Chemistry of 2-aminothiophene-3-carboxamide and related compounds

23 Pages·2011·1.04 MB·English

Turk JChem
35 (2011) , 815 – 837.
(cid:2)c TU¨BI˙TAK
doi:10.3906/kim-1011-813
Chemistry of 2-aminothiophene-3-carboxamide and
related compounds
Moustafa A. GOUDA1,2,∗, Moged A. BERGHOT1, Ghada E. ABD EL-GHANI1,
Khaled M. ELATTAR1, Abd El Galil M. KHALIL1
1Department of Chemistry, Faculty of Science, Mansoura University,
35516 Mansour-EGYPT
e-mail: mostafa [email protected]
2Department of Chemistry, Faculty of Science and Arts, Taibah University-KSA
Received: 14.11.2010
Thisreviewdescribesthesynthesisandreactionsof2-aminothiophene-3-carboxamides asbuildingblocks
for the syntheses of polyfunctionalized heterocyclic compounds.
Key Words: 2-Aminothiophene-3-carboxamides, syntheses, reactivity,reactions, heterocycles
Introduction
Substituted 2-aminothiophene-3-carboxamides are versatile building blocks for the synthesis of agrochemicals,
dyes,andpharmacologicallyactivecompounds.1−3 Severalmethodswerereportedintheliteraturefortheprepa-
ration of these materials.4−31 The most convergent and well-established classical approach for the preparation
of 2-aminothiophenes is Gewald’s method.32 Our review deals with the effective use of 2-aminothiophene-3-
carboxamides inthe synthesis ofdifferent polyfunctionalheterocyclic compounds. Areview includingthe inter-
esting biologicaland medicinalactivities of substituted 2-aminothiophenes was published recently by Puterova´
et al.33
Synthesis
Gewald devised the most facile and promising set of synthetic routes leading to 2-aminothiophene with a
carboxamide group in position 3 and alkyl, aryl, cycloalkyl, and hetaryl groups in positions 4 and 5. Three
∗Correspondingauthor
815
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
major variationsof this reaction have been described in detail. The first version34−48 consists of a single step,
by treatment of α-mercaptoaldehyde or an α-mercaptoketone with cyanoacetamide 2a in a solvent such as
ethanol,dimethylformamide(DMF),dioxane,orwater,inthepresence ofabasiccatalystsuch astriethylamine
(TEA) or piperidine at 50 ◦C.
R O R1 CONH2
1 CONH
2 Solvent
+
R2 SH CN Base R2 S NH2
1 2a 3;R1= Me, H; R2= H, Me
α−Mercaptoaldehyde or α-mercaptoketone is often generated in situ by the reaction of alkali sulfides
withthe corresponding α-halocarbonylcompounds. This versionhas afewdrawbacks; the startingcompounds
are unstable and difficult to prepare. The mechanism of this reaction is as followsin Scheme 1.34−48
B
R1 O H CONH R1 CONH2 R1 CONH2
+ 2
C N
R2 SH H CN R2 S: R2 H S NH
H
R1 CONH2
R S NH
2 2
Scheme 1.
ThesecondversionoftheGewaldreaction32,38−43 consistsofaone-potprocedure thatisveryextensively
used for this synthesis. The convenient technique includes the condensation of ketones with cyanoacetamide or
N-substituted derivatives 2 and a sulfur element in a solvent such as ethanol, DMF, or dioxane in the presence
of amine as dimethylamine,morpholine,or TEA at room temperature.
O X
X
S
+ NH
2
CN Amine S
2 5
2,5a, X= CONH2;b, X= CONHCH3;c, X= CONHC2H5;
d, X= CONHC6H5;e, X= CSNH2;f, X= CONHNH2
Aldehydessuchasphenylacetaldehydewereusedinsteadofketonesintheabovereactiontogive2-amino-
5-phenylthiophene-3-carboxamide (6).32
816
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
CONH
2
CHO
CONH S
2
+
Ph CN Amine Ph S NH2
2a 6
The mechanism of this reaction is as followsin Scheme 2.32,38−43
R1 O RHNOC CN R1 CONHR R1 CONHR
S / Base
8
C N -BH+ C N
R2 R2 R2 S-S -S-
6
-S H
7
R1 CONHR R1 CONHRBH+ R1 CONHR
R
R2 S NH2 R2 S NH -B 2 H S N-
H
Scheme 2.
