An efficient synthesis of l-thia-5-azaspiro[5.5]undec-2-ene and its recyclization to l,5-diazaspiro[5.5]undec-2-ene and/or Spiro-Thieno[2,3-d/] pyrimidin-4(lH)-one derivatives

Article abstract of DOI:10.1515/znb-2011-0508

An efficient and direct synthesis of l-thia-5-azaspiro[5.5]undec-2-ene is described, and the base-catalyzed recyclization of this compound was studied. The products have been characterized by elemental analyses, and IR, MS, ^lHNMR,and ^l3

Full text of DOI:10.1515/znb-2011-0508

An Efficient Synthesis of 1-Thia-5-azaspiro[5.5]undec-2-ene
and its Recyclization to 1,5-Diazaspiro[5.5]undec-2-ene
and/or Spiro-Thieno[2,3-d]pyrimidin-4(1H)-one Derivatives
Raafat M. Shakera,b, Asmaa Hamodab, Yusria R. Ibrahimb, Kamal M. El-Shaiebb,
and Fathy F. Abdel-Latifb
a Current address: Chemistry Department, College of Science, Al-Jouf University, Sakaka,
Saudi Arabia
b Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
Reprint requests to Prof. Dr. Raafat M. Shaker. E-mail: rmshaker@yahoo.com
Z. Naturforsch. 2011, 66b, 487 – 492; received January, 16, 2011
An efficient and direct synthesis of 1-thia-5-azaspiro[5.5]undec-2-ene is described, and the base-
catalyzed recyclization of this compound was studied. The products have been characterized by ele-
mental analyses, and IR, MS, 1H NMR, and 13C NMR spectroscopy.
Key words: 4-Oxo-1-phenylcyclohexanecarbonitrile, 1-Thia-5-azaspiro[5.5]undec-2-ene,
Spiro-1,3-thiazine, Spiropyrimidine, Spiro-thieno[2,3-d]pyrimidine
Introduction
Recently, we reported an efficient and direct pro-
cedure for the synthesis of 2,2ꢀ-(1,4-phenylene)bis-
3,4-dihydro-2H-1,3-thiazin-4-ones 3 [12] and 1-thia-
5,9-diaza-spiro[5.5]undec-2-enes 5 [13] via the cy-
clocondensation of 3-arylamino-2-cyano-3-mercapto-
acrylamide (1) with terephthalaldehyde (2) and/or
4-oxo-piperidine derivatives 4 in the presence of
catalytic amounts of p-toluenesulfonic (p-TsOH)
acid in boiling ethanol (Scheme 1). Compounds 3
and 4 could have interesting effects on biological
targets.
Spiro-heterocyclic compounds are well known to
posses various pharmacological activities, and hence
their synthesis has always been a challenge and of at-
traction to organic chemists. These compounds may
display pronounced antimicrobial [1], analgesic [2],
antiinflammatory [2], antimycobacterial [3], antifun-
gal [4], antitumor [5, 6], and antiviral [5, 6] activities.
Furthermore, 1,3-thiazines are an important type of
heterocycles showing also a wide variety of related
properties [7 – 11].
Scheme 1. Synthesis of bis-1,3-thiazines 3 and
1-thia-5,9-diaza-spiro[5.5]undec-2-enes 5.
c
0932–0776 / 11 / 0500–0487 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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488
Prompted by the aforesaid biological and pharma-
R. M. Shaker et al. · 1-Thia-5-azaspiro[5.5]undec-2-ene
ceutical activities, and as a part of our continuing in-
terest in the synthesis of new polyfunctionally sub-
stituted heterocyclic [14 – 25] and spiro-heterocyclic
compounds [26 – 29] of expected biological activity,
we report here the versatile and hitherto unreported
synthesis of a spiro-fused 1,3-thiazine-4-one 7 and its
base-catalyzed recyclization to spiro-fused pyrimidin-
4-one and spiro-thieno[2,3-d]pyrimidin-4-one deriva-
tives with the purpose of investigating in the future
their possible biological activity.
Scheme 3. Formation of the S-methylated spiro-fused pyrim-
idine 8.
The reaction of 7 with dimethyl sulfate involved the
sulfur atom thus affording the S-methylated deriva-
tive 8 (Scheme 3). The structural assignment of com-
pound 8 was confirmed by its spectroscopic data.
