technically, and the cheap intermediate products can be
converted into heterocyclic sulfur compounds [2-41 in
[l] XVIIth Communication on Sulfur Heterocycles. - XVIth
Communication: J. Frunke and R . Mayer, J. prakt. Chem., in
the press.
[2] J. Jentzsch, J. Fabian, and R . Mayer, Chem. Ber. 95, 1764
(1962).
[3] B. Magnusson, Acta chem. scand. 13, 1715 (1959); R . Mayer
and J. Jentzsch, Angew. Chem. internat. Edit. 1, 217 (1962); J.
Jentzsch and R . Mayer, J. prakt. Chem. (4) 18, 211 (1962).
[4] H.Burreru and R . E. Lyle, J. org. Chemistry 27, 641 (1962).
370
various ways. Some new results from our work will
therefore be summarized in the following report.
The Base-Catalysed Reaction of Monoketones
with Hydrogen Sulfide
If hydrogen sulfide is passed into a solution of a monoketone in the presence of a basic catalyst, gem-dithiols
( 1 ) or in special cases thioketones (2) are formed in
varying yields.
We have recently described [2] this simple and most
productive synthesis of the gem-dithiols ( 1 ) ;hydrogen
Angew. Chem. intcrnat. Edit.
Vol. 2 (1963)
No. 7
sulfide and ketones react in the presence of ammonia or
amines at room temperature without the application of
pressure. A little later, Mugnusson [ 5 ] confirmed this
result independently.
Ketone
0.5 mole
Dimethyl ketone
Ethyl methyl ketone
Diethyl ketone
Cyclopentanone
Cyclohexanone
Cycloheptanone
Cyclohexyl methyl
ketone
Acetophenone
Cairns and his collaborators [6] had already obtained compounds of type ( I ) in 1952 by allowing hydrogen sulfide to
react with ketones or aldehydes at medium temperature and
pressures of 35 to 8500 atm. Here addition of an amine did
not lead to ( I ) as in our case, but to polysulfides; besides, it
turned out that gem-dithiols are formed more readily from
aldehydes than from ketones and that sterically hindered
ketones react under these conditions only to a small extent.
We discovered recently that such gem-dithiols ( 1 ) are very
easily formed [7] and also arise by the action of H2S in the
cold on basic ketones [4] and ketimines [5J. Furthermore,
Djerassi [8] and we ourselves [2] simultaneously succeeded in
splitting enamines to give dithiols using hydrogen sulfide
under mild conditions, whereas, according to Nomura and
Takeuchi [9], thioketones (2) or products formed from them
should be produced exclusively.
Compounds of type (1) are also accessible under acidic
conditions [lo, 1I], but these reactions will not be dealt with
here.
The reaction conditions for the synthesis of gemdithiols or thioketones depend on the ketone which is
converted and can therefore be generalized only within
1imits.Temperatures of 0 to 20°C have proved favorable;
at higher temperatures, heterocyclic sulfur compounds
occur as secondary products. Table 1 shows the optimum conditions under which gem-dithiols ( I ) or
thioketones (2) are formed from ketones.
Benzophenone does not react; acetophenone first forms a
yellow-orange oil, which decomposes on distillation to
give thioacetophenone (2h) and other products such as
ethylbenzene and styrene. On distillation of the product
resulting from the reaction of H2S and cyclohexyl methyl
ketone, H2S is eliminated and the unstable thioketone (2d) is
formed. Compound (2d) absorbs at 236 and 508 m p (in
cyclohexane). Cycloheptanone is converted into cycloheptanethione (2g), which shows characteristic maxima at 234 and
5 1 1 m p (in cyclohexane).
Ammonia, primary, secondary and, in principle, also
tertiary amines are suitable as catalysts (see Table 2),
whereas alkali hydroxides and alkoxides are not.
Tertiary amines appear to activate the ketone only when
[5] B. Magnusson, Acta chem. scand. 16, 1536 (1962).
