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Modification of the Orientation of Substitution Reactions on Thiophene and Furan Derivatives.

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6.2.3. A b s t r a c t i o n R e a c t i o n s
R*-i-R,H + RH-f-Rl-
The activation energies for hydrogen abstraction by
most radicals are too high for detectable reaction to
occur at 77°K. Phenyl, cyclopropyl, vinyl, and CF3
radicals are the exceptions and these attack other
molecules with great ease even at 77”K[58,761. This
clearly demonstrates their higher reactivity and it is of
some interest to note that all these radicals are of the
o-type, in which the free electron is in a localized
orbital projecting away from the rest of the molecule.
Received: August 7, 1967
[A 636 IE]
German version: Angew. Chem. 80, 519 (1968)
Modification of the Orientation of Substitution Reactions on Thiophene
and Furan Derivatives
BY JA. L. GOLDFARB, JU. B. VOLKENSTEIN, AND L. I. BELENKIJ [*I
Under normal conditions, thiophene and furan derivatives are substituted in the a position,
and no convenient alternative methods for the preparation of ,&substitution products have
been available until now. The present article describes a method that permits the synthesis
of many P-substituted thiophenes and furans. In this method, the carbonyl group in aaldehydes or ketones of the thiophene and furan series is blocked by complex formation
with an excess of aluminum chloride, so that etectrophilic substitution takes place in
position 4. In another useful method, the carbonyl group is blocked by acetalization.
The acetals can be metalated in the ring by organolithium compounds.
1. Introduction
Though the term “aromaticity” [**I was first introduced more than a century ago, there is still no satisfactory
definition or experimental test that could be applied to
establish whether o r not a system is aromatic. Our
present ideas on aromatic systems are dominated by
generalizations that follow from Hiickel’s application
of the MO theory to aromatic molecules and from the
further development of this author’s views. Despite
the simplifications and approximations involved, the
resulting physical picture enables us to explain some
of the properties of such systems more or less precisely,
and to predict the existence of new, similar compounds.
However, questions concerning the properties of individual types of aromatic compounds were largely
ignored for a long time.
Peculiarities in the behavior even of compounds that
are formally very similar have inthe meantime attracted considerable attention, from both the theoretical
and the practical points of view. A comparison of the
thiophenes with the furans shows that many properties
are changed when a sulfur atom is replaced by an oxygen. Greater differences are observed on comparison
of these and other heteroaromatic compounds with
[*I
Prof. Dr. Ja. L. Goldfarb, Dr. Ju. B. VolkenStein, and
Dr. L. I. Belenkij
N. D. Zelinskij Institute of Organic Chemistry of the
AS USSR
Moscow V-334, Leninskij Prospekt 47 (USSR).
[**I The term “aromatic” is also used for heteroaromatic systems in this paper.
Angew. Chem. internat. Edit. / Vol. 7 (1968) No. 7
benzene derivatives. These differences are particularly
obvious in substitution reactions; the unsubstituted
hetcroaroinatic compounds can very often be regarded
purely formally as monofunctional compounds.
One peculiarity of thiophene and furan is the strict
orientation of electrophilic and protophilic substitutions, in which the substituent always becomes attached to the a position of the ring [** *]. In the few cases in
which $substitution products were found, these were
probably formed by isomerization of the a-substituted
compound formed initially [4,51. Thus P-substituted
products can generally be obtained only indirectly.
How can the orienting effect of the hetero atom be
overcome in thiophene and furan chemistry? A solution to this problem would be valuable, since e.g.
many natural products are fJ-substituted furans and
thiophenes. The $-substitution products may also
include physiologically active compounds.
[***I The deuterium exchange kinetics show that thea position of
thiophene reacts three orders of magnitude faster than the p
position in electrophilic substitutions 11, 21 and six orders of
magnitude faster in protophilic substitutions 121. The a position
in furan reacts three orders of magnitude faster than the p position in protophilic substitutions [3].
[l] K . Halvarson and L. Melander, Ark. Kemi 8, 29 (1955).
121 A . I . SatenSIein, A. G. Kamrad, I. 0 . Snpiro, Ju. I. Rnnneva,
and E. N.Zvjaginceva, Doklady Akad. Nauk SSSR 168,364 (1966).
[3] A. I. SatenStein, A . C. Kamrad, I . 0.sapiro, Ju. I. Ranneva,
and S. A . GiIIer, Chim. geterocikliieskich Soedinenij 1966, 643.
141 H. Wynberg and U.E. Wiersum, J. org. Chemistry 30, 1058
(1965).
[5] N . I. h i k i n , B. L. Lebedev, V . G . Nikolskij, 0. A . Korytina,
A. V . Kessenich, and E. P . Prokofev, Izvest. Akad. Nauk SSSR,
Ser. chim. 1967, 1618.
519
Significant work on the synthesis of 2- and 3-substituted thiophenes and their biological action in comparison with one
another and with benzene derivatives has been carried out by
Campaigne e t al. [6J.Having examined the literature data (cf.
e.g. 179, we can agree with Campaigne's opinion that the biological activity of 3-substituted thiophene cannot be estimated
from the activity of the corresponding 2-substituted thiophene or of a benzene analog. Thus the $-substituted isomer
should not he forgotten in the testing of thiophene analogs
of biologically active benzene derivatives. There is a very high
probability that this isomer is more active than the a-isomer.
We know of only one case in which the antibiotic activity
present in the a isomer (5-nitro-2-acetylthiophene) (1) does
not occur in the @ isomer (2) [*I.
There is considerably less literature o n the comparison of the
physiological activities of CL- and @-substituted furans, since
@-substitutedfurans are much more difficult to obtain. However, many of the @ derivatives again exhibit greater bioiogical
activity than the t~ isomer (analgesics 191, antihistaminics [lo],
antiseptics 1 1 1 9 121).
Four methods are available for the synthesis of
substituted thiophenes:
P-
1. Ring closure of bifunctional aliphatic compounds.
2. Side-chain bromination of 3-methylthiophene with
N-bromosuccinimide.
3. Introduction of functional groups into a 2,5-disubstituted thiophene, followed by removal of the original
substituents (generally halogen).
2-bromo-3-methylthiophene as a by-product, although it has given satisfactory yields of 3-substituted
thiophenes in some cases 1141.
2,5-Dichloro-3-chloroniethyl thiophene [151, alkyl 2 3 dichloro-3-thienyl ketones 116,171, and 2,5-dichloro-3thiophenecarboxylic acid 1181 have so far been obtained
by method 3. It is very difficult in this case to eliminate
the halogen atoms without alteration of the functional
group introduced.
In our view the most suitable method for the preparation of 3-substituted thiophenes is that based on the
use of 3-bromothiophene (method 4). The latter compound is generally obtained from 2,3,5-tribromothiophene by elimination of two bromine atoms. The
simplest method of dehalogenation is that described
by Gronowitz[191, in which zinc dust and acetic acid
are used. This author also showed that the bromine in
3-bromothiophene can be almost quantitatively replaced by lithium under the action of n-butyllithium
at -70 "C [201. It would be difficult to overestimate the
possibilities offered by 3-thienyllithium.