A distinction between the thiazine and pyrimidine
structure types is clearly manifested in the 1H and
13C NMR spectra. The 1H NMR spectrum of 8 showed
the absence of an exocyclic NH proton, and in the
13C NMR spectrum the resonance of the aminal car-
bon atom (δ = 73.87 ppm) is shifted downfield from
that of the thioaminal carbon atom in compound 7.
The mass spectrum of 8 showed the molecular ion
peak at m/z = 414, corresponding to the molecular for-
mula C24H22N4OS. Compounds 8 was prepared in-
dependently by the reaction of 3-(phenylamino)acryl-
amide 9a with compound 6 in boiling ethanol and in
the presence of catalytic amounts of p-toluenesulfon-
ic acid. Both products had the same melting point, IR,
and 1H NMR data (Scheme 3).
Results and Discussion
Scheme 2 outlines the synthesis of 1-thia-5-
azaspiro[5.5]undec-2-ene 7 from the cyclocond-
ensation of 2-cyano-3-mercapto-3-phenylamino-acryl-
amide (1a) with 4-oxo-1-phenyl-cyclohexanecarbo-
nitrile (6) in the presence of catalytic amounts of p-
toluenesulfonic acid in boiling ethanol.
Scheme 2. Synthesis of the spiro-1,3-thiazine 7.
The reaction of the spirothiazine 7 with ethyl iodide
in DMF at r. t. and in the presence of anhydrous potas-
sium carbonate did not afford the expected S-ethylated
derivative 11, but rather the diethylated species 10
(Scheme 4). The elemental analysis and the spectral
data of compound 10 are in good agreement with the
proposed structure. The IR and 1H NMR spectra of 10
revealed the absence of NH groups and of signals at-
tributable to the endo- and exocyclic NH protons of 7,
respectively. Also, the mass spectrum of 10 showed the
molecular ion peak at m/z = 456, corresponding to the
molecular formula C27H28N4OS.
The structure of compound 7 was determined on the
basis of elemental analysis, spectral data and the chem-
ical transformations outlined below. Thus, compound 7
exhibits an IR spectrum with strong absorption bands
at 3174 (NH), 2208 (CN) and 1636 cm−1 (CO). Its
1H NMR spectrum shows characteristic singlets at
δ = 10.24 and 8.43 ppm for the exocyclic and endo-
cyclic NH proton, respectively, in addition to an eight-
proton multiplet in the region of δ = 2.01 – 2.43 ppm
of the cyclohexyl protons, and a multiplet at δ =
7.23– 7.57 ppm for the aromatic protons. The struc-
ture 7 was further confirmed by a 13C NMR spec-
trum which revealed resonances at δ = 63.38 and
The S-ethylated derivative 11 was prepared by the
163.86 ppm consistent with the quaternary sp3 carbon reaction of 2-cyano-3-(ethylthio)-3-(phenylamino)acr-
(spiro carbon) and the carbonyl group of the thiazine ylamide (9b) with compound 6 in boiling ethanol and
ring, respectively. Furthermore, the structure assigned in the presence of catalytic amounts of p-toluenesulf-
for compound 7 was fully supported by its mass spec- onic acid (Scheme 4). The structure of compound 11
trum, which showed a molecular formula C23H20N4OS was proven by elemental analysis and spectral data.
(m/z = 400 (6.5 %), [M]+).
The formula, C25H24N4OS, of 11 was confirmed by
Next, we moved on to study the alkylation of 7 the mass spectrum, which exhibited the molecular ion
using dimethyl sulfate, ethyl iodide, benzyl chloride, at m/z = 428. Furthermore, the IR and 1H NMR spec-
ethyl bromoacetate, and bromoacetonitrile as alkylat- tra of 11 revealed the presence of an NH group and
ing agents under basic conditions (Schemes 3 – 5). a characteristic singlet at δ = 8.51 ppm attributable to
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R. M. Shaker et al. · 1-Thia-5-azaspiro[5.5]undec-2-ene
489
Scheme 4. Synthesis of S-ethylated and di-
ethylated spiro pyrimidines 10, 11.
Scheme 5. Synthesis of the
thio- and thienopyrimidines
13, 15 and 18.
the endocyclic NH proton which was exchangable with substituted thiopyrimidine 15. Its structure was de-
1
D2O.
Also, benzylation of 7 with benzyl chloride (12)
duced by IR, H NMR, 13C NMR, and mass spectra
as well as by elemental analysis.
in ethanol and in the presence of triethylamine gave
the the S-benzylated compound 13 in high yield
(Scheme 5). The structure of 13 was deduced on the
On the other hand, the reaction of 7 with bro-
moacetonitrile (16) under the same conditions gave the
thienopyrimidine 18 (Scheme 5). The elemental anal-
ysis and the spectral data are in good agreement with
1
basis of analytical and spectral data. The H NMR
1
spectrum revealed signals at δ = 4.19 and 8.41 ppm
attributable to the SCH2 and NH protons, respectively.
