5-Aminouracil as a building block in heterocyclic synthesis: Part IV. One-pot synthesis of 1H-Pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives using controlled microwave heating

Article abstract of DOI:10.1515/znb-2011-0810

An efficient and direct procedure for the synthesis of pyrrolo[2,3-d] pyrimidine-2,4-dione derivatives using controlled microwave heating has been described. The products were characterized by elemental analyses, IR, 1H NMR, ¹³C NMR and MS spec

Full text of DOI:10.1515/znb-2011-0810

5-Aminouracil as a Building Block in Heterocyclic Synthesis: Part IV.
One-pot Synthesis of 1H-Pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
Derivatives Using Controlled Microwave Heating
Raafat M. Shakera,b, Kamal U. Sadekb, Ebtisam A. Hafezc, and Mohamed Abd Elradyb
a Current address: Chemistry Department, College of Science, Al-Jouf University, Sakaka,
Saudi Kingdom
b Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
c Chemistry Department, Faculty of Science, Cairo University, Giza-12613, Egypt
Reprint requests to Prof. Dr. Raafat M. Shaker. E-mail: rmshaker@yahoo.com
Z. Naturforsch. 2011, 66b, 843 – 849; received June 6, 2011
An efficient and direct procedure for the synthesis of pyrrolo[2,3-d]pyrimidine-2,4-dione deriva-
tives using controlled microwave heating has been described. The products were characterized by
elemental analyses, IR, 1H NMR, 13C NMR and MS spectra.
Key words: 5-Aminouracil, Dimedone, Barbituric Acid, Thiobarbituric Acid, Controlled
Microwave Heating, One-pot Synthesis, Pyrrolo[2,3-d]pyrimidine-2,4-dione
Introduction
Fused pyrimidinone derivatives have attracted the
attention of numerous researchers over many years due
to their important biological activities [1 – 3]. Among
them, pyrrolo[2,3-d]pyrimidines, a class of 7-deaza-
purine analog, exhibit interesting biological activity
in part due to their resemblance to pyrimidines and
purines. For example, they have recently been re-
ported as enzyme inhibitors [4], cytotoxic [5], anti-
inflammatory [6], anti-microbial [6], antibacterial [7],
antifungal [7], anticancer [8], antitumor [9], antifo-
late [10], antiviral [11], vascular endothelial growth
factor receptor-2 inhibitors [12], and antiangiogenic
agents [12]. They also possess anti-HCV, anti-HIV
type 1, anti-HSV, adenosine kinase inhibition, Aurora-
A kinase inhibition and cAMP phosphodiesterase inhi-
bition activity [13– 15].
Recently, we have reported a simple and efficient
synthesis of pyrimido[5,4-b]quinoline-2,4,9-triones 3
[16], 4 [17] and pyrido[3,2-d : 6,5-dꢀ]dipyrimidines 6
[18] via the reaction of 5-aminouracil (1), aldehy-
Scheme 1. Synthesis of pyrimido[5,4-b]quinolines 3, 4 and
pyrido[3,2-d : 6,5-dꢀ]dipyrimidines 6.
des and dimedone (2) or barbituric acid derivatives 5 ple methods for the synthesis of polyfunctionally sub-
under microwave irradiation without catalyst, which stituted heterocyclic compounds [16 – 28], we wish to
could have interesting effects on biological targets report a novel and efficient one-pot method for the
(Scheme 1).
synthesis of pyrrolo[2,3-d]pyrimidine-2,4-dione and
pyrimido[5,4-b]quinoline-2,4,9-trione derivatives with
expected interesting biological activity.
Considering the above reports and in continuation
of our interest in the development of new and sim-
c
0932–0776 / 11 / 0800–0843 $ 06.00 ꢀ 2011 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
Scheme 2. Synthesis of 1H-pyrro-
lo[2,3-d]pyrimidine-2,4(3H,7H)-
dione (10).
Scheme 3. Ethylation of 10.
