Synthesis of Oxa-aza- and Bis-oxathiaaza[33.3]propellanes from Dicyanomethylene-1,3-indanedione and 2,5-Dithiobiureas

Article abstract of DOI:10.1055/s-0034-1380447

An efficient route for the synthesis of oxa-aza- and bis-oxathiaaza[3.3.3]propellanes via reactions of symmetrical and unsymmetrical N¹,N²-disubstituted hydrazine-1,2-dicarbothioamides (2,5-dithiobiureas) with (1,3-dioxo-2,3-dihydro-

Full text of DOI:10.1055/s-0034-1380447

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 3036–3042
3036
paper
Synthesis
A. A. Hassan et al.
Paper
Synthesis of Oxa-aza- and Bis-oxathiaaza[3.3.3]propellanes from
Dicyanomethylene-1,3-indanedione and 2,5-Dithiobiureas
Alaa A. Hassan*a
Nasr K. Mohameda
Maysa M. Makhloufa
Stefan Bräseb
Martin Niegerc
O
H2N
CN
CN
CN
O
NC
O
CN
O
O
R1
S
NH2
O
N
O
.0 mmol
+
THF
HN
N
+
N
R2
3
N
O
OH
O
r.t., 96 h
H2N
S
a
Chemistry Department, Faculty of Science, Minia University,
S
11–16%
O
H
H
58–63%
6
1519 El-Minia, A. R. of Egypt
R1
CN
N
N
b
c
R2
Institute of Organic Chemistry, Karlsruhe Institute of
Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Laboratory of Inorganic Chemistry, Department of Chemistry,
University of Helsinki, P.O. Box 55 (A. I. Virtasen aukio I),
N
N
N
H
N
H
+
S
1
NHR2
R HN
S
1.0 mmol
5 examples
14–19%
00014 Helsinki, Finland
alaahassan2001@mu.edu.eg
Received: 17.03.2015
Accepted after revision: 06.05.2015
Published online: 07.07.2015
Recently, multicomponent reactions (MCRs) have been
used for the synthesis of heteropropellanes. For example,
the addition of ninhydrin and malononitrile to arylisothio-
DOI: 10.1055/s-0034-1380447; Art ID: ss-2015-z0174-op
cyanates and primary amines led to the formation of oxa-
Abstract An efficient route for the synthesis of oxa-aza- and bis-oxa-
thiaaza[3.3.3]propellanes.7 The reaction of trichloroacet-
thiaaza[3.3.3]propellanes via reactions of symmetrical and unsym-
amidine with the Knoevenagel condensation product of
ninhydrin and malononitrile afforded trichloromethylated
[3.3.3]propellanes.24 Oxa-aza[3.3.3]propellanes have been
synthesized via the multicomponent reaction of malononi-
1
2
metrical N ,N -disubstituted hydrazine-1,2-dicarbothioamides (2,5-
dithiobiureas) with (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)pro-
panedinitrile in tetrahydrofuran is described. The rationale behind these
conversions involving nucleophilic addition on the dicyanomethylene
carbon atom is presented. The structures of these unusual products are
confirmed by X-ray crystal structure analysis.
25
trile and ninhydrin with ketene aminals, arylisothiocya-
nates26 or hydrazine derivatives with an electron-with-
27
drawing group close to the NHNH moiety.
Key words dicyanomethylene-1,3-indanedione,
oxa-aza[3.3.3]propellane, bis-oxathiaaza[3.3.3]propellanes, N ,N -
2,5-dithiobiureas,
2
2
5
28
On the other hand, spiro-indenepyrazoles and spiro-
disubstituted 1,3,4-thiadiazoles
29,30
indenethiazines
have been isolated from the reactions
of thiosemicarbazide or thiosemicarbazone derivatives
with 2-(1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)pro-
Molecules such as cubanes, prismanes and propellanes,
31
which possess unusual shapes and inherent strain, have at-
tracted the interest of many chemists as they are useful in-
termediates and target compounds in organic synthesis.1
In addition, some of these molecules, for example those ex-
hibiting propellane skeletons, are present in natural prod-
panedinitrile (1). Additionally, Döpp et al. have reported
that the known compounds: 1,3-dihydroxy-2H-inden-2-
ylidenepropanedinitrile (4), benzo[d,e]isoquinoline-1-car-
bonitriles 3 and dispirocyclopropane derivative 5 (Scheme
1) were formed from compound 1 via reactions with N-
aryl-2,3-dihydro-1H-benzo[d,e]isoquinolines 2a–d in ace-
tonitrile or ethanol.31
Herein, we describe the synthesis of new oxa-aza- and
bis-oxathiaaza[3.3.3]propellanes 7 and 8a–e (Table 1) via
the reaction of compound 1 with symmetrical and unsym-
metrical 1,6-disubstituted-2,5-dithiobiureas 6a–e in the
molar ratio of 3:1 in tetrahydrofuran. The reaction mixtures
were stirred at room temperature (open to air) for 96 hours
resulting in the formation of fine colorless precipitates of
bis-oxathiaaza[3.3.3]propellane derivatives 8a–e. The fil-
trate was separated by preparative thin-layer chromatogra-
phy to give two zones; the fastest migrating zone contained
thiadiazoles 9a–e whilst the slower-moving zone consisted
of the oxa-aza[3.3.3]propellane 7.
–3
4–9
ucts.
Propellanes are unique compounds in which one
common C–C single bond is shared by three different rings
in the overall three-dimensional structure.1
0
Nitrogen- and oxygen-containing propellanes and their
analogues have attracted attention due to their presence in
biologically active natural products and pharmaceuticals
such as periglaucine A, sinoacutine and hasubanan alka-
1
1,12
loids.