Microwaveirradiation(MW)hasbecome animportantmethod inorganicsynthesis andcouldbe applied
to a wide range of reactions within short times and with high yields. The microwave irradiation of 1,4-
dithiane-2,5-diol(thioacetaldehydedimmer)(7)withcyanoacetamideor2-cyano-N-(2-nitrophenyl)acetamide(8)
inboilingethanolormethanolcontainingacatalyticamountofTEAfurnishedcorresponding2-aminothiophene-
3-carboxamide derivative 9.49,50
CONHR
HO S
CONHR MW
+
EtOH or MeOH NH
S OH CN TEA S 2
7 8 9
R= H, 2-nitrophenyl
Furthermore, a new synthesis of substituted-2-aminothiophene-3-carboxamide 11 was achieved via a 1-
pot MW-assisted Gewald reaction using aluminumoxide as a solid support in the presence of morpholine as a
basic catalyst and under solvent-free conditions for several minutes.51
O O
O Ar
Ar Morpholine / Al O N
+ HN + S 2 3 H
MW / 160 W / 10 min
CN H N S
2
10
11
10,11a, Ar= C6H4-4-OMe; b, Ar= C6H4-4-Me ;
c, Ar =C6H4-3-Cl-4- F ; d, Ar= C6H4-4-CF3
817
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
α,β-Unsaturated nitrile 12 was prepared by a Knoevenagel-Cope condensation followed by treatment
with sulfur and amine,34,38,42,52−63 and this method gave high yields. Alkyl and aryl ketone do not yield
thiophenes in the 1-step modification,but gave acceptable yields in the 2-step techniques.
X X
CN S
NH
2
Amine S
12 5
5,12a, X= CONH2;b, X= CONHC6H4-3-CF3;c, X=CONHC6H4-3-OCH3;
d, X= CONHC6H4-4-Cl; e, X=CONHC6H4-4-Br; f, X= CONHC6H4-4-I;
g, X= CONHC6H4-4-CF3;h, X= 4-antipyrinyl
Reactivity
2-Aminothiophene-3-carboxamide derivatives could be treated with various reagents, such that the attack can
take place at 5 possible positions. The nucleophiles are able to attack the carbon atom of the carbonyl group
at position 1 and carbon 2 at position 2, while the electrophiles attack the amino group of the carboxamidoat
position 3, the amino group at position 4, and carbon atom 5 at position 5.
O
R 1
1
NH
2
3
5 4
R2 S 2 NH2 E Nu
E
when R = H
2
Reactions
The reactions of 2-aminothiophene-3-carboxamide with numerous reagents are classified separately in a single
category due tothehuge numberofreferences. Wehavearrangedthislargevolumeofdatainterms ofthe type
of heterocyclic, starting with 5- and 6-membered rings in order to increase the number of hetero atoms. Such
systematic treatment provided a clear idea about the synthetic possibilities of the methods and may be useful
in selecting the direction of further research.
818
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
Formation of 5-membered rings with 2 hetero atoms
Formation of thieno[2,3-d]pyrazolo derivatives
Pyrazolo derivatives 14 were prepared by the reaction of 2-aminothiophene-3-carboxamides13 with hydrazine
hydrate in sodium ethoxide.64
O H N
NH 2
2
N
R R
NH NH H O
2 2. 2 NH
NH
2
S NaOEt S
13 14
13,14a, R= C6H5;b, R= C6H4-2-Cl; c, R= C6H3-3,4-Cl2;d, R= C6H4-4-OCH3;
e, R= C6H2-3,4,5-(OCH3)3;f, R= C6H3-3-OCH3,4-OH; g, R= C6H4-4-NO2;
h, R= C6H3-4-Cl; i, R= C6H4-2-OCH3
Formation of 6-membered rings with 2 hetero atoms
Synthesis of thieno[2,3-d]pyrimidine derivatives
Dave et al.65 reported that the reaction of 2-aminothiophene-3-carboxamide derivatives 15 with nitriles in
dioxane in the presence of hydrochloric acid yielded corresponding pyrimidine derivatives 16.