Results and Discussion
synthesis of its ethylated derivative 12 via the reaction
of 10 with ethyl iodide in DMF and in the presence of
Thus, 5-aminouracil (1), dimedone (2) and phenyl-
glyoxal hydrate (7) in DMF gave under controlled mi-
crowave heating for 20 min at 160 C a solid product
anhydrous potassium carbonate (Scheme 3).
◦
A distinction between compounds 10 and 12 is
of molecular formula C20H19N3O4 (m/z = 365 (30 %) clearly manifested in the spectroscopic data. For ex-
[M]+) which may be formulated as the pyrrolo[2,3-d]- ample, the H NMR spectrum of compound 12 re-
1
pyrimidine-2,4-dione 10 or pyrimido[5,4-b]quinoline- vealed no NH protons, and the presence of four ethyl
2,4,9(1H,3H,5H)-trione 11 (Scheme 2).
groups indicated that the alkylation occurs at the N-1,
The product was assigned structure 10 on the basis N-3, N-7 and OH atoms. Furthermore, the structure
of spectral data and the chemical transformations out- assigned to 12 was fully supported by its mass spec-
lined below. Thus, its 1H NMR spectrum revealed the trum, which showed a molecular formula C28H35N3O4
presence of D2O-exchangeable protons at δ = 10.36, (m/z = 477 (35 %) [M]+). With these spectroscopic
10.53 and 11.95 ppm which are attributable to the data the proposed structure of 10 is identified. The for-
three NH protons, 1-NH, 3-NH and 7-NH, respec- mation of 10 was rationalized in terms of the initial
tively. Also, the structure assigned for compound 10 formation of the intermediate 8 [29]. A subsequent re-
was fully supported by its 13C NMR spectrium. Fur- action at the nucleophilic carbon atom C-6 in 5-amino-
ther confirmation of structure 10 was achieved via the uracil (1) leads to the formation of intermediate 9,
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
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Scheme 4. Synthesis of pyrimido[5,4-b]quinol-
ines 11 and 15.
which was cyclized via loss of water to finally form pound 15 contained signals from the N1CH2 (δ = 3.80)
pyrrolopyrimidine 10 (Scheme 2). The same product and N3CH2 protons (δ = 4.00 ppm). Furthermore, the
was obtained by refluxing 5-aminouracil (1), dimedone structure assigned to 15 was fully supported by its
(2) and phenylglyoxal hydrate (7) in DMF for 10 h.
mass spectrum, which indicated the molecular formula
In addition, the structure of 10 was confirmed C24H25N3O4 (m/z = 419 (35 %) [M]+). Further confir-
mation of structure 15 was obtained via the reaction of
ethylated enaminoketone 16 [17] with 7 in DMF under
controlled microwave heating (Scheme 4).
As an extension of our synthetic methodology, 5-
aminouracil (1), phenylglyoxal hydrate (7) and bar-
bituric acids 5a, b were also exposed to MW irradi-
ation. The reaction proceeded similarly to give 17ab
(Scheme 5). The proposed molecular structures
of 17a, b are supported by elemental and spectral anal-
yses. The fragmentation patterns of the mass spec-
further by an alternative synthesis of its isomer 11
(Scheme 4). The reaction of phenylglyoxal hydrate
(7) with enaminoketone 13◦ [16] in DMF under
microwave irradiation at 160 C for 20 min afforded
10-benzoyl-7,7-dimethyl-7,8-dihydropyrimido[5,4-b]-
quinoline-2,4,9(1H,3H,6H)-trione (11) (Scheme 4).
The structure of the product 11 was confirmed by
elemental analysis and spectral data. The disappear-
1
ance of signals for 10-H and 5-NH in the H NMR
spectrum indicated the formation of compound 11.
We also studied the alkylation of 11 with ethyl io- tra of 17a and 17b showed the molecular ion peaks
dide. The reaction was carried out at r. t. in DMF and in [M]+ at m/z = 369 (70 %) and 353 (25%), respec-
the presence of anhydrous potassium carbonate to af- tively, in good agreement with the assigned structure.