Aza-propellanes can be used as synthons for natu-
13–15
ral products,
as ligands for transition-metal-mediated
16
reactions and as building blocks for the cucurbiturils. Al-
though the strain present in propellane compounds may be
the reason for their instability and makes their synthesis
difficult, many derivatives of these compounds have been
17–23
prepared.
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3
037
Synthesis
A. A. Hassan et al.
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1
The H NMR spectrum of compound 7 showed broad ex-
Ar
N
O
O
changeable (with D O) signals at 10.90, 8.38 and 7.62 ppm
2
CN
CN
due to the amide NH, NH and hydroxy groups. The eight
aromatic hydrogens gave rise to characteristic signals in the
aromatic region of the spectrum.
2
+
The decoupled 13C NMR spectrum showed a signal at
96.5 ppm due to the aliphatic quaternary carbon atom
bearing a hydroxy group. The C3 and C4 furan carbons reso-
nated at 75.9 and 71.5 ppm, respectively, whereas C5 of the
furan was evident as a downfield shifted signal at 145.4
1
2a–d
MeCN
EtOH
O
Ar
N
O
NC
HO
13
ppm due to the adjacent NH and oxygen. The C NMR spec-
NC
NC
1
trum of 7 supported the H NMR spectroscopic data with
+
the appearance of characteristic aromatic C–H carbon sig-
nals. The pyrrole C4 (C13) carbon and pyrrole C=O resonat-
ed at 56.8 and 169.9 ppm, respectively. In addition, the C11
and C12 carbons resonating at 51.7 and 164.2 ppm were in
NC
CN O
O
HO
3
4
5
2
, 3 a, Ar = Ph; b, Ar = 4-MeC6H4;
c, Ar = 4-MeOC6H4; d, Ar = 4-ClC6H4
accord with the observed trends in chemical shift values for
carbon atoms in push–pull alkenes.3
3,34
The signals at 193.3
Scheme 1 Previous work on the reactions of compound 1 with ben-
zo[d,e]isoquinolines 2a–d
and 193.4 ppm were due to the carbonyl carbons of the in-
deno moiety. The mass spectrum of compound 7 displayed
the molecular ion peak at m/z 436.
1
The IR spectrum of product 7 clearly indicated the pres-
Aside from the H and 13C NMR spectra which demon-
strate the presence of two oxoindenylidene units, two cya-
no groups, amide CO and other functional groups, it is very
difficult to elucidate the three-dimensional structure of
propellane 7. However, the structure of 7 was unambigu-
ously determined by single crystal X-ray structure analysis,
which confirmed the presence of a propellane system (Fig-
ure 1, and Tables S1–S7 in the Supporting Information; note
that the crystallographic numbering does not correspond
with the symmetric IUPAC numbering rules).
–
1
–1
ence of OH, NH and NH (3425–3209 cm ), CN (2210 cm ),
2
–1
–1 32
C=O (1734, 1654 cm ) and C–O–C (1098 cm ) functional
groups.
Table 1 Reactions of Compound 1 with 2,5-Dithiobiureas 6a–e
O
CN
CN
S
H
N
4
H
N
6
THF
R1
1
N
H
3
N
H
+
R2
S
O
1
6a–e
H2N
CN
1
2
NC
O
1
1
N
N
O
1
3
10
O
+
1
NHR2
+
R HN
1
4
15
S
HN
O
OH
9
a–e
7
CN
3
O
R1
S
4
NH2
O
N
2
N
9
N
R2
N
O
H2N
S
O
8a–e
Figure 1 X-ray crystal structure of 7 (ORTEP plot; displacement param-
eters are drawn at the 30% probability level)
CN
Products, yields (%)
R2
R1
Substrate
19
16
14
15
14
9a
9b
9c
9d
9e
59
63
61
58
62
8a
8b
8c
8d
8e
11
7
7
7
7
7
Ph
Ph
Bn
6a
6b
6c
6d
6e
In addition to compound 7, the results of combustion
analysis and spectroscopic data suggested the presence of
other novel compounds, which were regularly detected and
identified as symmetrical and unsymmetrical bis-oxathia-
aza[3.3.3]propellane derivatives 8a–e.
12
15
13
16
Bn
allyl
Bn
allyl
Ph
Bn
allyl
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Synthesis
A. A. Hassan et al.
Paper
The structures of 8a–e were delineated from their spec-
troscopic properties. The salient features were the changes
in the carbon–carbon double bond of 1 and the NH reso-
nances of 6a–e on reacting to give products 8a–e. As a re-
sult of the formation of the propellane rings, new signals
The analytical data of compounds 8 would also match
with the other possible regioisomeric products 12 and 14.
3
4
Compounds 6a–e may react via their sulfur atom, HN , HN
1
6
and HN , HN as nucleophilic sites. It is probable that the
observed products 8a–e are formed from one of three labile
1:2 adducts (A–C) (Scheme 2).
13
were observed in the C NMR spectra.