O HO CH3
NHCH
3 N
RCN R
NH2 N
Dioxane
S
S
15 16
16a, R= Me; b, R= Ph; c, R= CH2CO2Et; d, R= CH2Ph;
e, R= CH2CH2Cl; f, R= CH:CHPh; g, R= C6H4-4-Cl;
h, R= pyridyl
2-Mercaptothieno[2,3-d]pyrimidin-4-(3H)-one derivatives 18 were prepared by the cyclocondensation of
2-aminothiophene-3-carboxamides17 with thiourea.66
O S O
R1 NH R1 NH
2 H N NH
2 2
SH
N
R S NH R S
2 2 2
17 18
17,18a, R1= H, R2= Me; b, R1=R2= Me
819
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
Thienopyrimidines 20 were obtained in yields of 58%-92% by the condensation of 19 with different
aldehydes.67
O O
NH2 NH
R
RCHO
NH NH
2
S S
19 20a, R= 3,4,5-(MeO)3C6H2;
b, R= 4-MeO C6H4;
c, R= 2-Cl C6H4;
d, R= 3,4-(MeO)2C6H3;
e, R= 4-MeC6H4
Itwasfoundthatthereactionof2-amino-4-methylthiophene-3-carboxamide(21)witharomaticaldehydes
gave corresponding thienopyrimidinederivatives 22.67
O
O
H C H C NH
3 NH2 RCHO 3 R
R R N
S NH S
2
21 22a, R= Ph;
b, R= 3,4-(MeO) C H ;
2 6 3
c, R= 3-pyridyl
In addition,the reaction of furfurals with 19 in sodiumethoxide furnished thieno[2,3-d]pyrimidin-4-ones
23.68 Similarly, some cyclocondensation products (24) were obtained from the reaction of different aromatic
aldehydes with 19 in n-butanol in the presence of hydrochloric acid (Scheme 3).69
On the other hand, the reaction of cinnamaldehyde with 19 in ethanol in the presence of dry hydrogen
chloridegasaffordedcorresponding2-stryl-thienopyrimidine25.70 Treatmentof25withphosphorusoxychloride
yielded 26, which, upon reaction with hydrazine hydrate, gave 4-hydrazino-2-styryl-thieno[2,3-d]pyrimidine
derivative 27. Triazolopyrimidine 28 could be obtained through the cyclization of 27 with formic acid.
Triazolopyrimidine derivative 28 was converted into its isomeric structure (29) upon refluxing in a sodium
ethoxide/ethanol mixture. Furthermore, it was reported recently that the reaction of compound 19 with 6-
carboxaldehyde chromenes in boilingpyridine furnished corresponding pyrimidines30 (Scheme 4).71
820
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
O
NH
OHC O R
NH O R
NaOEt
S
23, R= H, NO2
19
OHC
O
NH R
R
NH
HCl (Cat.)
S
n-butanol
80oC, 10 h 24a, R= 3,4,5-Trimethoxy phenyl;
b, R= 4-Hydroxy-naphthalen-1-y;
c, R= 2-Bromo-3,4-dimethoxy phenyl;
d, R= 3-Acetyloxy phenyl;
e, R= 3-Chloro-4-hydroxy-5-methoxy phenyl
Scheme 3.
O Cl
NH Ph N Ph
Ph
OHC POCl
3
N N
EtOH/ HCl S S
25 26
NH NH H O
2 2. 2
N
N N N
H NHN
N Ph N Ph 2 N Ph
NaOEt HCOOH
19 N N N
S S S
29 28 27
R O
1
O
OHC
O R
1 CH
NH 3
R O CH O
2 3
R3 N
R
Pyridine S R2 3
30a, R1= OCH3, R2= OH, R3= H;
b, R1= R2= OCH3, R3= H;
c, R1= R2= OH, R3= Br;
d, R1= OCH3, R2= OH, R3= NO2
Scheme 4.