The range of reactions available for the synthesis of @substituted furans is even smaller than that given for
P-substituted thiophenes. We know of only two cases
in which substituents were introduced directly into the
@-position of a furan ring having at least one free u
position. One was the reaction of mercury acetate with
2-furancarboxylic acid (3) to form a P-mercurated
compound (4) 1211, while the other was the formation of
4-isopropylfurfural from furfural1221 by alkylation
with 2-chloropropane.
4. Reactions of 3-bromothiophene.
Though method 1 has been used for the synthesis of
several interesting compounds, it is not very promising, since the bifunctional aliphatic compounds required as starting material are generally difficult to
obtain. Moreover, thiophene derivatives can be synthesized from thiophene itself and its lower homologs,
which are formed on thermal decomposition of natural
raw materials or can be obtained from aliphatic hydrocarbons and sulfur or simple sulfur compounds. Quite
apart from that, the tendency in thiophene chemistry
is more toward the opposite course, i.e. the preparation
of aliphatic compounds from thiophenes.
Method 2, which was proposed by Campaigne"31, is
more feasible; however, it is fairly laborious and yields
161 E. Campaigne, J. Amer. pharmac. Assoc. 46,129(1957);Chem.
Ahstr. 51, 6873 (1957).
[7] M. Martin-Smith and S. T. Reid, J. med. pharmac. Chem. I ,
507 (1959).
[a] M. Bellenghi, G. Carrara, F. Fava, E. Ginoulhiac, C . Martinuzzi, A. Vecchi, and G . Weitnauer, Gazz. chim. ital. 82, 173
(1952); 48, Chem. Ahstr. 2029 (1954).
[9] V. Leutner, Arzneimittel-Forsch. 7, 505 (1960).
[lo] J. LaBarre, G. Berouaux, and S . Oleffkopmansch, Arch. int.
Pharmacodynam. ThCrap., 147 (3-4), 497 (1964); Chem. Abstr.
60,9793 (1964).
[ll] R . R. Burtner. US-Pat. 2206804and 2206805; (July 2,1940)
G. D. Searle & Co.; Chem. Abstr. 34, 7546 (1940).
[12] C . N . Anderson, US-Pat. 2022997; (Dec. 3, 1935) Lever
Bros. Co.; Chem. Abstr. 30, 820 (1936).
[13] E. Campaigne and W. M. LeSuer, J. Amer. chem. SOC.70,
1555 (1948).
520
(3)
1-
co2
In the first case the reaction proceeds via a mixed
mercury salt of acetic acid and 2-furancarboxylic acid.
Isomerization of 2-isopropylfurfural into the 3-isomer
cannot be ruled out in the second case (cf. 9 .
In view of these difficulties, 3-monosubstituted and
2,3- and 2,4-disubstituted furans are usually obtained
by cyclization of aliphatic compounds or by removal
[14] P. Cagniant and G. Merle, C.R. hehd. Seances Acad. Sci.(C)
264, 112 (1967).
[15] S. Gronowitz, Ark. Kemi 8, 441 (1955).
[16] W. Steinkopfand W. Kohler, Liebigs Ann. Chem. 532, 250
(1937).
[17] H. D. Hartough and L . G. Conley, J. Amer. chem. SOC.69,
3096 (1947).
1181 J. A . Blanchette and E. V. Brown, J. Amer. chem. SOC.73,
2779 (1951).
[19] S. Gronowitz, Acta chem. scand. 13, 1045 (1959).
[20] S. Gronowitz, Ark. Kemi 7, 361 (1954).
[21] H . Gilman and C. F. Wright, I. Amer. chem. SOC.55, 3302
(1933).
1221 H. Gilman, N . 0. Calloway, and R . R. Burtner, J. Amer.
chem. SOC. 57,906 (1935).
Angew. Chem. internat. Edit. 1 Vol. 7 (1968) 1 No. 7
of substituents from 2,3,5-trisubstituted furans. All
these reactions proceed less readily than in the thiophene series, and the desired products are formed in
lower yields.
2. Modification of the Orientation by Complex
Formation
2.1. Problem
None of the preparative methods permits the direct
introduction of substituents into the f5-position of thiophenes or furans containing at least one freecr position.
We attempted to develop a direct method of P substitution suitable for at least some types of compounds
of these series. As our first model we chose derivatives
having a carbonyl group in one a position in the ring.
The directing influences of the ring hetero atom and of the
electron-attracting substituent in position 2 of thiophene are
superimposed in such a complex manner that the direction of
electrophilic substitution cannot be predicted accurately for
such compounds (for review seec231).
However, it was observed some time ago [241 that the ortho,
metu, and para positions of benzene approximately correspond to the 3,4, and 5 positions in a 2-substituted thiophene.
MO calculations [251 and dipole moment measurements [261
confirm that, t o a satisfactory approximation, these positions
can in fact be compared. On applying the Hammett equation
t o heterocycles, Iinoto et al. [27,281 found that the constants
p for reactions of thiophene and benzene derivatives d o not
differ greatly if apala is used for 2,s-disubstituted thiophenes
and smcfnfor 2,4-disubstituted thiophenes.
Owing to the competition of the 4-directing effect of
the substituent and the a-directing effect of the hetero
atom, electrophilic substitutions on furan and thiophene derivatives having class I1 substituents in the a
position practically always lead to mixtures of the 4and 5-substitution products. The proportion of the 4
isomer formed increases with the strength of the -M
effect of the substituent in position 2 1231.
Intensification of the electron-attracting properties of
the substituent, e.g. by protonation of the carbonyl
group in a strongly acidic medium, increases the percentage of the 4 isomer. Thus the 4 isomer predominates on nitration of 2-thiophenecarbaldehyde with
nitric acid/sulfuric acid, whereas bromination of the
aldehyde in chloroform leads almost exclusively to 5bromo-2-thiophenecarbaldehyde [291. Literature data
relevant to this problem are listed in Table 1.
1231 S. Gronowitz, Ark. Kemi 13, 295 (1959).
[24] W. Steinkopf: Die Chemie des Thiophenes. Verlag Th.
Steinkopf, Dresden and Leipzig 1941, pp. 26, 27.
1251 L . Melander, Ark. Kemi 11, 397 (1957).
1261 R . Keswani and H . Freiser, J. Amer. chem. SOC. 71, 1789
(1949).
(271 Y. Orsunii and E. Imoto, J. chem. SOC.Japan, pure Chem.
Sect. (Nippon Kagaku Zasshi) 80, 1297 (1959); Chern. Abstr. 55,
64768 (1961).
[28] Y. Otsumi, M . Kubo, and E. Imoto, J. chem. SOC.Japan,
pure Chem. Sect. (Nippon Kagaku Zasshi) 80, 1300 (1959);
Chem. Abstr. 55, 64761 (1961).