The molecular formula of 8e, as an example, was con-
firmed by mass spectrometry. The molecular ion was ob-
served at m/z = 696 (23%), which was in agreement with
the proposed structure and clearly indicated that the addi-
tion of one molecule of 6e to two molecules of 1 had oc-
curred without any associated elimination. The IR spectrum
The product would have structure 8 if the reaction took
1
6
place through SH and HN , HN via adduct A and intermedi-
ate 10 (Schemes 2 and 3). Product 12 would be isolated if
3
4
the reaction involved the participation of HN , HN and
1
6
HN , HN by way of adduct B and intermediate 11 (Schemes
2 and 3). If the SH group attacks the carbon–carbon double
bond of 1, adduct C would be observed followed by intra-
of 8e showed absorptions at 3340 (NH ), 2197 (CN), 1725
2
–
1
3
4
(
CO), 1650 (C=N) and 1094 (C–O–C) cm .
molecular nucleophilic attack of HN , HN at the carbonyl
group of 1; this would lead to product 14 via intermediate
13 (Schemes 2 and 3).
1
The H NMR spectrum of 8e displayed one broad singlet
at 8.12 ppm (4 H) for the NH protons. The downfield shift
2
of the NH group may be due to intermolecular H-bonding
2
between the NH and the oxygen of the carbonyl group of
acetone (the solvent of crystallization). The allyl group res-
2
HN
CN
O
R1
S
N
onated as three multiplets at 4.30–4.40 (–CH N), 5.10–5.18
2
HO
N
(
H C=) and 5.72–5.80 (–CH=) ppm, respectively. The pres-
N
2
13
A
N
ence of allyl and benzyl groups was evident from the
C
R2
OH
S
NMR DEPT spectrum which exhibited positive signals at
O
1
4
36.3 ppm (–CH=) and negative signals at 46.2 (–CH N),
2
NC
NH
10
13
CN
7.4 (CH Ph) and 117.9 (H C=) ppm. In the C NMR spec-
2
2
O
trum of 8e, the thiazole C4 and C-4 carbons resonated at
08.2 and 70.8 ppm, respectively. Additional diagnostic res-
onances occurred at 53.4 (furan-C3), 165.9 (furan-C2),
R1
S
N
NH2
1
O
N
C
N
N
O
116.2 (CN), 158.1 (C=N) and 193.1 (indeno-CO).
R2
H2N
S
O
8
CN
R1
R1
H CN
O
HN
S
CN
NC
O
O
N
S
HO
N
1
+
6a–e
S
N
B
N
N
NH
R2
O
OH
CN
C
N
O
NC H
O
O
CN NH S
R2
A
1
1
R1
R1
O
H
CN
N
S
S
O
NH2
NC
NC
O
S
1
+
6a–e
N
N
N
N
H2N
R1
O
O
N
S
CN
CN
O
O
NH
R2
R2
R1
NC
12
H
NH2
O
CN
N
O
N
B
S
CN
S
HN
C
O
NC
O
N
R1
H CN
N
NC
N
O
C
HO
S
O
N
H2N
NH
HN
CN
NC H
O
N
O
N
S
S
OH
R2
1
+
6a–e
CN
S
C
N
O
R2
NH
R2
O
14
13
C
Scheme 3 Structures of the possible alternative regioisomers 12 and
Scheme 2 Possible adducts formed via reactions of 1 with 6a–e
14
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3
039
Synthesis
A. A. Hassan et al.
Paper
S
H
H
N
R1
+ 1
N
N
N
R2
[CT complexes]
H
H
S
–
6
a–e
S
NHR2
O
O
S
CN
CN
R1
•
+
• –
N
6
a–e + 1
+
N
N
H+
H
H
15
16
NC O
O NC
CN
NC
+
H+
1
+
16
from 6
O
O
17
NH2
Figure 2 X-ray crystal structure of 8b (ORTEP plot; one crystallograph-
ically independent molecule is shown)
NC
O
CN
HN
O
NC
O
•
CN
NC
O
Structure 12 was excluded on the basis of 13C NMR spec-
NC
O
O
troscopy and by the absence of a C=S functional group in
1
13
O
compound 8. A comparison of the H NMR or C NMR
chemical shifts of the possible isomers 8 and 14 does not
serve as a useful supplementary tool in confirming the cor-
rect structure. Therefore, the propellane-type structure of
compounds 8a–e was determined by X-ray crystallographic
analysis. The X-ray crystal structure of compound 8b con-
sists of three fused five-membered rings (Figure 2, and Ta-
bles S8–S10 in the Supporting Information).
O
18
H2O
CN
NH2
NH2
O
NC
O
O
NC
O
CN
HO
HN
O
H2N
O
O
O
O
Plausible mechanism for the formation of propellanes 7
and 8a–e have been proposed based on previous results
19
20
(
Schemes 4 and 5).
H2N
NC
O
In order to rationalize the formation of products 7–9,
O
CN
H2N
NC
O
the generation of cation 15 and anion 16 may be regarded
as the initial event, whereby charge-transfer (CT) complex-
es may form (but not necessarily) during intermediate stag-
es. The nucleophilic addition of 16 to the dicyanomethylene
carbon atom of 1 in the presence of a proton (possibly origi-
nating from 6) affords intermediate 18. This subsequently
undergoes addition of a molecule of water, and via interme-
diates 19–21 gives oxa-aza[3.3.3]propellane 7 (Scheme 4).
The nucleophilic attack of compound 6 on the carbon–
carbon double bond of dinitrile 1 affords the intermediate
O
CN
O
O
HN
OH
HN
O
O
OH
7
21
Scheme 4 A possible mechanism for the formation of compound 7
anomethylene-1,3-indanedione 1. The products were syn-
thesized in good yields from readily accessible starting
materials, using a simple experimental procedure and sub-
strates that did not require any prior activation. In order to
be reactive, the symmetrical and unsymmetrical 2,5-di-
2
2. Since the formation of compounds 9a–e involves intra-
molecular nucleophilic attack of the hydrazine NH on the
thiocarbonyl group, it is conceivable that 1 accelerates the
process by functioning as a Lewis acid, through intermedi-
ate 22 (Scheme 5), activating the respective C=S bonds to-
ward nucleophilic addition. After cyclization, dinitrile 1 is
1
6
3
thiobiureas required the availability of HN , HN and HN ,
HN as well as sulfur atoms as nucleophilic sites.