821
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
Maksymetal.72 introduced anovelmethodforthesynthesis ofcompoundscontainingthiophene,pyrim-
idine, and coumarin ring systems. Thus, the reaction of 19 with 2-imino-2H-1-benzopyran-3-carboxamides in
glacialaceticacid(AcOH)yielded31,which,uponrefluxinginappropriatesolvents,gavethieno[2,3-d]pyrimidin-
4-ones 32a and 32b. The cyclocondensation of 19 with acetyl acetone or 2-hydroxy-1,2-diphenylethanone in
ethanol containing hydrochloric acid yielded corresponding thieno[2,3-d]pyrimidin-4-ones 33a and 33b.73,74
O
R
NH
2
R CONH
2
S
O NH
O N
AcOH
67%-92% O
H N
31 2
Method A: PhNO , reflux, 2.5 h
2
Method B: AcOH, reflux, 4 h
O
HN
R
N S
O O
32a, R= H; b, R= Cl
OH
O
O
NH
Ph
R
Ph
19 N
or O O S
R R 33a, R= Me; b, R= Ph
O O
NH
RCOOEt NH2 i .NaOH R
NHCOR N
S ii.MeOH S
34 35
34,35a, R= CO2Me; b, R= CO2Et;
O c, R= CH2CO2Et;d, R= CH=CH-CO2Et
O O O NH
NH (CH ) CO H
2 2 2 2
O
NH N
S CO(CH ) CO H S
2 2 2
36 37
Scheme 5.
822
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
The refluxing of 19 with a variety of diesters for 1.5-2 h gave 34a-34d, which cyclized and esterified with the
use of sodium hydroxide to form thienopyrimidines 35a-35d.75,76 Similarly, the heating of 19 and succinic
anhydride gave 4-(3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobutanoic acid (36), which
cyclized in a basic medium to give corresponding thienopyrimidine derivative37 (Scheme 5).77
The treatment of 38 with different orthoesters in ethanol containinga catalytic amount of tungstophos-
phoric acid gave corresponding thienopyrimidinone derivatives39a-39c.78
O O
H3C H3C NH
NH
2 RC(OEt)
3 R
N
H3C S NH2 H3C S
38
39a, R= H; b, R= CH3;c, R= Et
Compound 40 was obtained by reacting 19 with ethyl 2-chloro-2-oxoacetate, which cyclized in sodium
hydroxide to give corresponding thienopyrimidines41a and 41b (Scheme 6).79−81
O
O
O
Cl OEt NH2 NH
R
19 O N COCO2Et NaOH N
H
S S
40
41a, R= CO Et; b, R= CO Na
2 2
Scheme 6.
Ph
O O O
NHPh NHPh N
OH
ClCO Et CO Et KOH
NH 2 N 2 N
S 2 S H -EtOH S
42 43 44
POCl / PCl
3 5
Ph Ph Ph
O O O
N N N
N NHNH Cl
3 NaNO 2 NH NH H O
N 2 N 2 2. 2 N
S HCl S S
47 46 45
Scheme 7.
In addition,compound42,upontreatment withethylchloroformateinpyridine,gave43,whichcyclized
with potassium hydroxide to yield thienopyrimidinone derivative 44. Treatment of 44 with a mixture of
phosphorus oxychloride (POCl ) and phosphorus pentachloride (PCl ) gave 45. Nucleophilic displacement
3 5
823
Chemistry of 2-aminothiophene-3-carboxamideand related compounds, M. A. GOUDA, et al.
of the chlorine atom in compound 45 with hydrazine hydrate gave 2-hydrazino-thienopyrimidin-4-one (46).
Diazotization of 46 with sodium nitrite solution and 50% concentrated hydrochloric acid at 0-5 ◦C afforded
2-azido-thienopyrimidin-4-onederivative 47 (Scheme 7).82
Variousapproacheshavebeen used tosynthesize thecondensed triazolopyrimidines,involvingcyclization
of 2-hydrazinoderivatives46 witha variety ofsingle-carbon donors. The reaction of 46 witharomaticacids in
dioxane/POCl ,CS /pyridine,CNBr/EtOH,benzoylisothiocyanateinacetone,orbenzoylchloridefollowedby
3 2
polyphosphoric acid gave the corresponding triazolopyrimidinederivatives47-51 and 53,respectively (Scheme
8).82
Ph
O
N
N
RCOOH
N N
Dioxane
S
R
47
Ph
O Ph O
N
N
N N
CS /pyridine [O]
2 N N N N
S S
SH OH
48 49
O Ph
N
N
CNBr
46 N N
EtOH S
NH
50 2
O Ph
N
N
PhCONCS
N N
Acetone S
NHCOC H
6 5
51
O Ph O Ph
N N
NH N
PhCOCl PPA
NH NH N N
S S
O
Ph Ph
52 53
Scheme 8.
Compound 54 was obtained by the reaction of 19 with methyl chloroacetate in a basic medium. Cy-
clization of 54 was accomplished by reaction with different amines to give thienopyrimidines55 (Scheme 9).83
824