1291 S . Gronowitz, Advances heterocyclic Chern. I , 1 (1963).
Angew. Chem. internat. Edit. / VoI. 7 (1968)/ No. 7
Table 1. Directing effects of c!ass I1 substituents in position 2 of the
thiophene ring
.,
n
R
Reaction
NO2
CHO
COCH,
CN
COOH
CH(OCOCH3)z
SO3H
SOZCl
NO2
SO3H
SO*CI
SOZCl
Nitration
Nitration
Nitration
Nitration
Nitration
Nitration
Nitration
Nitration
SuIfonation
Sulfonation
Chlorination
Sulfochlorination
Bromination
CHO
COCH,
COCH3
COCH,
Isopropylation
Acetylation
Chloromethylation
80-85
75
52
43
31
14
little
much
little
little
much
much
15-20
[lo, 111
t321
132. 381
1321
[32. 401
1321
[301
[31]
I301
[301
1301
[301
25 la1
48
[57 [bl
69
86
much
little
much
much
little
little
1
3
99
-
[a] For further data on the nitration of 2-thiophenecarbaldehyde, see
[33-37].
[bl For further data on the nitration of 2-thiophenecarbonitrile, see [391.
[c] These articles report: 5 isomer - very large proportion, 4 isomer very little.
[d] Product yield about 6 %
In the furans, the directing influence of the hetero
atom adequately explains the results in almost every
case. Exceptions to these rules are (i) the formation of
P-furylmercury acetate ( 4 ) by the action of mercury
acetate on 2-furancarboxylic acid (3) 17-11, (ii) the Palkylation of furfural with 2-chloropropane 1221 (see
1301 W. Steinkopf and T . Hopner, Liebigs Ann. Chem. 501, 174
(1933).
[31] A. H. Blatt, S . Bach, and L . W. Kresch, J. org. Chemistry 22,
1693 (1957).
[32] J. Tirouflet and P. Fournari, C.R. hebd. SCances Acad. Sci.
246, 2003 (1958).
[33] T. M. Parrick and W. C. Emerson, J. Amer. chern. SOC.74,
1356 (1952).
1341 E. Campaigne, P . A. Monroe, B. Arwine, and W. L. Archer.
f. Amer. chern. SOC. 75, 988 (1953).
[35] W. 0. Faye, J . J. Hefferren, and E. G. Feldmann, J. Arner.
chem. SOC.76,1378 (1954).
[36] G . Gewer, J. Arner. chem. SOC. 75, 4585 (1953); 77, 577
(1955).
1371 R. Motoyama, S . Nishimura, and E. Imoto, J. chem. SOC.
Japan, pure Chem. Sect. (Nippon Kagaku Zasshi) 78, 788 (1957).
1381 E. Benary, Ber. dtsch. chem. Ges. 46, 2103 (1913).
[39] P . Reynaud and R. Deluby, Bull. SOC.chim. France 1955,
1614.
1401 I. J. Rinkes, Recueil Trav. chim. Pays-Bas 51, 1134 (1932).
1411 Ja. L. Goldfarb, Ju. B. Volkenitein, and B. V. Loputin, i.
obSL Chim. 34, 969 (1964).
1421 S. Gronowitz, Ark. Kemi 8, 87 (1955).
1431 N . P . Buu-Hoi and D . Lavit, J. chem. SOC.(London) 1958,
1721.
[44] E. C. Spaeth and C. B. Germain, J. Amer. chem. SOC.77,
4066 (1955).
(451 H . D . Harthough and A. I . Kosak, J. Amer. chem. SOC.69.
3093 (1947).
1461 R. Luke$, M . Janda, and K . Kefurt, Collect. czechoslov.
chem. Commun. 25, 1058 (1960).
52 I
Section l),and (iii) the reaction of methyl furoate with
caproic anhydride in the presence of tin tetrachloride,
which yields a mixture of the 4- and 5-caproylated
products [47J.
Thus to introduce an electrophilic substituent into the
position of thiophene or furan, it is necessary to
reduce the mobility of the 01 hydrogen atom in the ring
without appreciably altering the mobility of the f3
hydrogens. Moreover, any side chains present must
not be attacked. To achieve this purpose, it seemed
reasonable to make use of the conjugation resulting
from the presence of an electronegative group such as
the carbonyl group in the molecule [see (7)].
p
8.3
x 0.2
1
co
In the halogenation of acetophenone and its homologs
in the presence of 2-3 moles of aluminum chloride and
without a solvent, Pearson et al, found that the halogen
was introduced, not into the side chain, but into the
ring position meta to the carbonyl group.
The main action of the aluminum chloride is probably the
blockage of the carbonyl group by complex formation. The
methyl group of the ketone is then no longer attacked, since
enolization is practically or completely prevented in the complex. One mole of aluminum chloride is thus used for complex formation, and the remainder acts as a catalyst by participation in the formation of the attacking agent.
(7)
R
The carbonyl compound can react with an excess of a
Lewis acid (particularly aluminum chloride) to form a
complex in which the substituent is more strongly
electron-attracting than in the free aldehyde or ketone;
this increases the probability of formation of the 4substituted, but not of the 5-substituted product. On
the other hand, the complex formation hinders or
prevents substitution in the side chain. Finally, the
well-known catalytic effect of Lewis acids on electrophilic substitutions is particularly important for the
less active p position.
It was shown as early as 1926 1481 that m-xylene, which
gives n o diketone under the usual conditions for the
Friedel-Crafts reaction, reacts in the presence of 3
moles of aluminum chloride and without a solvent to
give the diketone in a satisfactory yield. Campbell and
Spaeth 1491 obtained m-isopropylacetophenone by reaction of acetophenone with 2-chloropropane in a 4.5fold molar excess without a solvent or in a 2-fold molar
excess with a solvent. Practically pure 4-isopropyl-2acetylthiophene has been prepared in a similar manner
by alkylation of 2-acetylthiophene with 2-chloropropane and an excess of aluminum chloride 1441.
Pearson et al.[50,511 investigated the effect of the
quantity of aluminum chloride on the direction of
halogenation. It is well known that alkyl aryl ketones
are normally halogenated in the side chain, M to the
- HBr
a
R-C-CH2Br
[47] G. Robinson, J. org. Chemistry 31, 4252 (1966).
[48] 0.Wuv, DRP 515540 (1926); Chem. Abstr. 25,2439 (1931).
[49] B. N. CampbeN and E. S. Spaeth, J. Amer. chem. SOC.81.
5939 (1959).
[SO] D. E. Pearson and H. W. Pope, J. org. Chemistry 21, 381
(1956).
[51] D. E. Pearson, H. W. Pope, W. W. Hargrowe, and W. E.
Stamper, J. org. Chemistry 23, 1412 (1958).
522
carbonyl group. The first step is the enolization of the
ketone (8) [521.
This assumption is confirmed by the fact that the rate of the
reaction decreases when the quantity of catalyst added is
reduced from 2.5-3 mole to 1.2 mole. However, the aluminum chloride also acts as a medium having a high dielectric
constant, and so promotes dissociation I*].
This effect (“swamping catalyst effect”) also enabled
the authors to obtain satisfactory yields in the halogenation of several aromatic aldehydes and ketones 1511
and several derivatives of aromatic acids 1531,
aniline [541, pyridine, picoline [551, isoquinoline, and
quinoline 1561.