4
released and liberation of hydrogen sulfide (H S) occurs. On
2
the other hand, the addition of 22 to another molecule of
dinitrile 1 affords the bis-oxathiaaza[3.3.3]propellane 8 via
intermediate 10.
In conclusion, novel oxa-aza- and bis-oxathia-
aza[3.3.3]propellanes have been synthesized from the nu-
cleophilic addition reactions of 2,5-dithiobiureas on dicy-
Melting points (uncorrected) were determined using open glass capil-
laries on a Gallenkamp melting point apparatus. IR spectra were re-
corded on Shimadzu 408 or Bruker Alpha FT-IR instruments with
1
samples prepared as potassium bromide pellets. H NMR (400 MHz)
13
and C NMR (100 MHz) spectra were obtained using a Bruker AM
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3
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Synthesis
A. A. Hassan et al.
Paper
R1
NH
give colorless crystals of 8. The mother liquor was subjected to pre-
parative TLC using toluene–EtOAc (5:4) in the reactions of 1 with
NHR1
O
O
6a,e, toluene–EtOAc (1:1) in the reaction of 1 with 6b, toluene–EtOAc
S
N
N
(5:3) in the reaction of 1 with 6c, and toluene–EtOAc (2:1) in the re-
1
+ 6a–e
N
CN
NH
HN
S
action of 1 with 6d, resulting in numerous zones, the two most in-
S
–
–
1
H2S
tense of which were removed and extracted. The fastest migrating
CN
NHR2
2
5
R2
zone contained N ,N -disubstituted 1,3,4-thiadiazole-2,5-diamines 9.
The slowest migrating zone, which quenched all indicator fluores-
cence upon exposure to UV light (254 nm), contained product 7.
22
9a–e
R1
O
NH
NC O
12-Amino-5a-hydroxy-10,14,15-trioxo-5a,10,13,14-tetrahydro-
4b,13-(epiminomethano)cyclopenta[c]diindeno[1,2-b:2′,1′-d]fu-
ran-11,13-dicarbonitrile (7)
S
NC
N
1
+ 22
N
CN
S
Yield: 70 mg (16%); brown crystals (EtOH); mp 210–212 °C.
O
CN
HN
O
R2
IR (KBr): 3425–3209 (OH, NH , NH), 2210 (CN), 1734–1654 (CO),
2
–1
1
604 (Ar-C=C), 1098 (C–O–C) cm .
A
1
H NMR (400 MHz, DMSO-d ): δ = 7.20–7.44 (m, 3 H, H ), 7.58–7.60
6
Ar
HN
CN
O
(
m, 2 H, H ), 7.62 (br s, 1 H, OH), 7.72–7.80 (m, 3 H, H ), 8.38 (br s, 2
Ar
Ar
H, NH ), 10.90 (br s, 1 H, amide-NH).
R1
2
S
HO
13
N
C NMR (100 MHz, DMSO-d ): δ = 51.7 (C-11), 56.8 (C-13), 71.5 (fu-
6
N
N
ran-C4), 75.9 (furan-C3), 96.5 (quaternary-C-OH), 113.7, 116.0 (CN),
122.6, 123.2, 124.1, 124.3 (CH ), 130.9, 133.5, 136.0, 137.6 (C ),
N
R2
OH
Ar
Ar
S
1
45.4 (furan-C5), 164.2 (C-12) 169.9 (amide-CO), 193.3, 193.4 (inde-
no-CO).
MS (EI): m/z (%) = 436 (17) [M] , 410 (19), 382 (12), 370 (26), 104 (76),
6 (100), 66 (54).
Anal. Calcd for C24H12N O : C, 66.06; H, 2.77; N, 12.84. Found: C,
O
NC
NH
+
1
0
CN
7
O
4
5
R1
S
NH2
65.92; H, 2.66; N, 13.02.
O
N
N
N
N
O
(10E,10′E)-10,10′-(Hydrazine-1,2-diylidene)bis[2-amino-4-oxo-9-
phenyl-4H-3a,8b-(epithiomethanoimino)indeno[1,2-b]furan-3-
carbonitrile] (8a)
R2
H2N
S
O
8
CN
Yield: 424 mg (59%); colorless crystals (MeCN); mp 190–192 °C.
Scheme 5 A possible mechanism for the formation of compounds 8a–e
IR (KBr): 3409 (NH ), 2187 (CN), 1716 (CO), 1636 (C=N), 1602 (Ar-
2
–1
C=C), 1093 (C–O–C) cm
.