Moreover, the mass spectrum of 13 exhibited a molec-
ular ion peak at m/z = 490, and other significant peaks
were as expected.
the proposed structure. The H NMR spectrum of 18
revealed the absence of signals attributable to the ex-
ocyclic NH protons of 7 and showed the presence of
signals attributable to NH2 protons. The structure of 18
is rationalized in terms of the initial formation of the
Similarly, the alkylation of 7 with ethyl bromoac- intermediate 17, which on subsequent intramolecular
etate (14) in aqueous KOH gave the spiro-fused S- cyclization affords the final product (Scheme 5).
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490
R. M. Shaker et al. · 1-Thia-5-azaspiro[5.5]undec-2-ene
Experimental Section
General procedures
m. p. 242 – 244 ◦C. – IR (film): ν = 3181, 3059, 2209, 1652,
1524 cm−1. – 1H NMR (300 MHz, CDCl3): δ = 2.03 –
2.12 (m, 4H, 2CH2), 2.37 – 2.48 (m, 4H, 2CH2), 2.52 (s,
3H, SCH3), 7.24 – 7.66 (m, 10H, ArH), 9.28 (s, 1H, NH). –
13C NMR (75 MHz, CDCl3): δ = 17.73 (SCH3), 32.11
Melting points were measured with a Gallenkamp appa-
ratus and are uncorrected. The reactions and the purity of
the products were monitored by thin layer chromatography (CH2), 32.19 (CH2), 43.53 (CH2), 44.36 (CH2), 44.61 (C-
(TLC) on aluminum plates coated with silica gel with flu-
orescence indicator (Merck, 60 F254) using CHCl3/CH3OH
CN), 73.87 (C-6), 76.85 (C-3), 115.8 (CN), 121.34 (CN),
125.52, 125.82, 125.84, 125.95, 128.06, 128.83, 129.43,
(10 : 1) as eluent. The infrared spectra were recorded on a 129.50, 138.52, 139.08 (C-Ar), 173.78 (C=O), 173.79 (C-
2). – MS (EI, 70 eV): m/z (%) = 414 (3.61) [M]+. – Anal.
Jasco FT/IR-450 Plus infrared spectrophotometer. The NMR
spectra were obtained on a JHA-LAA 400 WB-FT spec-
for C24H22N4OS (414.52): calcd. C 69.54, H 5.35, N 13.52,
trometer (300 MHz for 1H NMR, 75 MHz for 13C NMR), S 7.74; found C 69.48, H 5.41, N 13.45, S 7.67.
with deuterated chloroform (CDCl3) or dimethylsulfoxide
([D6]DMSO) as solvents. Chemical shifts are quoted in δ
and are referenced to TMS or the solvent signal. The mass
spectra were recorded on a Trace GC 2000/Finngan Mat
SSQ 7000 and a Shimadzu GCMS-QP-1000EX mass spec-
trometer at 70 eV. Elemental analyses were measured with
a Vario EL III CHNOS elemental analyzer, in the Microan-
alytical Center of Cairo University. Compounds 1a [28], 1b
[12], 9a [29], and 9b [12] were synthesized using the pub-
lished procedures.
Alternative synthesis of 8
A mixture of compound 6 (1.99 g, 0.01 mol), 9a (2.33 g,
0.01 mol), and p-toluenesulfonic acid (0.076 g, 0.01 mol)
in ethanol (20 mL) was refluxed. A yellow precipitate was
formed after 30 min, and stirring was continued for 2 h. The
precipitate was filtered off, washed with ethanol, dried and
recrystallized from the appropriate solvents.
3,9-Dicyano-5-ethyl-2-ethylthio-1,9-diphenyl-4-oxo-1,5-di-
azaspiro [5.5]undec-2-ene (10)
3,9-Dicyano-4-oxo-9-phenyl-2-(phenylamino)-1-thia-5-aza-
spiro[5.5]undec-2-ene (7)
Ethyl iodide (0.31 g, 20 mmol) was added to a mixture
of 7 (0.40 g, 10 mmol) and anhydrous potassium carbonate
(0.28 g, 20 mmol) in DMF (5 mL). The reaction mixture was
stirred for 18 – 20 h at r. t. and then poured into cold water.