2.2. Bromination of Aldehydes and Ketones of the
Thiophene and Furan Series in the Presence of an
Excess of Aluminum Chloride
We decided to prepare the complex of 2-acetylthiophene with aluminum chloride first, and to examine it
by UVand I R spectroscopy[~711
sincecomplex formation
with the hetero atom, which is possible in principle
though not very probable in our case, could not be
ruled out. The 600 A increase in the wavelength of the
UV absorption maximum in relation to the spectrum
of the free ketone and the 70cm-1 decrease in the
characteristic carbonyl frequency in the I R spectrum
confirm that complex formation takes place at the
carbonyl group, as previously reported in the literature158-611. The complex is dissociated in very dilute
solutions in chloroform.
[521 A. Lapworth, J. chem. SOC.(London) 85.30 (1904).
[*] As has been shown in our laboratory, operation in the
absence of solvents is not essential to successful halogenation
(see Section 2.3).
1531 D. E. Pearson, W. E. Stamper, and B. R . Suthers; J. org.
Chemistry 28, 3147 (1963).
[54] B. R. Suthers, P. H . Piggins, and D . E. Pearson, J. org.
Chemistry 27, 447 (1962).
[55] D . E. Pearson, W. W. Hargrowe, K. T. Judith, and B. R.
Suthers, J. org. Chemistry 26, 789 (1961).
[56] M. Gordon and D . E. Pearson, J. org. Chemistry 29, 329
(1964).
[57] Ju. B. Volkenifein,B. V . Lopatin, and V. A . Petuchov, Izvest.
Akad. Nauk SSSR, Otdel. chim. Nauk 1962,917.
1581 N . N. Lebedev, 2. obSE. Chim. 21, 1788 (1951).
[59] B. Susz and J. Cooke, Helv. chim. Acta 37, 1273 (1954).
[60] B. Susz, C.R. hebd. Seances Acad. Sci. 248, 2569 (1959).
[61] A. N. Terenin, V. N. Filimonov, D. S . Bystrov, Izvest. Akad.
Nauk SSSR, Ser. fiz. 22, 1100 (1958).
Angew. Chem. internat. Edit. 1 Vol. 7 (1968)
1 No. 7
2-Acetylthiophene ( 9 ) [621 and other alkyl 2-thienyl
ketones (10)[631 are brominated in the side chain in
the presence of catalytic quantities of aluminum chloride in solution.
Q C 0 - C H 2 R Br,_ Q C O - C H B r R
(9), R = H
(lo), R = Alkyl
Bromination without a solvent and in an excess of
aluminum chloride [2.5 moles per mole of (9) or ( l o ) ]
yields 4-bromo-2-thienyl ketones 163,641. Some of the
reactions of 4-bromo-2-acetylthiophene (12) are
shown in Scheme 1.
QCOCH3
(9)
Br
QCOCH,
Br
Br
tion is the formation of the 2-(a-bromoacyI)thiophene, independent of the reaction conditions. In the presence of more
than the molar quantity of aluminum chloride, this product
could isomerize to give the ring-brominated product. HOWever, our experiments with 2-(~-bromOpropionyl)thiophene
and with 2-(a-bromobutyryl)thiophene in the presence of an
excess of aluminum chloride and in the absence of solvent
showed that a rearrangement of this type does not take place.
It was also found that 5-bromo-2-acetylthiophene could be
recovered unchanged after having been heated for several
hours with a n excess of aluminum chloride while hydrogen
bromide gas was passed through the mixture.
The experiments thus show that bromine, presumably as Br+,
attacks alkyl thienyl ketones directly o n C-4 of the ring.
We have also used this method for the bromination of
2-thiophenecarbaldehyde (13), which is brominated
almost exclusively in position 5 under normal conditions 142,431. The bromination of the complexed aldehyde 1411 leads to 4-bromo-2-thiophenecarbaldehyde
(yield about 90%), the structure of which was proved
by oxidation to the carboxylic acid (11) and by its
spectra.
P C H O
Br2
Br,
O C H O
-
B r,
Q C O O H
COOH
1
Br
Br
J
Scheme 1
The structure of (1.2) is confirmed by chemical reactions,
particularly by oxidation t o the known acid ( I I ) , as well as
by its UV and IR spectra [651. Polarographic measurements [661
indicate that the distilled 4-bromo-2-acetylthiophene ( I 2 )
contains at most 0.5 % of 5-bromo-2-acetylthiophene.
If the quantity of bromine is increased to 2.5-3 moles
per mole of carbonyl compound, the bromination of
2-thiophenecarbaldehyde and of the alkyl 2-thienyl
ketones with a n excess of aluminum chloride and in
the absence of solvent can be made to give very high
yields of the 4,Sdibrorno derivatives of the carbonyl
compounds.
It was of interest to study the reaction of 2-acetylfuran (14) with bromine in the presence of an excess
of aluminum chloride. According to E. V. Brown,
(14) is brominated in the side chain when little or no
catalyst is present 1671. It is also known t68-711 that in
the halogenation of furan derivatives having electronegative substituents in position 2, the u-directing
effect of the ring oxygen (which evidently influences
the substitution direction more strongly than the sulfur
in thiophene) predominates. Nevertheless, under the
conditions used by Pearson the question of orientation
in the bromination of 2-acetylfuran was difficult to
decide.
In view of the high reactivity of the a-methylene hydrogen in
ketones, it could be assumed that the first step in the bromina-
We found that the action of one mole of bromine on
2-acetylfuran (14) at room temperature in the presence
of three moles of aluminum chloride and without a
solvent results in attack on the furan ring. However,
this reaction, unlike that of 2-acetylthiophene, cannot
be stopped at the stage of the monobromo derivative (721. A little 2-acetyl-5-bromofuran can be isolated
[62] F. Kipnis, H. Soloway, and J. Ornfelt, J. Amer. chem. Soc.
71, 10 (1949).
[63] Ju. B. VolkenStein and Ja. L. Goldfarb, Doklady Akad.
Nauk SSSR 138, 115 (1961).
[641 Ja. L. Goldfarb and Ju. B. VolkentSein, Doklady Akad. Nauk
SSSR 128, 536 (1959).
[65] Ju. B. Volkenstein, B. V . Lopatin, and V. A . Petuchov, Izvest.
Akad. Nauk SSSR, Otdel. chim. Nauk 1961,1880.
[66] S. G. Mairanovskij, N. V. Baraskova, and Ju. B. VolkenStein,
Izvest. Akad. Nauk SSSR, Ser. chim. 1965, 1539.
[67] E. V. Brown, Iowa State Coll. J. Sci. 11, 221 (1936-37).
I681 2. N.Nazarova,
obSE. Chim. 24, 575 (1954).
[69] H . Gilman and G. F. Wright, J. Amer. chem. SOC.52, 1170
(1930).
[70] A . F. Shepard, N.R . Window, and J. R . Johnson, J. Amer.
chem. SOC.52, 2083 (1930).
[71] H . B. Hill and C. R. Sanger, Liebigs Ann. Chem. 232, 67
(1886).
[72] Ja. L. Goldfarb and L . D . Tarasova, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1960, 1304.