1
H NMR (400 MHz, DMSO-d ): δ = 7.12–7.21 (m, 4 H, HAr), 7.32–7.46
6
(
7
m, 4 H, H ), 7.55–7.64 (m, 2 H, H ), 7.66–7.69 (m, 2 H, H ), 7.72–
4
00 spectrometer with tetramethylsilane as an internal standard. The
Ar Ar Ar
.75 (m, 2 H, H ), 7.86–8.05 (m, 4 H, H ), 8.16 (br s, 4 H, 2 × NH ).
multiplicities are defined as follows: s = singlet, m = multiplet, br s =
Ar
Ar
2
broad singlet. The 1 C NMR signals were assigned on the basis of DEPT
3
13
C NMR (100 MHz, DMSO-d ): δ = 53.7 (furan-C3), 71.1 (thiazolidine-
6
1
35/90 spectra. Chemical shifts (δ) are expressed in ppm. Mass spec-
C5), 108.2 (furan-C5), 116.4 (CN), 125.8, 126.7, 127.2, 129.1, 131.4,
132.5, 134.5 (CH ), 136.9, 142.9, 143.9 (C ), 158.9 (C=N), 165.5 (fu-
ran-C2), 192.9 (indeno-CO).
tra (70 eV, electron impact mode) were recorded on a Finnigan MAT
instrument. Elemental analysis (C, H, N and S) was carried out at the
Microanalytical Center, Cairo University, Egypt. Preparative thin-layer
chromatography was accomplished using glass plates (48 cm wide
and 20 cm tall) covered with a layer (1.0 mm thick) of air-dried silica
gel (Merck Pf254). 1,6-Disubstituted 2,5-dithiobiureas were prepared
Ar
Ar
+
MS (EI): m/z (%) = 718 (12) [M] , 652 (17), 583 (44), 517 (9), 359 (12),
45 (10), 135 (66), 77 (100), 66 (41).
Anal. Calcd for C38H22N O S : C, 63.50; H, 3.09; N, 15.59; S, 8.92.
3
8
4 2
1
2
Found: C, 63.34; H, 2.95; N, 15.76; S, 9.13.
according to published procedures, as were N ,N -diphenylhydrazine-
35
1
2
1,2-dicarbothioamide (6a),
N ,N -dibenzylhydrazine-1,2-dicarbo-
36
1
2
37
thioamide (6b), N ,N -diallylhydrazine-1,2-dicarbothioamide (6c),
N -benzyl-N -phenylhydrazine-1,2-dicarbothioamide (6d), N -allyl-
N -benzylhydrazine-1,2-dicarbothioamide (6e). (1,3-Di-oxo-2,3-di-
hydro-1H-inden-2-ylidene)propanedinitrile (1) was prepared accord-
ing to the method reported by Chatterjee.
(10E,10′E)-10,10′-(Hydrazine-1,2-diylidene)bis[2-amino-9-benzyl-
4-oxo-4H-3a,8b-(epithiomethanoimino)indeno[1,2-b]furan-3-
carbonitrile] (8b)
1
2
38
1
2
39
Yield: 470 mg (63%); colorless crystals (acetone); mp 234–236 °C.
40
IR (KBr): 3329 (NH ), 2194 (CN), 1725 (CO), 1638 (C=N), 1597 (Ar-
2
–1
C=C), 1106 (C–O–C) cm
.
General Procedure
1
H NMR (400 MHz, DMSO-d ): δ = 4.89 (s, 4 H, CH Ph), 7.00–7.05 (m,
6
2
A solution of 6 (1.0 mmol) and 1 (624 mg, 3.0 mmol) in dry THF (50
mL) was stirred at r.t. for 96 hours, during which time the color
changed from yellow to reddish brown and a fine colorless precipitate
formed. The solid was collected and recrystallized from acetone to
2
H, H ), 7.14–7.22 (m, 4 H, H ), 7.36–7.44 (m, 4 H, H ), 7.52–7.60
Ar Ar Ar
(
m, 4 H, H ), 7.65–7.74 (m, 2 H, H ), 7.90–8.03 (m, 2 H, H ), 8.10 (br
Ar Ar Ar
s, 4 H, 2 × NH2).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3036–3042

3
041
Synthesis
A. A. Hassan et al.
Paper
13
1
C NMR (100 MHz, DMSO-d ): δ = 47.9 (CH Ph), 53.5 (furan-C3), 70.9
H NMR (400 MHz, DMSO-d ): δ = 4.30–4.40 (m, 2 H, allyl-CH N),
6
2
6
2
(thiazolidine-C5), 107.9 (furan-C5), 116.5 (CN), 125.3, 125.9, 127.1,
4.90 (s, 2 H, CH Ph), 5.10–5.18 (m, 2 H, allyl-CH =), 5.72–5.80 (m, 1 H,
2
2
1
28.6, 129.5, 132.5, 135.2 (CH ), 137.2, 142.7, 143.7 (C ), 158.6
allyl-CH=), 7.00–7.22 (m, 4 H, H ), 7.78–7.90 (m, 5 H, H ), 7.92–8.05
Ar
Ar
Ar
Ar
(C=N), 165.7 (furan-C2), 193.0 (indeno-CO).
(m, 4 H, H ), 8.12 (br s, 4 H, 2 × NH ).
Ar
2
+
13
MS (EI): m/z (%) = 746 (22) [M] , 614 (19), 465 (12), 378 (11), 364 (22),
C NMR (100 MHz, DMSO-d ): δ = 46.2 (allyl-CH N), 47.4 (CH Ph),
6 2 2
1
49 (76), 91 (100), 66 (42).
53.4 (furan-C3), 70.8 (thiazolidine-C5), 108.2 (furan-C5), 116.2 (CN),
17.9 (allyl-CH =), 125.4, 125.5, 126.9, 127.0, 128.0, 131.9, 132.4
1
Anal. Calcd for C40H26N O S : C, 64.33; H, 3.51; N, 15.00; S, 8.59.
Found: C, 64.51; H, 3.40; N, 14.87; S, 8.76.
2
8
4 2
(
CH ), 136.3 (allyl-CH=), 137.1, 143.9, 144.1 (C ), 158.0, 158.1 (C=N),
Ar
Ar
1
65.9 (furan-C2), 193.0, 193.1 (indeno-CO).