1
ford the ethylated derivative 15 (Scheme 4). The struc- The IR, H NMR as well as the 13C NMR spectra
ture of the product 15 was established by elemental agreed with the proposed structures 17a, b. For exam-
1
analysis and spectral data. Its IR spectrum revealed ple, the H NMR spectrum of 17a revealed five rela-
absorption bands around 1654– 1690 cm−1, charac- tively sharp singlets at δ = 10.55, 10.69, 12.11, 12.13
1
teristic of a carbonyl function. The H NMR spec- and 12.26 ppm assigned to the five NH groups, in
trum revealed that the alkylation occurs at the N-1 addition to the signals for the dimedone and phenyl
and N-3 atoms. Thus, the 1H NMR spectrum of com- protons. Moreover, the ethylated derivative 18 was
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846
R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
Scheme 5. Synthesis of 17 and 18.
obtained by reacting 17a with ethyl iodide in DMF GC 2000/Finnigan Mat SSQ 7000 and a Shimadzu GCMS-
QP-1000EX mass spectrometer at 70 eV. Elemental analy-
ses were measured with a Vario EL III CHNOS Elemental
Analyzer in the Microanalytical Center of Cairo University.
Compounds 13 [16] and 16 [17] were synthesized using the
published procedures.
and in the presence of anhydrous potassium carbon-
ate (Scheme 5). The structure of 18 was confirmed by
its elemental and spectral analyses, which showed the
molecular ion peak [M]+ at m/z = 509 (100%). Also,
the 1H NMR spectrum of 18 displayed signals of five
ethyl groups indicating that the alkylation occurred at
the N-1, N-3, N-7, OH and SH atoms. The imide hy-
drogen atoms in thiobarbituric acid take part in tau-
tomerism so that the alkylation of this compound leads
to a mixture of N- and S-alkyl derivatives [30, 31]
Preparation of 5-(2-hydroxy-4,4-dimethyl-6-oxocyclo-
hex-1-en-1-yl)-6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-
2,4(3H,7H)-dione (10)
Method A: A mixture of 5-aminouracil (1) (0.127 g,
1 mmol), dimedone (2) (0.140 g, 1 mmol) and phenylglyoxal
hydrate (7) (0.134 g, 1 mmol) in DMF (5 mL) was heated
under reflux in a Milestone Microwave Labstation at 160 ◦C
for 20 min. The solvent was evaporated under reduced pres-
Experimental Section
General procedures
Melting points were measured with a Gallenkamp appara- sure. The solid product was collected by filtration and recrys-
tus and are uncorrected. The reactions and purity were mon- tallized from ethanol; yield 76 %.
itored by thin layer chromatography (TLC) on aluminum
Method B: A solution of equimolar amounts of 1 (0.127 g,
plates coated with silica gel with fluorescence indicator 1 mmol), 2 (0.140 g, 1 mmol) and 7 (0.134 g, 1 mmol) in
(Merck, 60 F254) using CHCl3-CH3OH (10 : 5) as eluent. DMF (10 mL) was refluxed for 10 h. Product 10 was isolated
Microwave irradiation was carried out using the Milestone as described above; yield 70 %.