The only impurity isolated from (12) was 4,5-dibromo-2acetylthiophene. The yield of 4-bromo-2-acetylthiophene was
about 70%, that of its homologs (in the reactions of higher
alkyl 2-thienyl ketones) 43-62 %. and that of 4.5-dibromo2-acetylthiophene 12%.
Angew. Chem. internat. Edit.
Vol. 7 (1968) 1 No. 7
z.
523
only at low temperatures and with short reaction
times, together with 2-acetyl-4,5-dibromofuran (I5),
which is the principal product at room temperature.
The yield of 2-acetyl-4,5-dibromofuran (15) rises from 34 to
62% when the molar ratio of bromine to 2-acetylfuran is increased to 2:l. The structure of (15) is proved by oxidation
to the known 4,5-dibromo-2-furancarboxylic acid, which is
also obtained directly by bromination of 2-furancarboxylic
acid 1711.
Br
It was later found that furfural[41’731 behaves in the same
way as 2-acetylfuran o n bromination in the presence of an
excess of aluminum chloride, i.e. two atoms of bromine enter
the nucleus at the same time, and 4,5-dibromofurfural (16)
is formed as the sole product (identification by oxidation to
the carboxylic acid).
chloride per mole of carbonyl compound. The same reaction
direction and yield were obtained with only 1.5 mole of aluminum chloride per mole of ketone. A further decrease in the
quantity of aluminum chloride leads to a decrease in the rate
of the reaction, but the bromination, as before, still takesplace
on C-4 (see Table 2).
AlCII: acetophenone
(mole)
2.5: 1
1.5: 1
1.3: 1
1.1:1
1.0: 1
Acetophenone
recovered
( %)
4.2
11.6
24.0
69.0
68.0
Yield of
m-bromoacetophenone (%)
57.0
60.0
45.0
29.5
- [bl
[a] In all the experiments the aluminum chloride was added t o a solution
of 0.1 mole of acetophenone in 50 ml of chloroform, and 0.1 mole of
bromine was then added. The mixture was heated for 2 hours, allowed
to stand f o r I8 hours a t 20”C, and then worked up in the usual way.
The product was finally distilled off.
[bl I n addition to the recovered acetophenone (6873, a high-boiling
fraction (24% of the weight of acetophenone used) was obtained. Apart
f r o m acetophenone, this fraction contained traces of m-bromoacetophenone and phenacyl bromide (detected by gas chromatography).
The bromination of furfural itself [68J and of its diacetate 1691
in the absence of catalyst leads exclusively to 5-bromofurfural.
2.3. Influence of the Solvent
According to Pearson et al., the bromination of a n alkyl aryl
ketone such as acetophenone, or of a n aromatic aldehyde,
without a solvent and with 2.5-3 moles of aluminum chloride
per mole of aldehyde or ketone exhibits the “swamping
catalyst effect”. Pearson claims that three conditions are
essential to ring halogenation [51J:
1. The carbonyl compound must be present as the aluminum
chloride complex until the bromine is added.
2. Solvents must not be used.
3. The complex must be liquid, so that the mass can be
stirred during the addition of the bromine.
Critical investigation of these conditions 1741 has shown that
the absence of solvents is not necessary, and sometimes actually hinders the isolation of the product from the reaction
mixture and leads to low yields. It can be concluded from the
proposed course of the reaction (see Section 2.1) that an excess of aluminum chloride and a practically homogeneous
medium are essential to the success of the bromination. Any
solvent that is inert under the conditions of the reaction may
be used if it dissolves the complex of the aluminum chloride
and the carbonyl compound without noticeable dissociation,
and does notprevent the activationof the halogen by formation
of a stable complex with the excess of aluminum chloride. The
quantity of solvent that may be used is naturally limited,
since the complex may dissociate if the solution is too dilute.
Even a small excess of aluminum chloride should direct the
reaction in the desired direction; however, the optimum
quantity that ensures an adequate reaction rate must be determined experimentally.
These conclusions have been fully confirmed by experiment.
In the bromination of acetophenone in chloroform, we obtained the same results as under the conditions described by
Pearson, and it was unnecessary to use 2.5 moles of aluminum
[73] Ja. L. Goldfarb and L. D. Tarasova, Izvest. Akad. Nauk
SSSR, Ser. chim. 1965, 1079.
[74] L. I. Belenkg, G. P. Gromova, and Ja. L. Goldfarb, Izvest.
Akad. Nauk SSSR, Ser. chim. 1967. 1621.
524
The yield of m-bromoacetophenone increases to 80-85 ”/,
when the bromination of acetophenone is carried out in dichloroethane. Methylene chloride, carbon tetrachloride, and
carbon disulfide may also be used as solvents. On the other
hand, bromination does not proceed in nitrobenzene; this is
due to the low activity of the catalyst (the excess of aluminum chloride forms a complex with nitrobenzene). Saturated
hydrocarbons are unsuitable, since the complex of acetophenone with aluminum chloride is completely insoluble in
these solvents.
As expected, the bromination of 2-acetylthiophene, of 2thiophenecarbaldehyde, and of furfural in solvents led to the
same results as those obtained earlier under Pearson’s conditions. Both the products obtained by Pearson’s method and
those obtained under our conditions contained 0.5-1.5% of
the initial carbonyl compound, which was difficult to eliminate, and in the case of theketone 0.5-1 % ofw-bromo ketone.
The formation of the w-bromo ketone in the presence of an
excess of aluminum chloride can be attributed to the low
equilibrium concentration of free ketone. An increase in the
quantity of solvent used naturally favors the dissociation of
the complex, and so leads to an increase in the quantity of
w-bromo ketone formed. Thus with 300 ml of chloroform
instead of 50 ml per 0.1 mole of acetophenone (see Table 2).
the bromination product consists almost entirely of phenacyl
bromide.
Thus the solvent does not cause any essential change in the
character of the reaction, and no specific “swamping catalyst
effect” exists. In our opinion the only advantage of the large
excess of aluminum chloride is that it lowers the melting point
of the reaction mass. On the other hand, the use of a solvent
permits an appreciable reduction of the quantity of aluminum chloride used, and also simplifies the isolation of the
product; it is well known that when no solvent is used, the
reaction mixture frequently solidifies toward the end of the
reaction.
2.4. Acylation of Thienyl Ketones
On the assumption that bromination is not the only
electrophilic substitution in the thiophene series to
which the blockage of the carbonyl group by an excess
of aluminum chloride could be applied, Goldfarb and
Litvinov studied the acylation of some thienyl keAngew. Chem. internat. Edit. Vol. 7 (1968) 1 No. 7
tones [75J. It is known that the action of acetic anhydride
on 2-acetylthiophene in the presence of zinc chloride
leads to 2,s-diacetylthiophene [451, but only in 6 %
yield. It was hoped that 2,4-diacetylthiophene, possibly contaminated with the 2,5-isomer, might be obtained by the action of acetyl chloride in the presence
of an excess of aluminum chloride and without a
solvent, i.e. under W u r s conditions for the diacetylation of m-xylene [481. However, the expected reaction
did not take place, and the 2-acetylthiophene was
recovered unchanged [751. The introduction of the
second acetyl group into position 4 proceeds only
when the a position is occupied by a n alkyl group, as
in 5-methyl- ( I 7) and 5-ethyl-2-acetylthiophene (18).