+
MS (EI): m/z (%) = 696 (23) [M] , 506 (33), 478 (12), 456 (18), 149
(
10E,10′E)-10,10′-(Hydrazine-1,2-diylidene)bis[9-allyl-2-amino-4-
(100), 135 (28), 91 (57), 41 (36).
oxo-4H-3a,8b-(epithiomethanoimino)indeno[1,2-b]furan-3-car-
bonitrile] (8c)
Anal. Calcd for C36H24N O S : C, 62.06; H, 3.47; N, 16.08; S, 9.20.
8
4 2
Yield: 394 mg (61%); colorless crystals (MeCN); mp 268–270 °C.
Found: C, 62.21; H, 3.61; N, 15.91; S, 9.36.
IR (KBr): 3333 (NH ), 2194 (CN), 1725 (CO), 1628 (C=N), 1598 (Ar-
2
2
5
41
–1
N ,N -Diphenyl-1,3,4-thiadiazole-2,5-diamine (9a)
C=C), 1095 (C–O–C) cm
.
1
Yield: 51 mg (19%); colorless crystals.
H NMR (400 MHz, DMSO-d ): δ = 4.35–4.37 (m, 4 H, allyl-CH N),
6
2
5
.05–5.08 (m, 4 H, allyl-CH =), 5.81–5.83 (m, 2 H, allyl-CH=), 7.20–
2
2
5
42
7.32 (m, 2 H, H ), 7.63–7.71 (m, 6 H, H ), 8.08 (br s, 4 H, 2 × NH ).
N ,N -Dibenzyl-1,3,4-thiadiazole-2,5-diamine (9b)
Ar
Ar
2
13
Yield: 47 mg (16%); colorless crystals.
C NMR (100 MHz, DMSO-d ): δ = 46.6 (allyl-CH N), 53.2 (furan-C3),
6
2
7
1.2 (thiazolidine-C5), 107.8 (furan-C5), 116.2 (CN), 118.0 (allyl-
2
5
43
CH =), 125.7, 126.9, 128.3, 130.2 (CH ), 135.9 (allyl-CH=), 143.8,
N ,N -Diallyl-1,3,4-thiadiazole-2,5-diamine (9c)
2
Ar
1
44.1 (C ), 158.4 (C=N), 166.2 (furan-C2), 193.4 (indeno-CO).
Ar
Yield: 27 mg (14%); colorless crystals.
+
MS (EI): m/z (%) = 646 (22) [M] , 592 (52), 564 (32), 464 (26), 297
2
5
44
(100), 91 (83).
N -Benzyl-N -phenyl-1,3,4-thiadiazole-2,5-diamine (9d)
Anal. Calcd for C32H22N O S : C, 59.43; H, 3.43; N, 17.33; S, 9.92.
Yield: 42 mg (15%); colorless crystals.
8
4 2
Found: C, 59.29; H, 3.51; N, 17.21; S, 10.08.
2
5
45
N -Allyl-N -benzyl-1,3,4-thiadiazole-2,5-diamine (9e)
(
3
E)-2-Amino-10-{[(E)-2-amino-3-cyano-4-oxo-9-phenyl-4H-
a,8b-(epithiomethanoimino)indeno-[1,2-b]furan-10-ylidene]hy-
Yield: 34 mg (14%); colorless crystals.
drazone}-9-benzyl-4-oxo-4H-3a,8b-(epithiomethanoimino)inde-
no[1,2-b]furan-3-carbonitrile (8d)
Single Crystal X-ray Structure Determinations of 7 and 8b
Single crystal X-ray diffraction was carried out on an Agilent Super-
Nova diffractometer at 173 K (for 7) using an EOS CCD-detector and
MoKα radiation (λ = 0.71073 Å), and an Agilent SuperNova dual
source diffractometer at 120 K (for 8b) using an ATLAS CCD-detector
and CuKα radiation (λ = 1.54178 Å). Dual space methods (for 7,
Yield: 425 mg (58%); colorless crystals (MeCN); mp 230–232 °C.
IR (KBr): 3334 (NH ), 2194 (CN), 1726 (CO), 1651 (C=N), 1584 (Ar-
2
–1
C=C), 1075 (C–O–C) cm
.
1
H NMR (400 MHz, DMSO-d ): δ = 4.92 (s, 2 H, CH Ph), 7.05–7.10 (m,
6
2
46
46
SHELXD) and direct methods (for 8b, SHELXS-98) were used for
2
H, H ), 7.20–7.40 (m, 4 H, H ), 7.50–7.58 (m, 4 H, H ), 7.62–7.70
Ar Ar Ar
46
structure solution. Refinement was carried out using SHELXL-2013
(
m, 2 H, H ), 7.73–7.80 (m, 4 H, H ), 7.82–8.00 (m, 2 H, H ), 8.20 (br
Ar Ar Ar
2
(
full-matrix least-squares on F ). Hydrogen atoms were localized us-
s, 4 H, 2 × NH2).
ing a difference Fourier synthesis map and refined using a riding
model [H(N)-free]. Semi-empirical absorption corrections were ap-
13
C NMR (100 MHz, DMSO-d ): δ = 47.4 (CH Ph), 53.3 (furan-C3), 70.8
6
2
(thiazolidine-C5), 107.9 (furan-C5), 116.2 (CN), 124.5, 125.4, 125.5,
47
plied.
Compound 7: C24H12N O ·C H O, M = 482.44 g mol–1, brown blocks,
1
27.0, 128.1, 129.3, 129.4, 132.5, 132.6, 136.2 (CH ), 137.9, 139.7,
Ar
1
43.8, 144.1 (C ), 158.5, 159.5 (C=N), 165.9 (furan-C2), 192.9, 193.0
4
5
2
6
r
Ar
size
= 0.22 × 0.18 × 0.12 mm, monoclinic P2 /n (no. 14), a =
(
indeno-CO).