After stirring for 15 min, the precipitated product was col-
lected by filtration, washed with water, dried and recrystal-
lized from ethanol. Yellow crystals, yield: 76 %, m. p. 190 –
192 ◦C. – IR (film): ν = 2940, 2200, 1638 cm−1. – 1H NMR
(300 MHz, [D6]DMSO): δ = 1.14 (t, 3H, CH3, J = 1.8 Hz),
1.30 (t, 3H, CH3, J = 1.8 Hz), 1.79 – 2.39 (m, 8H, 4CH2),
2.87 (q, 2H, SCH2, J = 7.2 Hz), 4.22 (q, 2H, NCH2, J =
7.2 Hz), 7.34 – 7.51 ( m, 10H, ArH). – MS (EI, 70 eV): m/z
(%) = 456 (8) [M]+. – Anal. for C27H28N4OS (456.60):
calcd. C 71.02, H 6.18, N 12.27, S 7.02; found C 70.92,
H 6.24, N 12.21, S 6.94.
A mixture of compound 1a (2.19 g, 0.01 mol), 4-oxo-
1-phenylcyclohexanecarbonitrile (6) (1.99 g, 0.01 mol) and
p-toluenesulfonic acid (0.038 g, 0.002 mol) in ethanol
(20 mL) was refluxed. A pale-yellow precipitate was formed
after 3 h, and the reaction was continued for 5 h. The precip-
itate was filtered off, washed with ethanol, dried and recrys-
tallized from DMF/EtOH. Pale-yellow powder, yield: 82 %,
m. p. 237 – 238 ◦C. – IR (film): ν = 3174, 3032, 2943, 2208,
1636, 1551 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
2.01 – 2.43 (m, 8H, 4CH2), 7.23 – 7.57 (m, 10H, ArH), 8.43
(s, 1H, NH, D2O-exchangeable), 10.24 (s, 1H, NH, D2O-
exchangeable). – 13C NMR (75 MHz, [D6]DMSO): δ =
31.27 (CH2), 32.55 (CH2), 34.42 (CH2), 36.27 (CH2), 42.51
(C-CN), 63.38 (C-6), 76.82 (C-3), 116.09 (CN), 121.85
(CN), 125.39, 126.73, 126.79, 128.17, 128.97, 129.11,
137.96, 139.55, 154.31 (C-Ar), 163.86 (C=O), 164.48 (C-
2). – MS (EI, 70 eV): m/z (%) = 400 (6) [M]+. – Anal.
for C23H20N4OS (400.50): calcd. C 68.98, H 5.03, N 13.99,
S 8.01; found C 68.86, H 5.19, N 13.87, S 7.91.
3,9-Dicyano-2-ethylthio-4-oxo-1,9-diphenyl-1,5-diazaspiro-
[5.5]undec-2-ene (11)
A mixture of compound 6 (1.99 g, 0.01 mol), 9b (2.47 g,
0.01 mol), and p-toluenesulfonic acid (0.076 g, 0.01 mol)
in ethanol (20 mL) was refluxed. A colorless precipi-
tate was formed after 30 min, and stirring was continued
for 2 h. The precipitate was filtered off, washed with ethanol,
3,9-Dicyano-2-methylthio-4-oxo-1,9-diphenyl-1,5-diaza-
spiro[5.5]undec-2-ene (8)
To a stirred 0.75 N aqueous KOH solution (20 mL), com- dried and recrystallized from DMF/EtOH. Colorless crys-
◦
pound 7 (0.40 g, 10 mmol) and dimethyl sulfate (0.25 g, tals yield: 74 %, m. p. 248 – 250 C. – IR (film): ν = 3161,
20 mmol) were added successively. The resulting precip- 3042, 2965, 2207, 1644, 1504 cm−1. – 1H NMR (300 MHz,
itate was filtered off, washed with water, dried and re- [D6]DMSO): δ = 1.11 (t, 3H, CH3, J = 7.2 Hz), 1.86 –
crystallized from ethanol. Colorless powder, yield: 77 %, 1.92 (m, 2H, CH2), 2.02 – 2.07 (m, 2H, CH2), 2.21 – 2.25
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491
(m, 4H, 2CH2), 2.91 (q, 2H, SCH2, J = 7.2 Hz), 7.36 – recrystallized from ethanol. Colorless powder, yield: 77 %,
7.55 (m, 10H, ArH), 8.51 (s, 1H, NH, D2O-exchangeable). – m. p. 251 – 252 ◦C. – IR (film): ν = 3202, 3059, 2212, 1671,
MS (EI, 70 eV): m/z (%) = 428 (36.46) [M]+. – Anal. for 1633, 1585 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
C25H24N4OS (428.55): calcd. C 70.07, H 5.64, N 13.07, 1.21 (t, 3H, CH3, J = 7.2 Hz), 1.88 – 2.23 (m, 8H, 4CH2),
S 7.48; found C 69.96, H 5.72, N 12.95, S 7.41.