HRCOC.
(17), R = CH3
(I8). R CzH,
It should be noted that 2,5-dirnethyl-3-acetylthiophene
(19) and teut-butyl 2J-dimethyl-3-thienyl ketone (20)
are acetylated in yields of up to 87 % [751 with an excess
of AlC13 and in absence of solvents, though in these
cases, in contrast to the 5-alkyl-2-acetylthiophene, the
orientation toward position 4 is absent.
There are two possible reasons for this. The first is the high
activity of the p position in 2.5-dialkylated thiophenes; the
activity of this position in 2,s-dimethylthiophene is approximately the same as that of the tc position in unsubstituted
thiophene[7sl The second possible reason is that the carbony1 group in the p position is not coplanar with the thiophene ring1771 so that the withdrawal of electrons from
position 4 by the -M effect is hindered.
2.5. Chloromethylation of Aldehydes and Ketones of
the Thiophene and Benzene Series
products of acetaldehyde and of methyl ethyl ketone
were isolated in lower yields 1791.
The unsubstituted aliphatic-aromatic and aromatic
aldehydes and ketones (acetophenone 180-821, benzophenone 1821, anthraquinone [839 cannot be chloromethylated. However, two methyl groups in the ring
of an aliphatic-aromatic ketone permit the introduction of the chloromethyl group into the ring 1821. Chloromethylation is even easier in ketones containing
alkoxyl or hydroxyl groups. 4-Alkoxyacetophenones [841,2-hydroxyacetophenone c851, and 2-hydroxypropiophenone
react in high yields. The chloromethylation of salicylaldehyde, of o-homosalicylaldehyde 1873, and of anisaldehyde [881 has also been reported, Thus the reaction is facilitated by the presence
of a hydroxyl or methoxyl group. Acetophenone,
propiophenone, 4-methylacetophenone, and 3,4-dimethylacetophenone have been chloromethylated in
the side chain in the presence of boron trifluorideether [89,901.
Even less work has been done on the chloromethylation of ketones of the five-membered heterocycles.
It is interesting to note that in all the known cases
prior to our work, the substituent entered the ring in
position 5 (2-acetyl-5-chloromethylfuran [91J, 2-acetyl5-chloromethylselenophene 1921, and 2-acetyl-5-chloromethylthiophenec46J). The yield in the case of 2acetylthiophenewas 5.7 %based on the ketone introduced or 37 % based on the ketone that reacted. According
to the work of Lukei et al. 1463, Hautough’s report 1931
that 2-acetylthiophene is chloromethylated in the side
chain by formaldehyde and hydrochloric acid must be
regarded as unsupported. We were unable to reproduce
the work of Janda and Dvo?ak[94,951 on the orienta[79] 0. C. Dermer and J. Newcombe, J. Amer. chem. SOC.74,
3417 (1952).
[80] G. Vavon, J . Bolle, and J. Calin, Bull. SOC.chim. France
6 ( 5 ) , 1023 (1939).
[81] L. Schmid, W. Swoboda, and M. Wichtl, Mh. Chem. 83,185
(1952).
[82] R. C . Fuson and C. H . McKeever, J. Amer. chem. SOC.62,
784 (1940).
[83] H. Stephen, W. Short, and G. Gladding, J. chem. SOC.(London) 117, 510 (1920).
[84] E. Proft and R. Drux, J. prakt. Chem. 4, 236 (1957).
[ 8 5 ] R. Trave, Gazz. chim. ital. 80, 502 (1950).
It seemed interesting to examine the question of
whether an excess of aluminum chloride can also be
used for the chloromethylation of the ring in acetophenone, 2-acetylthiophene, and 2-thiophenecarbaldehyde. Little is known about the chloromethylation of
aldehydes and ketones. In 1936, the chloromethylation
products of pinacolone and of diethyl and dipropyl
ketones 1781 were obtained in 30-35 % yield; acetone
was later chloromethylated and the chloromethylation
__
[75] Ja. L. Goldfarb and V. P. Litvinov, 2. obSE. Chim. 30, 2719
(1960).
obSb.
[76] Ja. L. Goldfarb, V. P. Litvinov, and V. I. gvedov,
Chim. 30, 534 (1960).
[77] V . P . Litvinov and V . A . Morozov, Izvest. Akad. Nauk SSSR,
Otdel. chim. Nauk 1961, 166.
[78] J . Colonge, Bull. SOC.chim. France 3 (5), 2116 (1936).
z.
Angew. Ckem. internat. Edit. J Vol. 7 (1968) / No. 7
[86] P . DaRe and L. Verlicchi, Ann. Chimica 46, 910 (1956).
[87] R. Stoermer and K. Behn, Ber. dtsch. chem. Ges. 34, 2455
(1901).
I881 R. Quebt and J . Allard, C.R. hebd. Siances Acad. Sci. 205,
238 (1937).
[89] M . N . TiliCenko and V. A. Popova, 2. obSE. Chim. 23, 118
(1953).
[90] V. A. caikovskaja, Izvest. vysSich uEebnych Zavedenij
(Ivanovo), Chimija i chim. Technol. 2, 895 (1959).
[91] A . L . Mndiojan, V. G . Afrikjan, and M. G. Grigorjan, Doklady Akad. Nauk Arm. SSR 17,97 (1953).
[92] Ju. K. Jurev, N . K . Sadovaja, and E. N . Ljubimova, 2. obSE.
Chim. 30, 2732 (1960).
[93] H . D. Hartough: Thiophene and its Derivatives. Interscience
Publishers, New York 1952, p. 189, 335.
I941 M . Janda and F. Dvofak, Collect. czechoslov. chem. Commun. 27, 327 (1962).
(951 M . Janda and F. Dvoiak, CSSR-Pat. 105005 (1962).
525
tion of the chloromethylation in 2-propionylthiophene [961.
and 2-acetylthiophene are partly converted into derivatives
of diphenyl- and dithienylmethane on chloromethylation [971.
The chloromethylation of acetophenone with chloromethyl methyl ether in the presence of 2.5 moles of
aluminum chloride and without a solvent[971 led to
m-chloromethylacetophenone (39 % yield based on the
acetophenone introduced, and 54 % based on the
acetophenone that had reacted), a compound that had
not previously been described in the literature. The
structure of the product was proved by oxidation to
isophthalic acid, which was identified in the form of
its dimethyl ester.
It is interesting in this connection t o note that 5-ethyI-2acetylthiophene, which gives 5-ethyl-4-chloromethyl-2-acetylthiophene (21) in 47 or 76% yield when formaldehyde or
paraformaldehyde, respectively, is used under normal conditions, is converted exclusively into bis(2-ethyl-5-acetyl-3thieny1)methane (22) (yield 77%) by the action of chloromethyl methyl ether and an excess of aluminum chloride [loo].
The chloromethylations of 2-acetylthiophene 1971and of
2-thiophenecarbaldehyde with an excess of aluminum
chloride are not so simple. The product in both cases
was a mixture of the 4-and 5-chloromethylation products, in which the 4 isomer predominated.