MS (EI): m/z (%) = 732 (11) [M] , 615 (9), 597 (26), 583 (11), 359 (32),
49 (27), 135 (36), 91 (86), 77 (100), 66 (54).
Anal. Calcd for C39H24N O S : C, 63.92; H, 3.30; N, 15.29; S, 8.75.
1
o
1
1.2100(4) Å, b = 14.2407(3) Å, c = 15.8004(6) Å, β = 109.173(4) , V =
+
3
–3
2382.44(14) Å , Z = 4, D
= 1.345 mg m , F(000) = 1000, μ = 0.098
calcd
1
–1
o
mm , Τ = 173 K, 10196 measured reflections (2θmax = 60.2 ), 5985 in-
dependent reflections [Rint = 0.021], 337 parameters, 21 restraints, R1
8
4 2
Found: C, 64.12; H, 3.22; N, 15.16; S, 8.91.
[
for 3967, I > 2σ(I)] = 0.076, wR2 (for all data) = 0.242, S = 1.04, largest
–3
–3
diff. peak and hole = 0.913 eÅ and –0.659 eÅ
.
(
4
E)-9-Allyl-2-amino-10-{[(E)-2-amino-9-benzyl-3-cyano-4-oxo-
H-3a,8b-(epithiomethanoimino)indeno[1,2-b]furan-10-
Compound 8b: C40H26N O S ·C H O, M = 804.88 g mol–1, colorless
8
4
2
3
6
r
plates, size
= 0.16 × 0.12 × 0.06 mm, orthorhombic Pca21, a =
ylidene]hydrazono}-4-oxo-4H-3a,8b-(epithiomethanoimino)in-
deno[1,2-b]furan-3-carbonitrile (8e)
3
30.5182(7) Å, b = 8.2651(2) Å , c = 30.6114(5) Å, V = 7721.3(3) Å , Z =
–3
–1
8, Dcalcd = 1.385 mg m , F(000) = 3344, μ = 1.73 mm , Τ = 120 K,
o
Yield: 432 mg (62%); colorless crystals (MeCN); mp 218–220 °C.
17226 measured reflections (2θmax = 153 ), 10507 independent re-
flections [Rint = 0.035], 1074 parameters, 9 restraints, R1 [for 9962, I >
2σ(I)] = 0.085, wR2 (for all data) = 0.207, S = 1.06, largest diff. peak and
IR (KBr): 3340 (NH ), 2197 (CN), 1725 (CO), 1650 (C=N), 1598 (Ar-
C=C), 1094 (C–O–C) cm
2
–1
.
–3
–3
hole = 2.42 eÅ and –0.47 eÅ . The structure was refined as racemic
twin [absolute structure parameter 0.40(3)]. Due to the poor quality
of the crystal and unresolved high electron density, only the constitu-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3036–3042

3
042
Synthesis
A. A. Hassan et al.
Paper
tion and conformation of the structure could be determined (these
data have not been included in the Supporting Information and have
not been deposited at the Cambridge Crystallographic Data Centre).
(23) Weinberg, O.; Knowles, P.; Ginsburg, D. Helv. Chim. Acta 1985,
68, 610.
(24) Yavari, I.; Malekafzali, A.; Skoulika, S. Tetrahedron Lett. 2014, 55,
3154.
(25) Rezvanian, A.; Alizadeh, A. Tetrahedron 2012, 68, 10164.
(26) Alizadeh, A.; Bayat, F.; Zhu, L. G. Aust. J. Chem. 2014, 67, 949.
(27) Alizadeh, A.; Bayat, F. Helv. Chim. Acta 2014, 97, 694.
Supporting Information
Supporting information for this article is available online at
(28) Hassan, A. A.; Nour El-Din, A. M.; Abdel-Latif, F. F.; Mostafa, S.
http://dx.doi.org/10.1055/s-34-1380447.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
M.; Bräse, S. J. Chem. Res. 2010, 493.
(29) Hassan, A. A.; Nour El-Din, A. M.; Abdel-Latif, F. F.; Mostafa, S.
M.; Bräse, S. Chem. Pap. 2012, 66, 295.
References
(30) Hassan, A. A.; Ibrahim, Y. R.; El-Sheref, E. M.; Abdel-Hamid, M.
A.; Bräse, S. J. Heterocycl. Chem. 2015, in press; DOI:
(1) Wiberg, K. B. Chem. Rev. 1989, 89, 975.
10.1002/jhet.2240.
(2) Hopf, H. Classics in Hydrocarbon Chemistry: Syntheses, Concepts,
Perspectives; Wiley-VCH: Weinheim, 2000.
(
(
31) Döpp, D.; Jüschke, S.; Henkel, G. Z. Naturforsch. B 2002, 57, 460.
32) Charistos, D. A.; Vagenas, G. V.; Tzavellas, L. C.; Tsoleridis, C. A.;
Rodios, N. A. J. Heterocycl. Chem. 1994, 31, 1593.
(3) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley & Sons: New York, 1994.
(
33) Gewald, K.; Schindler, R. J. Prakt. Chem. 1990, 332, 223.
(4) Miao, M. Z.; Cao, J.; Zhang, J. J.; Huang, X.; Wu, L. L. J. Org. Chem.
13
(34) Kalinowski, H.-O.; Berger, S.; Braun, S. C-NMR-Spektroskopie;
2013, 78, 2687.