3.36 (s, 2H, SCH2), 4.12 (q, 2H, OCH2, J = 7.2 Hz), 7.37 –
7.51 (m, 10H, ArH), 8.55 (s, 1H, NH). – 13C NMR (75 MHz,
[D6]DMSO): δ = 13.89 (CH3), 31.36 (CH2), 31.82 (CH2),
34.84 (2CH2), 42.67 (SCH2), 61.50 (C-CN), 73.73 (C-6),
86.87 (C-3), 116.30 (CN), 121.60 (CN), 125.52, 128.12,
128.90, 129.42, 129.57, 138.35, 139.45 (C-Ar), 160.66 (CO),
162.27 (CO), 167.42 (C-2) . – MS (EI, 70 eV): m/z (%) = 486
(20.33) [M]+. – Anal. for C27H26N4O3S (486.59): calcd.
C 66.65, H 5.39, N 11.51, S 6.59; found C 66.47, H 5.51,
N 11.42, S 6.53.
2-Benzylthio-3,9-dicyano-1,9-diphenyl-4-oxo-1,5-diaza-
spiro[5.5]undec-2-ene (13)
A mixture of compound 7 (4.00 g, 0.01 mol), benzyl
chloride (1.68 g, 0.011 mol), and triethylamine (2.1 mL,
0.015 mol) in ethanol (20 mL) was refluxed, and a color-
less precipitate was formed after half an hour. The reaction
was continued for 2 h, and the resulting precipitate was fil-
tered off, dried, and recrystallized from DMF / EtOH. Color-
less crystals yield: 79 %, m. p. 261 – 262 ◦C. – IR (film): ν =
3162, 3053, 2209, 1651, 1530 cm−1. – 1H NMR (300 MHz,
[D6]DMSO): δ = 1.72 – 1.81 (m, 2H, CH2), 1.97 – 2.24 (m,
6H, 3CH2), 4.19 (s, 2H, SCH2), 7.08 – 7.52 (m, 15H, ArH),
8.41 (s, 1H, NH, D2O-exchangeable). – MS (EI, 70 eV): m/z
(%) = 490 (5.6) [M]+. – Anal. for C30H26N4OS (490.62):
calcd. C 73.44, H 5.34, N 11.42, S 6.54; found C 73.36,
H 5.42, N 11.32, S 6.48.
5ꢀ-Amino-4,6ꢀ-dicyano-1ꢀ,4-diphenyl-4ꢀ-oxo-3ꢀ,4ꢀ-dihydro-
1ꢀH-spiro[cyclohexane-1,2ꢀ-thieno[2,3-d]pyrimidine] (18)
To a stirred 0.75 N aqueous KOH solution (20 mL),
compound 7 (0.40 g, 10 mmol) and bromoacetonitrile (16)
(0.24 g, 20 mmol) were added successively. The result-
ing precipitate was filtered off, washed with water, dried
and recrystallized from ethanol. Grey powder, yield: 80 %,
m. p. 330 – 332 ◦C. – IR (film): ν = 3429 – 3310, 3202, 2185,
1642, 1514 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
1.85 – 2.36 (m, 8H, 4CH2), 6.82 (s, 2H, NH2), 7.34 – 7.59 (m,
10H, ArH), 8.50 (s, 1H, NH). – MS (EI, 70 eV): m/z (%) =
439 (46) [M]+. – Anal. for C25H21N5OS (439.53): calcd.
C 68.32, H 4.82, N 15.93, S 7.30; found C 68.24, H 4.93,
N 15.84, S 7.18.
Ethyl 2-(3,9-dicyano-4-oxo-1,9-diphenyl-1,5-diazaspiro-
[5.5]undec-2-en-2-ylthio)acetate (15)
To a stirred 0.75 N aqueous KOH solution (20 mL), com-
pound 7 (0.40 g, 10 mmol) and ethyl bromoacetate (14)
(0.33 g, 20 mmol) were added successively. The resulting
precipitate was filtered off, washed with water, dried and
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