[6] T. L. Cairns, G. L. Evans, A . W.Larchar, and B. C. McKusick,
J . Amer. chem. SOC.74, 3982 (1952).
[7] Cf. supposition of E. Baumann, Ber. dtsch. chem. Ges. 23,
1869 (1890); 28, 895 (1895).
(81 C. Djerassi and B.Tursch, J. org. Chemistry 27, 1041 (1962).
[9] Y. Nomura and Y.Takeuchi, Bull. chem. SOC.Japan 33, 1743
(1960).
[lo] R . Mayer et al., unpublished results; cf. G. A . Berchtold, B.
E. Edwards, E. Campaigne, and M. Carmack, J. Amer. chem. SOC.
81, 3148 (1959); E . Campaigne and B. E. Edwards, J. org. Chemistry 27, 3760 (1962).
[ I l l Moreover, under the conditions given by D. C. Sen, J.
Indian chem. SOC. 13, 268 (1936), enethiols are not formed
exclusively, but also gem-dithiols; cf. [lo].
Angew. Chem. internat. Edit.
Vol. 2 (1963) No. 7
Amine
o,05 mole
Product
Morpholine
Morpholine
n-Butylamine
Morpholine
Morpholine
n-Butylamine
I
B'p'
[Vmm
Yield
Hgl
57/100
73/73
72/30
63/10
84/12
6213
34
44
31
72
83
22
1.5069
1.5072
1.5080
1.5469
1.5448
1.5563
n-Butylamine
n-Butylamine
1.5158
1.5609
complex formation can occur, as has, for example,
been demonstrated for cyclohexanone and trimethylamine at 0 "C [12]. Cyclohexanone is the only ketone of
our series [13] which gives the corresponding dithiol
(Ifl with H 2 S and triethylamine, albeit in only 11 %
yield. These results can be seen from Table 2.
Table 2. Influence of the basic catalyst on the reaction of monoketones
with hydrogen sulfide in dimethylformamide. Temperature: 0 to 20 "C:
reaction time: 7 h.
Ketone (0.5 mole)
Ethyl methyl ketone
Diethyl ketone
Cyclohexyl methyl ketone
Cyclopentanone
Cyclohexanone
Cycloheptanone
Acetophenone
Benzophenone
Catalyst
(0.05 mole)
n-Butylamine
Morplioline
Triethylamine
Ammonia
n-Butylamine
Morpholine
Triethylamine
Ammonia
n-Butylamine
Morpholine
Triethylamine
Ammonia
Morpholine
Triethylamine
Ammonia
M orpholine
Triethylamine
Ammonia
n-Buty lamine
Morplioline
Trieth ylamine
Ammonia
n-Butylamine
Morpholine
Triethylamine
Ammonia
n-Butylamine
Morpholine
Triethylamine
Ammonia
Product
Yield [%I
39
29
-
31
31
3
-
23
20
-
9
72
-
20
83
11
25
22
14
-
13
12
-
-
-
Although some ketones react with hydrogen sulfide to give
gem-dithiols without solvent having to be added, polar
solvents in which H2S is readily soluble are especially
suitable. Such solvents are, e.g. dimethyl sulfoxide, dimethylformamide, and methanol. The influence of some
solvents on the reaction of ethyl methyl ketone with
hydrogen sulfide is shown in Table 3.
The mechanism of this base-catalysed synthesis of dithiols is
still unclear. Nitrogenous bases certainly increase the nucleophilic properties of hydrogen sulfide, so that addition onto
[12] 0. H. Wheeler and E. M. Levy, Canad. J. Chem. 37, 1727
(1959).
[ 131 R . Mayer and J. Fabian, unpublished results.
371
Table 3. Influence of solvent on the yield of dithiol ( I b ) from ethyl
methyl ketone (0.5 mole) and H2S in the presence of morpholine
(0.05 mole).