Georg Thieme Verlag: Stuttgart, 1984.
(
(
(
(
(
5) Zhang, L. J.; Yan, C. G. Tetrahedron 2013, 69, 4915.
(35) Kepe, V.; Požgan, F.; Golobič, A.; Polanc, S.; Kočevar, M. J. Chem.
Soc., Perkin Trans. 1 1998, 2813.
6) Jansone-Popova, S.; May, J. A. J. Am. Chem. Soc. 2012, 134, 17877.
7) Rezvanian, A.; Alizadeh, A.; Zhu, L. G. Synlett 2012, 23, 2526.
8) Asahi, K.; Nishino, H. Tetrahedron 2008, 64, 1620.
(
36) Mizrakh, L. T.; Polanskaya, L. Yu.; Gvozdetskii, A. N.; Vosil’ev, A.
M.; Ivanova, T. M.; Lisina, N. I. S. Khim. Farm. Zh. 1987, 21, 322;
Chem. Abstr. 1988, 108, 21771r.
9) Almog, J.; Stepanov, N.; Dubnikova, F. Tetrahedron Lett. 2008, 49,
1870.
(
(
(
37) Silberg, A.; Simiti, I.; Cosma, N.; Proinov, I. Acad. Rep. Pop. Rom.
(
(
(
(
(
10) Osawa, E.; Yonemitsu, O. Carbocyclic Cage Compounds: Chemis-
try and Applications; VCH: Weinheim, 1992, 125.
11) Sugimoto, Y.; Babiker, H. A. A.; Saisho, T.; Furumoto, T.; Inanaga,
S.; Kato, M. J. Org. Chem. 2001, 66, 3299.
12) Yu, B.-W.; Chen, J.-Y.; Wang, Y.-P.; Cheng, K.-F.; Li, X.-Y.; Qin, G.-
W. Phytochemistry 2002, 61, 439.
13) Lagona, J.; Mukhopadhyay, P.; Chakrabarti, S.; Isaacs, L. Angew.
Chem. Int. Ed. 2005, 44, 4844.
14) Kim, K.; Selvapalam, N.; Ko, Y. H.; Park, K. M.; Kim, D.; Kim, J.
Chem. Soc. Rev. 2007, 36, 267.
Filiala Cluj, Studi Cercetavdri Chim. 1957, 8, 315; Chem. Abstr.
1961, 55, 17626e.
38) Bazavova, I. M.; Dubenko, R. G.; Shevchenko, L. I.; Pel’kis, P. S.
Ukr. Khim. Zh. (Russ. Ed.) 1980, 46, 286; Chem. Abstr. 1980, 93,
7
1237p.
39) Udo, E.; Johannes, D. DD 86815, 1972; Chem. Abstr. 1973, 78,
1063f.
1
(40) Chatterjee, S. J. Chem. Soc. B 1969, 725.
(41) Yella, R.; Khatun, N.; Rout, S. K.; Patel, B. K. Org. Biomol. Chem.
2011, 9, 3235.
(
(
15) Keshavarz, M. H. J. Hazard. Mater. 2007, 141, 536.
16) Shin, M.; Kim, M. H.; Ha, T. H.; Jeon, J.; Chung, K. H.; Kim, J. S.;
Kim, Y. G. Tetrahedron 2014, 70, 1617.
(
42) (a) Eggensperger, H.; Berscheid, R. SOFW J. 1994, 120, 286;
Chem. Abstr. 1996, 124, 55859w. (b) Eggensperger, H.;
Berscheid, R. SOFW J. 1994, 120, 289; Chem. Abstr. 1996, 124,
(17) Ortíz, A.; Carrasco, J.; Höpfl, H.; Santillan, R.; Farfán, N. Synth.
Commun. 1998, 28, 1293.
55859w.
(
(
(
43) Hassan, A. A.; Mourad, A. E.; El-Shaieb, K. M.; Abou-Zied, A. H.;
(
18) Yamamoto, N.; Fujii, H.; Nemoto, T.; Nakajima, R.; Momen, S.;
Izumimoto, N.; Hasebe, K.; Mochizuki, H.; Nagase, H. Bioorg.
Med. Chem. Lett. 2011, 21, 4104.
Döpp, D. Heteroat. Chem. 2003, 14, 535.
44) Shen, T.-Y.; Clark, R. L.; Pessolano, A. A. ZA7503527, 1976; Chem.
Abstr. 1977, 86, 72662r.
45) Hassan, A. A.; Mohamed, N. K.; Makhlouf, M. M.; Bräse, S.;
Nieger, M. Synthesis 2014, 46, 3097.
(19) Nagase, H.; Akiyama, J.; Nakajima, R.; Hirayama, S.; Nemoto, T.;
Gouda, H.; Hirono, S.; Fujii, H. Bioorg. Med. Chem. Lett. 2012, 22,
2775.
(
(
46) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
47) Crystallographic data (excluding structure factors) for the
structure reported in this work have been deposited at the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 1034843 (7). Copies of the data can be
obtained free of charge on application to the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033; e-
mail: deposit@ccdc.cam.ac.uk.
(
20) Fujii, H.; Nakajima, R.; Akiyama, J.; Yamamoto, N.; Hirayama, S.;
Nemoto, T.; Gouda, H.; Hirono, S.; Nagase, H. Bioorg. Med. Chem.
Lett. 2012, 22, 7697.
(
(
21) Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885.
22) Kotha, S.; Chinnam, A. K.; Tiwari, A. Beilstein J. Org. Chem. 2013,
9, 2709.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3036–3042