◦
Start Labstation for microwave-enhanced chemistry. Infrared
Pale-yellow powder, m. p. 335 – 337 C. – IR (film): ν =
spectra were recorded in potassium bromide disks on a Jasco 3186, 3059, 2953, 1692 cm−1. – 1H NMR (400 MHz,
FT/IR-450 Plus infrared spectrophotometer. 1H NMR and [D6]DMSO): δ = 1.03 (s, 3H, CH3), 1.07 (s, 3H, CH3),
13C NMR spectra were recorded on a Bruker DPX spectrom- 2.12 (brs, 2H, CH2), 2.47 (brs, 2H, CH2), 7.28 (t, 1H, J =
eter operating at 400 MHz for 1H NMR and 100 MHz for 6.8 Hz, Ar-H), 7.31 (t, 2H, J = 7.2 Hz, Ar-H), 7.50 (d, 2H, J =
13C NMR, with deuterated chloroform (CDCl3) or dimethyl- 7.2 Hz, Ar-H), 10.36 (s, 1H, NH, D2O-exchangeable), 10.53
sulfoxide ([D6]DMSO) as solvent. Chemical shifts are re- (s, 1H, NH, D2O-exchangeable), 11.95 (s, 1H, NH, D2O-
ported in δ (ppm) and with TMS or the solvent signal as exchangeable). – 13C NMR (100 MHz, [D6]DMSO): δ =
internal standard. Mass spectra were recorded on a Trace 26.45, 30.40, 31.22, 38.89, 40.28, 100.30, 105.93, 109.97,
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
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126.93, 127.59, 128.02, 131.98, 135.74, 137.80, 151.64, Preparation of 10-benzoyl-1,3-diethyl-7,7-dimethyl-7,8-di-
155.66, 162.05, 195.94. – MS (EI, 70 eV): m/z (%) = 366 hydropyrimido[5,4-b]quinoline-2,4,9 (1H,3H,6H)-trione
(23) [M+1]+, 365 (100) [M]+. – C20H19N3O4 (365.38): (15)
calcd. C 65.74, H 5.24, N 11.50; found C 65.49, H 5.17,
N 11.66
Method A: Ethyl iodide (0.624 g, 4 mmol) was added
to a mixture of 11 (0.363 g, 1 mmol) and anhydrous potas-
sium carbonate (0.276 g, 2 mmol) in DMF (10 mL). The re-
Preparation of 5-(2-ethoxy-4,4-dimethyl-6-oxocyclohex-1-
action mixture was stirred for 70 h at r. t. and then poured
enyl)-1,3,7-triethyl-6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-
into cold water and extracted with chloroform (3 × 20 mL).
2,4(3H,7H)-dione (12)
The combined organic extracts were washed with water and
dried (anhydrous magnesium sulfate). After evaporation of
some of the solvent (∼ 10 mL), petroleum ether (40 mL) was
added, and the resulting precipitate was collected, dried and
recrystallized from petroleum ether-chloroform to give 14;
yield 43 %.
Ethyl iodide (2.496 g, 16 mmol) was added to a mixture
of 10 (0.73 g, 2 mmol) and anhydrous potassium carbon-
ate (1.104 g, 8 mmol) in DMF (20 mL). The reaction mix-
ture was stirred for 80 h at r. t. and then poured into cold
water and extracted with carbon tetrachloride (3 × 20 mL).
The combined organic extracts were washed with water and
dried (anhydrous magnesium sulfate). After evaporation of
Method B: A mixture of 5-((5,5-dimethyl-3-oxocyclo-
hex-1-en-1-yl)amino)-1,3-diethyl pyrimidine-2,4(1H,3H)-
some of the solvent (∼ 5 mL), petroleum ether (30 mL) dione (16) (0.710 g, 1 mmol) and 7 (0.134 g, 1 mmol)
was added, and the resulting precipitate was collected, dried in DMF (5 mL) was heated under reflux in a Milestone
Microwave Labstation at 160 ◦C for 50 min. The sol-
and recrystallized from diphenylether-n-hexane to afford 12
(yield 50 %). Colorless solid, m. p. 220 – 222 ◦C. – IR (film): vent was evaporated under vacuum. Product 14 was
ν = 3064, 2968, 1683, 1642 cm−1. – 1H NMR (400 MHz, isolated by filtration and recrystallized as described above;
[D6]DMSO): δ = 0.92 (s, 6H, 2CH3), 1.11 – 1.14 (m, 12H,
4CH3), 1.95 (d, 1H, J = 15.6 Hz, CH2), 2.25 (d, 1H,
J = 15.6 Hz, CH2), 2.32 (d, 1H, J = 18 Hz, CH2), 2.58
(d, 1H, J = 18 Hz, CH2), 3.87 (q, 2H, J = 8 Hz, CH2),
3.96 (q, 2H, J = 11 Hz, CH2), 4.06 (q, 2H, J = 7 Hz,
CH2), 4.17 (q, 2H, J = 7 Hz, CH2), 7.17 – 7.41 (m, 5H,
ArH). – 13C NMR (100 MHz, [D6]DMSO): δ = 13.23,
13.30, 15.29, 16.70, 25.81, 25.98, 27.17, 31.16, 31.31, 35.22,
38.66, 49.93, 63.73, 99.97, 100.61, 107.56, 109.23, 110.18,
120.64, 128.03, 128.68, 129.59, 130.03, 133.03, 141.96,
150.15, 154.21, 174.05, 196.99. – MS (EI, 70 eV): m/z (%) =
478 (40) [M+1]+, 477 (35) [M]+. – C28H35N3O4 (477.60):
calcd. C 70.42, H 7.39, N 8.80; found C 70.59, H 7.37,
N 8.66.
yield 5 %.