Solvent [I00ml]
None
Dimethylformamide
Dimethyl sulfoxide
Methanol
Ether
Water
Glycol
Petroleum ether
Methylene chloride
Chloroform
Yield ( I b )
[%I
15
29
44
11
7
Trace
Trace
Trace
Trace
Trace
In contrast to the unconjugatcd, deep red thioketones,
these compounds are golden yellow. Their smell is
pungent, but less penetrating than that of the simple
thioketones. N o lead salt is formed with lead acetate,
as with other unstable mcrcapto compounds ; instead,
lead sulfide separates out. The lack of SH-absorption in
the infrared spectrum of (3) implies strong chelation. In
methanolic sulfuric acid, monothiodiketones (3) give
dark red mono-2,4-dinitrophenylhydrazones,with retention of the mercapto group.
Base- Catalysed Reaction of Hydrogen Sulfide with
1,3-Diketones:
the polarized carbonyl group is facilitated. Besides, methylthiol also reacts in an analogous manner with ketones such
as acetone, cyclopentanone, and cyclohexanone in the
presence of morpholine in diniethylformamide to give dimethylthioketals [I 31. However, this hardly explains the
varying activities of different bases with the same ketone and
the fact that primary amines are, as a rule, better catalysts
than secondary amines. I t is also not understandable why
only cyclohexanone reacts with hydrogen sulfide in the
presence of triethylamine. Since the amines act differently,
since enamines and ketimines can also be split into dithiols,
and since inorganic bases show n o catalytic activity, in some
cases primary formation of a gem-hydroxyamino compound
should be considered, this being substituted by SH ion in the
following step. We are at present trying to clarify these
complicated circumstances.
The formation of thioketones (2) observed in some
cases is interesting. It is true that some thioketones only
arise as secondary products during the distillation by
elimination of H2S from the dithiols ( I ) , but it is not
yet known whether this mode of formation is of general
validity. Preparatively, the monomeric thioketones are
best obtained at present by thermal decomposition of
adducts [2,3].
Base- Catalysed Reaction of Monoketones with H2S:
A rapid stream of hydrogen sulfide is passed for about 7 h
into an ice-cooled solution of 0.5 mole of the ketone in 100 ml
of a polar solvent, which has been mixed beforehand with
0.05 mole of the amine catalyst. The mixture is poured onto
ice, acidified with dilute hydrochloric acid, and extracted
twice with petroleum ether. The extract is washed with water
until free from acid, dried with sodium sulfate, and distilled
through a 30 cm Vigreux column a t a pressure low enough
to ensure that the boiling point of the product is below 100 "C.
For details, see Table 1. All operations should be carried out
under a hood; the outgoing air and waste-water should be
purified chemically.
The infrared spectra of the gem-dithiols show characristic SH-absorption at 2555 cm-1.
The Base-Catalysed Action of H2S on 1,3-Diketones
Here 0.5 mole of the diketone is treated with 0.05 mole of
morpholine. Then a rapid stream of hydrogen sulfide is
passed into the precipitate, the reaction mixture becoming
clear and intense yellow. Thc reaction is complete after about
7 h. The mixture is diluted with 100 ml of light petroleum,
washed with dilute hydrochloric acid, then with water, dried
over sodium sulfate, and distilled at a pressure of under 1 mm
Hg after removal of the solvent in vacuo. For example, 2rnercapto-2-penten-4-oneis formed from acetylacetone by
this method in 24 % yield; its 2,4-dinitrophenylhydrazone
has m.p. 167-168°C (decomp.).
Base-Catalysed Reduction of 1,2-Diketones
with Hydrogen Sulfide
Surprising preparative results, which may also be of
great theoretical importance and significance, for
example for the Willgerodt reaction, were obtained by
the action of hydrogen sulfide, with ice-cooling, on
1,2-diketones in methanol or dimethylformamide in the
presence of an amine catalyst. Here gem-dithiols or
thioketones are not formed; elemental sulfur is eliminated, and depending on the reaction conditions, one of
the two carbonyl groups is reduced selectively, to either
a methylene group [type ( 4 ) ] or to a secondary alcohol
[type ( 5 ) ] . Almost invariably, the reaction proceeds
amazingly simply and quantitatively; the second carbonyl group remains unattacked.