0-
HOOC
Hooc?&OOH
HOOC-~H-(CH~)~COOH
CH3
-
2.6. Some Reactions of the Synthesized Products
The blockage of a carbonyl group in derivatives of
thiophene and furan permits the easy introduction of
a functional group into position 4 of the ring. 4-Bromo2-acetylthiophene, 4-bromo-2-thiophenecarbaldehyde,
and 2-acetyl-4-bromofuran (which is obtained from
2-acetyl-4,5-dibromofuran by elimination of the
HOH~C-
COCH3
HOOC (CH2)4COOH
The reasons for the difference in orientation in the chloromethylation and in the bromination are not yet clear. There
is still also some uncertainty concerning the action of the
chloromethyl ether in normal chloromethylations; this evidently explains the contradictions in the literature [ 9 8 m 8 3 1 .
In the ch~oromethy~ation
of aromatic compounds in the
presence of aluminum chloride, diarylmethane derivatives
are often formed as by-products. We found that acetophenone
1961 B. P. FabriEnyj, Ju. B. VolkenStein, V. I. Rogovik, I. B. Karmanova, and Ja. L. Goldfarb, Chim. geterocikliEeskich Soedinenij
1965.
.
.
, 504.
---Chim. 31,
1971 Ja. L. Goldfarb and Ju. B. VolkenStein, Z.
616 (1961).
[98] G. Ogata and M. Okano, J. Amer. chem. SOC. 78, 5423
(1956).
bromine from the a position [loll) are readily obtainable starting materials for a number of syntheses. ln
particular, the reduction of the carbonyl group in
these compounds, followed by replacement of the
bromine in position 4 by lithium, offers a convenient
method for the preparation of 5-ethyl- and 5-methyl-3thiophenecarbaldehyde [102,411, 5-methyl-3-thiophene-
~~
[99] I, N. Nazarov and A. V. Semenovskij, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1957,972.
526
[1001 Ja. L. Goldfarb and Ju. B. Volkenjtein, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1963, 738.
[loll Ja. L. Goldfarb and L. D.Tarasova, Doklady Akad. Nauk
SSSR 163,1393 (1965).
[lo21 Ja. L. Goldfarb, M . L. Kirmalova, and M . A. Kalik, Izvest.
Akad. Nauk SSSR, Otdel. chim. Nauk 1962, 701.
Angew. Chem. internat. Edit. / Vol. 7 (I968) / No. 7
carboxylic acid[41], a series of new furan derivatives
with a functional group in the $ position, efc. 5-Ethyl3-methylthieno[3,2-b]thiophene-2-carboxylic acid (23)
has been prepared from 4-bromo-2-acetylthiophene [1031.
a second carbonyl group by the action of dimethylformamide, was first achieved in 1960 [1061. 5-Formyl2-acetylthiophene (26) was obtained in this way. In
3. Metalation of Acetals of the Thiophene and
Furan Series; Syntheses on this Basis
New synthetic paths are opened up by a reversible reaction in which a carbonyl derivative of thiophene or
furan is converted in the usual manner into the acetal,
which is then treated with an organolithium compound.
In contrast to the reaction of organomagnesium compounds with acetals [104,1051, the acetal group remains
unchanged and lithium is introduced into position 5
of the ring. The resulting lithium-substituted acetal
(24), which need not be isolated, can be converted
this synthesis, the thiophene derivative was metalated
by butyllithium exclusively in position 5 of the thiophene ring, as was shown by the oxidation of (26) to
5-acetyl-2-thiophenecarboxylicacid [I061 and 2,5-thiophenedicarboxylic acid 1961.
Some reactions of the acetals of 2-thiophenecarbaldehyde are illustrated in Scheme 2 [96,107,1051.
O H C Q C H O
t
into a bifunctional compound [e.g. (25)]; the acetal
group can, if necessary, be readily changed into an
aldehyde or keto group, depending on the starting
it'
it'
(24)
compound. The special feature of this method is that
it permits the preparation of bifunctional thiophene
derivatives having similar or different substituents, the
synthesis of which is always very difficult, if not practically impossible, by other routes.
3. I. Syntheses of 2,5-Disubstitution Products
Ring metalation of compounds of the thiophene series
containing a carbonyl group protected by acetalization, and subsequent replacement of the lithium with
11031 Ja. L . Goldfarb and V . P. Litvinov, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1963, 352.
11041 A . E. Tschitschibabin and S . A . Elgazin, 2. russ. fizikochim.
ObStestva 46, 39 (1914); Ber. dtsch. chem. Ges. 47, 48 (1914).
11051 A . E. Tschitschibabin and S . A . Elgazin,
russ. fizikochim. ObBEestva 46, 802 (1914).
z.
Angew. Chem. internat. Edit.
1 Vol. 7 (1968) No. 7
5-Propionyl-2-thiophenecarbaldehyde (27) was obtained,
not only by the method shown in Scheme 2, but also by the
action of dirnethylforrnarnide on the diethyl ketal of 5-lithiurn-2-propionylthiophene [961. Compound (27) is crystalline,
m.p. 101OC, and can be oxidized t o the carboxylic acid (proof
of structure). O n the other hand, a product obtained from
5-chloromethyl-2-propionylthiophene,which was thought to
be /27), is a liquid[94.951.
The syntheses of unsymmetrical bifunctional thiophenes from the monoacetal of thiophene-2,5-dicarbaldehyde (28) [lo91 are particularly important. The
acetal group in the monoacetal is not affected during
the reduction of the free aldehyde group and its condensation with amines, hydroxylamine, compounds
containing active methylene groups, etc. (see Section 3).
The Schiff bases (30) can be readily reduced to the
amino acetals (31) by NaBH4. Under the usual conditions these give the N-acyl derivatives (32), which
form the acylamino aldehydes (33) on careful hydrolysis. When (28) is heated with malonic ester, the sub11061 Ja. L . Goldfarb and Ju. B. Volkenitein, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1960, 2238.
11071 Ja. L . Goldfarb, B. P. Fabricnyi, and V. I. Rogovik, Izvest.
Akad. Nauk SSSR, Ser. chim. 1963,2172.
[lo81 Ja. L. Goldfarb, B. P . Fabritnyi, and V. I. Rogovik, Izvest.
Akad. Nauk SSSR, Ser. chim. 1965, 515.
11091 V. I. Rogovik and Ja. L . Goldfarb, Izvest. Akad. Nauk
SSSR, Ser. chim. 1963, 2178.
527
(31)
1
\
( RO)ZCH
G
(32)
C H2 - R’
COR2
( RO)zC H
G
O H C G C H =CH NO2
C H = C ( C OOC 2H5)2
\
(34)
stituted thenylidenemalonic ester (34) is formed. The
reactions of the monoacetal (28) with malonic acid,
hydroxylamine, and nitromethane, followed by hydrolysis, lead to (35), (36), and (37) respectively. The
oxime of the hydroxymethyl aldehyde (38) can be obtained by reduction of (28) to the alcohol. 5-Furfuryl-
(37)
Thus in the thienyl ketones, it is possible to direct
bromine into the side chain (under normal conditions),
into position 4 (by complex formation with an excess
of aluminum chloride), or into position 5 (by bromination of the ketal).