Brown powder, m. p. 183 – 185 ◦C. – IR (film): ν = 3060,
2954, 2877, 1690, 1654 cm−1. – 1H NMR (400 MHz,
CDCl3): δ = 1.05 (s, 6H, 2 CH3), 1.20 (t, 3H, J = 6 Hz,
CH3), 1.27 (t, 3H, J = 6 Hz, CH3), 2.53 (s, 2H, CH2),
3.35 (s, 2H, CH2), 3.80 (q, 2H, J = 9 Hz, CH2), 4.00 (q,
2H, J = 6 Hz, CH2), 7.25 – 7.33 (m, 3H, Ar-H), 7.50 (d,
2H, Ar-H, J = 7.2 Hz). – MS (EI, 70 eV): m/z (%) = 419
(35) [M]+. – C24H25N3O4(419.47): calcd. C 68.72, H 6.01,
N 10.02; found C 68.90, H 5.96, N 10.11.
Preparation of 6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-
2,4(3H,7H)-diones (17a, b)
A solution of equimolar amounts of 1 (0.127 g, 1 mmol),
7 (0.134 g, 1 mmol) and thiobarbituric acid 5a (0.144 g,
1 mmol) and/or barbituric acid 5b (0.128 g, 1 mmol) in
DMF (5 mL) was heated under reflux in a Milestone Mi-
Preparation of 10-benzoyl-7,7-dimethyl-7,8-dihydropyr-
imido[5,4-b]quinoline-2,4,9(1H,3H,6H)trione (11)
◦
A mixture of 5-((5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-
amino)pyrimidine-2,4(1H,3H)-dione (13) (0.249 g, 1 mmol)
and 7 (0.134 g, 1 mmol) in DMF (5 mL) was heated un-
crowave Labstation at 160 C for 20 min. The solvent was
evaporated under reduced pressure. The solid product was
collected by filtration and crystallized from the appropriate
solvent.
◦
der reflux in a Microwave Labstation at 160 C for 30 min.
The solvent was evaporated under vacuum. The solid prod-
uct was collected by filtration and crystallized from benzene,
yield 60 %. Pale-brown powder, m. p. 282 – 285 ◦C. – IR
(film): ν = 3157, 3028, 2931, 1675, 1632 cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.02 (s, 6H, 2CH3), 2.49 (s,
2H, CH2), 3.22 (s, 2H, CH2), 7.40 – 7.55 (m, 5H, Ar-H),
5-(6-Hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)-6-phenyl-1H-pyrrolo[2,3d]pyrimidine-2,4(3H,7H)-
dione (17a)
Pale-brown crystals, yield 80 % (EtOH); m. p. > 360 ◦C. –
10.32 (s, 1H, NH, D2O-exchangeable), 10.48 (s, 1H, NH, IR (film): ν = 3147, 3018, 2954, 1667 cm−1. – 1H NMR
D2O-exchangeable). – MS (EI, 70 eV): m/z (%) = 364 (40) (400 MHz, [D6]DMSO): δ = 7.27 (t, 1H, Ar-H, J = 6.2 Hz),
[M+1]+, 363 (60) [M]+. – C20H17N3O4 (363.37): calcd. 7.40 (t, 2H, Ar-H, J = 6.9 Hz), 7.49 (d, 2H, Ar-H, J = 7.2 Hz),
C 66.11, H 4.72, N 11.56; found C 65.89, H 4.75, N 11.61.