R-CO-CH(OH)-R
R-CO-CHz-CO-R
+ R-CO-CHZ-R
(4)
Table 4. Dependence of product\ of reduction with H2S on solvent and
amine.
Solvent
Dimethylformamide
Pyridine
Morpholine
Piperidine
Aniline
n-Butylamine
None
None
(4)
(4)
( 4 ) I- ( 5 )
(4)
[**I
+ (5)
+
(4)
(4)
(5)
N o reaction
(4)
N o reaction
(5)
HzS, amine
> R-CO-CH=C-R
(3)
312
R-CO-CO-R
Both reduction stages ( 4 ) and ( 5 ) are to be regarded as
end-products under the given conditions, as (5) cannot
be converted into ( 4 ) , and ( 4 ) cannot be reduced further. Which end-product arises is determined by the
amine added and by the solvent. This can be seen for
benzil, for example, from Table 4.
Amine
Whereas monoketones react with hydrogen sulfide in
the above manner to give either dithiols or thioketones,
1,3-diketones yield monothiodiketones of type ( 3 ) . The
second carbonyl group is not attacked under the
conditions used.
c
(5)
I
SH
[*I Only 33 % conversion after 7 h.
["I Quantitative conversion afler only 1 h.
Angew. Chem. inicrmat. Edii.
Vol. 2 (1963) I No. 7
In all cases without solvent, addition of pyridine causes
a quantitative reduction of the 1,Zdiketone to the
monoketone (4). The latter is likewise obtained in
almost quantitative yield by working with methanol/
morpholine or with dimethylformamide/aniline. Methanol/piperidine gives a conversion of only 33 % after 7 h.
Without addition of amine, or in the presence of a
primary amine, no reaction occurs in methanol.
In a peculiar way, hydrogen sulfide in carefully purified
dimethylformamide can reduce the 1,2-diketone quantitatively to the monoketone (4) without addition of an
amine, whereas in the presence of a secondary amine,
only the hydroxyketone ( 5 ) is formed.
With piperidine, quantitative reduction to ( 5 ) is
complete after only 1 h ; in the presence of morpholine
a mixture of both reduction products (4) and ( 5 ) is
obtained after 4 h. In the absence of solvent, only
pyridine, morpholine, and piperidine catalyse the
reduction.
Reduction of 1,2-Diketonrs with Hydrogen Sul’de:
Hydrogen sulfide is passed for up to 4 h into a solution of
0.2 mole cf the 1,2-diketone and about 30 ml of amine in
methanol or dimeth>lformamidc, the solution being cooled
with ice; separation of elemental sulfur occurs during the
process. The mixture is acidificd with dilute hydrochloric
acid, the resulting precipitate filtcred off with suction, roughly
separated from sulfur by warming gently with methanol, and
the reduction product, dissolved by the methanol, purified by
recrystallization. Liquid reduction products resulting from
acidification are extracted with cther and, after being dried
over sodium sulfate, distilled.
Examples:
Benzoin from benzil: Reaction in pyridine/dimethylformamide; HzS passed in for 1 h; yield quantitative. Identification by analysis, mixed melting-point, 2,4-dinitrophenylhydrazone, and comparison of infrared spectra.
Deoxybenzoin f r o m benzil: Reaction in pyridine/methanol;
H2S passed in for 4 11; yield quantitative. Identification as
above.
Received, January 7th, 1963
[A 287/82 IE]
German version: To appear in Angew, Chem. 75, No. 16 (1963).