2-acetylthiophene (39) [11OJ has been synthesized by
the reaction of the diethyl ketal of 5-lithium-2-acetylthiophene with 2-chloromethylfuran.
Br
Q C O R -+
Br
Q C O R
--+
@$(oC2H5)2
R
-
(40), R = CHs
(41), R = H
3.2. Syntheses of 2,4-Disubstitution Products
By combination of the two blocking methods and
replacement of the p’-bromine atom in the thiophene
acetal by lithium, we obtained 4-formyl-2-acetylthiophene (40) [lo61 and 2,4-thiophenedicarbaldehyde
(41) 1411.
The blockage of a carbonyl group by acetalization also
increases the range of methods available for the preparation of symmetrical and unsymmetrical bifunctional furan compounds. 2,5-Furandicarbaldehyde
(42) and 45-formyl-2-furancarboxylic acid (43) were
synthesized as early as 1962 [1121.
1. n-C
Q C H O
-w
H Li
A
@ ~ H ( O C ~ H ~ ) Z 2.DMF
i
O H C G C H O
It should be finally recalled that the acetalization of
the carbonyl group also permits the bromination of the
thienyl ketones in position 5 11111 (see Section 2.1 1291).
Ill01 Ja. L. Goldfarb and Ja. L. Danjufevskij, Izvest. Akad.
Nauk SSSR, Otdel. chim. Nauk 1963, 540.
[I1 11 V . I . Rogovik and Ja.L. Goldfarb, Chim. geterociklieeskich
Soedinenij 1965, 657.
11121 Ja. L.Goldfarb and V.I. Rogovik, Author’s license (USSR)
184877 (July 5, 1962).
528
The compounds (45)-(48) in Scheme 4 have been
prepared 11133 from the acetal of 4,5-dibromofurfural
(44).
The monoacetal of 3-bromo-2,5-furandicarbaldehyde
(49) is particularly important for the synthesis of unsymmetrical bifunctional compounds.
[113] L. D. Tarasova and Ja. L. Goldfarb, Izvest. Akad. Nauk
SSSR, Ser. chim. 1965,2013.
Angew. Chem. internal. Edit. ] Vol. 7 (1968) No. 7
(44)
Scheme 4
(47)
(49)
3.3. Further Applications of Protection by Acetal
Formation
acid by the acetalization method, which they also used
in conjunction with metalation to obtain 5-benzoylfurfural, [5-D]-furfural, and some organosilicon derivatives of furfural. The method has recently been used
for the synthesis of 2-formyl-3-furancarboxylic
acid L1221. Finally, Paulmier and Pastour [I231 have
prepared 2,5-~elenophenedicarbaldehydeand 5-formyl-2-selenophenecarboxylic acid by this method.
The value of protection by acetal formation is also
illustrated by the following examples. Whereas the
synthesis published in 1967 for the preparation of 5formyl-2-thiophenecarboxylic acid from 2-methylthiophene involves seven steps [114J, we synthesized the
acid in two steps from 2-thiophenecarbaldehyde.The
first step is the acetalization, while the second includes
metalation, reaction with COz, and hydrolysis of the
acetal; the intermediates need not be isolated [1091.
4. Conclusions
Gronowitz et al. rllsJ used the method of protection by
acetal formation in the metalation of 3-thiophenecarbaldehyde with n-butyllithium; the adjacent free 01 position of the_thiophene ringlreacts in this case.
Two methods of blockage of the carbonyl group have
been discussed, i.e. complex formation with aluminum
chloride and acetalization. The primary purpose of
blockage in this case is to provide the conditions
necessary for the establishment of a new reaction
center, but it should also protect the functional group
against attack.
Blockage in this sense can obviously also be applied to
other functional groups and be effected by processes
other than acetalization and complex formation. The
use of complexes involving the hetero atom and of
chelates as intramolecularly blocked compounds would
be particularly interesting. Compounds with an intramolecular hydrogen bond would also belong to this
group. One example is the difference in the reactions
of alkyl halides with the isomeric 01-(51) and a‘aminonicotines (50) 11241. (50) is alkylated exclusively,
Pastour, Savalle, and Emery [I161 obtained 2,3-thiophenedicarbaldehyde with the aid of this reaction.
Cronowitz and Bugge [I171 treated the acetals of 3bromo-2-thiophenecarbaldehyde and of 4-bromo-3thiophenecarbaldehyde with n-butyllithium and then
with tributylboron to obtain 2- and 4-formyl-3-thiopheneboronic acids respectively. The method was
recently used for the synthesis of organosilicon derivatives of 2-acetylthiophene and of 2-thiophenecarbaldehyde r1**,1191, and the authors published their
results as original work, though our findings had been
published and abstracted some time before.
Similar investigations have also been reported in the
furan series. In 1966 Pastour and Plantard independentlysynthesized 2,5-furandicarbaldehyde~l~OJ.Thames
and Odorn [1211 obtained 5-formyl-2-furancarboxylic
[114] V. N. Gogte, B. D. Tilak, K. N. Gudekar, and M . B.
Sahasrabudhe, Tetrahedron 23, 2443 (1967).
[115] S. Cronowitz, B. Gesterlom, and B. Matiasson, Ark. Kerni
20, 407 (1963).
[116] P. Pastour, P. Savalle, and P. Emery, C.R. hebd. Stances
Acad. Sci. 260, 6130 (1965).
[117] S. Gronowitz and A. Bugge, Acta chem. scand. 19, 1271
(48)
or mainly, on the pyrrolidine nitrogen, whereas ( 5 1 ) ,
in which this nitrogen is involved in hydrogen bonding 11251, reacts mainly at the pyridine nitrogen under
comparable conditions.
Received: December 4, 1967
[A 637 IEl
German version: Anaew. Chem. 80, 547 (1968)
Translated by Express Translation Service, London.
(1965).
[118] S. F. Thames and J. E. McCIeskey, J. heterocyclic Chem. 3,
104 (1966).
[1191 S. F. Tharnes and J. E. McCZeskey, J. heterocyclic Chem.
4, 146 (1967).
[1201 P. Pastour and C. Plantard, C.R. hebd. Stances Acad. Sci.
(C) 262, 1539 (1966).
[1211 S. F. Thames and H . C. Odorn, J. heterocyclic Chem. 3,
490 (1966).
Angew. Chem. internat. Edit. J VoI. 7 (1968) J No. 7
11221 M . Robba, H . C. Zaluski, and B. Roques, C.R. hebd. Seances Akad. Sci. (C) 264, 413 (1967).
[123] C. Paulmier and P. Pastour, Bull. SOC.chim. France 1966,
4021.
I1241 Ja. L. Goldfarb and M. S. Kondakova, Izvest. Akad. Nauk
SSSR, Otdel. chim. Nauk 1950, 418.
[125] Ja. L. Goldfarb, M . S . Kondakova, and D. N . Sigorin, Izvest. Akad. Nauk SSSR, Otdel. chim. Nauk 1956, 336.
529
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