10.55 (s, 1H, NH, D2O-exchangeable), 10.69 (s, 1H, NH,
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R. M. Shaker et al. · 5-Aminouracil as a Building Block in Heterocyclic Synthesis
D2O-exchangeable), 12.11 (s, 1H, NH, D2O-exchangeable), Synthesis of 5-(4-ethoxy-2-(ethylthio)-6-oxo-1,6-dihydro-
12.13 (s, 1H, NH, D2O-exchangeable), 12.26 (s, 1H, HN, pyrimidin-5-yl)-1,3,7-triethyl-6-phenyl-1H-pyrrolo[2,3-d]-
D2O-exchangeable). – 13C NMR (100 MHz, [D6]DMSO): pyrimidine-2,4(3H,7H)-dione (18)
δ = 86.57, 97.98, 109.25, 109.98, 126.75, 127.72, 128.25,
Ethyl iodide (3.79 g, 24 mmol) was added to a mixture
131.69, 136.54, 138.70, 151.58, 155.71, 161.33, 173.59,
of 17 (0.739 g, 2 mmol) and anhydrous potassium carbonate
200.11. – MS (EI, 70 eV): m/z (%) = 369.11 (70) [M]+,
(1.65 g, 12 mmol) in DMSO (10 mL). The reaction mixture
370.12 (25.6), 371.22 (20). – C16H11N5O4S (369.35): calcd.
was stirred for 86 h at r. t. and then poured into cold water, the
C 52.03, H 3.00, N 18.96; found C 52.19, H 2.96, N 18.91.
precipitate was collected by filtration and recrystallized from
diethyl ether-petroleum ether to give 18 (yield 40 %). Col-
orless solid, m. p. 230 – 233 ◦C. – IR (film): ν = 3205, 3064,
5-(6-Hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-
6-phenyl-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
2968, 1703, 1682 cm−1. – 1H NMR (400 MHz, [D6]DMSO):
δ = 1.01 (t, 3H, J = 9 Hz, CH3), 1.15 (t, 3H, J = 7 Hz,
CH3), 1.25 (t, 3H, J = 7 Hz, CH3), 1.31 (t, 3H, J = 7 Hz,
CH3), 1.36 (t, 3H, J = 11 Hz, CH3), 3.16 (q, 2H, J = 8 Hz,
CH2), 3.76 (q, 2H, J = 8 Hz, CH2), 3.94 (q, 2H, J = 10 Hz,
CH2), 4.14 (q, 2H, J = 7 Hz, CH2), 4.21 (q, 4H, J = 7 Hz,
CH2), 7.21 – 7.50 (m, 5H, ArH), 12.11 (s, 1H, NH). – MS
(EI, 70 eV): m/z (%) = 508.25 (6.87), 509.20 (100) [M]+,
510.20 (33), 511.15 (11). – C26H31N5O4S (509.62): calcd.
C 61.28, H 6.13, N 13.74; found C 61.21, H 6.22, N 13.79.
(17b)
Colorless powder, yield 76 % (DMF); m. p. > 350 ◦C. – IR
(film): ν = 3173, 3030, 2822, 1702, 1670 cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 7.21 (t, 1H, Ar-H, J = 7.0),
7.30 (t, 2H, Ar-H, J = 8), 7.68 (d, 2H, Ar-H, J = 7), 9.53
(s, 2H, NH, D2O-exchangeable), 10.08 (s, 1H, NH, D2O-
exchangeable), 10.44 (s, 1H, NH, D2O-exchangeable), 11.71
(s, 1H, NH, D2O-exchangeable). – 13C NMR (100 MHz,
[D6]DMSO): δ = 100.01, 109.72, 126.77, 127.35, 128.04,
132.16, 138.53, 151.15, 151.57, 155.74, 163.09. – MS (EI,
70 eV): m/z (%) = 355.2 (10) [M+2]+, 353.2 (25) [M]+. –
C16H11N5O5 (353.29): calcd. C 54.39, H 3.14, N 19.82;
found C 54.22, H 3.28, N 19.90.
Acknowledgement
The authors are grateful to the Alexander von Humboldt
foundation for a donation of a Milestone Microwave Labsta-
tion which was of great help in completing this work.
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