Formation and Cleavage of Dihydroxydiarylmethane Derivatives
BY DR. H. SCHNELL AND DR. H. KRIMM
FARBENFABRIKEN BAYER AG., WERK UER DINGEN (GERMANY)
Dihydroxydiarylmethane derivatives are formed by condensation of aromatic hydroxy and
carbonyl compounds in the presence of acidic condensing agent3 at low temperatures or in
the presence of bases at elevated temperatures. This article deals with formation and cleavage
mechanisms in acid and basic media. As a result of the investigations reported, new methods
of preparing unsymtnetric dihydroxydiarylrnethane derivatives und p-alkenylphenols have
been developed.
1. Preparation of Dihydroxydiarylmethane
Derivatives [*]
Bisphenol A started only after cpoxy resins were developed
from Bisphenol A and epichloiohydrin in 1938 [4]. This
application does not require Bisphenol A of high purity;
however, highly purified material is used in the production of
aromatic polycarbonates [ 5 ] .
The parent compound of the dihydroxydiarylmethane
was first prepaseries, 4>4’-dihydroxydiphenY1methane,
red in 1878 by Beck [I]. The method used involved
alkaline fusion of the corresponding disulfonic acid.
Nolting and Herrberg {Z] also prepared it in low yields
from phenol and formaldehyde in the presence of dilute
mineral acids. In 1891, Dianin [3] synthetized 2,2-bis-
Besides Bisphenol A, a few 4,4’-dihydroxydiarylmethane
derivatives bearing alkyl substituents on the aromatic radicals have also found application; they are used as nonstaining antioxidants for natural and synthetic rubber, polyvinyl compounds, and mineral oils [6]. 4,4’-Dihydroxydiphenylmethane derivatives have also been proposed as intermediates for the preparation of phenolic resins and tanning
(p-hydroxyphenyl)propane in good
from
and acetone in the presence of strong mineral acids.
2,2-Bis-(p-hydroxyphenyl)propane possesses estrogenic activity [7]. Other representatives of this class of compounds
For a long time, this readily obtainable substance, also
referred to as bisphenol, Bisphenol A or Dian, found no
significant industrial application. Large-scale production of
[*] Dihydroxydiarylmethane derivatives imply compounds in
which two equal or different hydroxyaryl groups are linked to the
same carbon atom. This atom can be substituted with hydrogen
or an aliphatic or aromatic radical or be a member of a cycloaliphatic ring.
[ l ] C. Beck, Liebigs Ann. Chem. 194, 318 (1878).
[2] Nolting and Herrberg, Chemiker-Ztg. 16, 185 (1892); see also
N . Caro, Ber. dtsch. chem. Ges. 25, 947 (1892).
[3] A . Dianin, J. russ. physik. Ges. 1891,488,523,601 ; Ber. dtsch.
chem. Ges. 25, Ref. 344 (1892).
Angew. Chem. internat. Edit. / Val. 2 (1963) NO.7
-
[4] Swiss Pat. 211 116 (1940), Gehr. de Trey A.G., inventor: P.
Castan; see also A. M. Paquin: Epoxydverbindungen und Epoxydharze. Springer, Berlm-Gottlngen-Heidelberg, 1958.
[ S ] H. Schnell, Angew. Chem. 68, 033 (1956); Ind. Engng. Chem.
51, 157 (1959); Plast. Inst., Trans. and J. 28, 143 (1960).
[6] US.-Pat. 2515906 (1950), Gulf Res. and Development Co.,
inventors: D. R. Stevens and A. C. Dubbs; US.-Pat. 2559932
(1951), I. C . I. Ltd., inventors: A. S. Bfiggs and J . Haworth;
US.-Pat. 2894004 (1959), Dow Chem. Co., inventor: A. J.
Dietzler; US.-Pat. 2917550 (1959, Dow Chem. Co., inventor:
A. J . Dietzler; US.-Pat. 2877210 I19-59), Hercules Powder C O . .
inventor: R. A. Bankert.
[7] G. Bornmann and A. Loeser, Arzneimittel-Forsch. 9, 9 (1959).
373
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