L-alanine benzylester as chiral inductor: Synthesis of enantiopure pyrazolo[1,5-a]-[1,4]benzodiazepine-4-ones via intramolecular nitrilimine cycloadditions

Article abstract of DOI:10.1081/SCC-100105392

The title compounds, of potential pharmacological interest, have been obtained in the enantiopure form through a stereo-selective intramolecular 1,3-dipolar cycloaddition of homochiral nitrilimines 5.

Full text of DOI:10.1081/SCC-100105392

This article was downloaded by: [University of Windsor]
On: 11 November 2014, At: 16:44
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
L-ALANINE BENZYLESTER AS CHIRAL INDUCTOR:
SYNTHESIS OF ENANTIOPURE PYRAZOLO[1,5-a]-
[1,4]BENZODIAZEPINE-4-ONES VIA INTRAMOLECULAR
NITRILIMINE CYCLOADDITIONS
Gianluigi Broggini a , Luisa Garanti b , Giorgio Molteni b & Tullio Pilati b
a Dipartimento di Scienze Chimiche, Fisiche e Matematiche , Università dell'Insubria , via
Lucini 3, Como, 22100, Italy
b Dipartimento di Chimica Organica e Industriale , Università di Milano , via Golgi 19,
Milano, 20133, Italy
Published online: 09 Nov 2006.
To cite this article: Gianluigi Broggini , Luisa Garanti , Giorgio Molteni & Tullio Pilati (2001) L-ALANINE BENZYLESTER AS
CHIRAL INDUCTOR: SYNTHESIS OF ENANTIOPURE PYRAZOLO[1,5-a]-[1,4]BENZODIAZEPINE-4-ONES VIA INTRAMOLECULAR
NITRILIMINE CYCLOADDITIONS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:17, 2649-2656, DOI: 10.1081/SCC-100105392
To link to this article: http://dx.doi.org/10.1081/SCC-100105392
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(17), 2649–2656 (2001)
L-ALANINE BENZYLESTER AS CHIRAL
INDUCTOR: SYNTHESIS OF
ENANTIOPURE PYRAZOLO[1,5-a]-
[1,4]BENZODIAZEPINE-4-ONES VIA
INTRAMOLECULAR NITRILIMINE
CYCLOADDITIONS
Gianluigi Broggini,2 Luisa Garanti,1,
*
Giorgio Molteni,1 and Tullio Pilati3
1Dipartimento di Chimica Organica e Industriale, Universita di
Milano, via Golgi 19, 20133 Milano, Italy
2Dipartimento di Scienze Chimiche, Fisiche e Matematiche,
Universita dell’Insubria, via Lucini 3, 22100 Como, Italy
3CNR-Centro per lo Studio delle Relazioni tra Struttura e
Reattivita Chimica c/o, Universita di Milano, via Golgi 19,
20133 Milano, Italy
ABSTRACT
The title compounds, of potential pharmacological interest,
have been obtained in the enantiopure form through a stereo-
selective intramolecular 1,3-dipolar cycloaddition of homo-
chiral nitrilimines 5.
*Corresponding author.
2649
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
2650
BROGGINI ET AL.
In the last years, we focussed our attention to stereoselective intra-
molecular cycloadditions of homochiral nitrilimines, which were proven to
be of wide applicability in the synthesis of optically active heterocyclic
systems.1–5 Among them, some derivatives containing the pyrazolo[1,5-a]-
[1,4]benzodiazepine skeleton4 were found endowed with biological activity
against breast cancer.6 Encouraged by these results, we synthesized some
new 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones by using
the inexpensive L-alanine benzyl ester as the starting chiral unity.
Our synthetic route, which is outlined in the Scheme, starts with the
reaction between L-alanine benzylester and 2-nitrobenzyl chloride in order
to obtain benzyl N-(2-nitrophenyl)methyl-L-alaninate 1. Subsequent steps
involve N-acylation of 1 with the appropriate alkenoyl chloride, reduction
Scheme.

ORDER
REPRINTS
L-ALANINE BENZYLESTER
2651
of the aromatic nitro group of 2, and diazotization of the so formed amino
group of 3 followed by coupling with methyl 2-chloroacetoacetate. Since
hydrazonoyl chlorides 4 were found rather unstable, we felt advisable to use
them as crude materials without full characterisation.7 The in situ generation
of nitrilimines 5 was accomplished by treating a solution of crude 4 with a two
fold molar excess of silver carbonate in dry dioxane at room temperature.
Products, isolation yields, reaction times and eluents are collected in the Table.
The extent of the one-pot like conversion 3 ! 6 þ 7 was fully satisfac-
tory, the ranging between 70 and 80%. It needs to be added that clean
separation of enantiopure cycloadducts 6 and 7 was achieved through
simple column chromatography. Structural assignment to the above
Table. Conversion of 3 into Cycloadducts 6 and 7
Products and Yields (%)a
Time
(h)
Product Ratio
Compd
6
7
6 : 7
Eluentb
3a
3b
3c
96
1270
120
56
43354 : 46
42
14
AcOEt-
28
80 : 20
Et2O-LP 3:1
n-hexane 1:1
Et2O-n-hexane 2:3
60 : 40
aIsolation yield of pure product. LP ¼ light petroleum, b.p. 40–60ꢀC.
b
Figure. ORTEP projection of 6a with the crystallographic numbering scheme.
Ellipsoids are at 50% probability level. H atoms not to scale.

ORDER
REPRINTS
2652
BROGGINI ET AL.
cycloadducts rely upon analytical and spectral data as well as upon the
X-ray diffractometric analysis of 6a, which proved the absolute (S) config-
uration to the pyrazolinic C-5 of major cycloadducts 6.
Intramolecular cycloadditions of nitrilimines 5 display a diastereo-
selectivity degree ranging from low to good, as can be inferred from the
ratio 6/7 (see Table). Furthermore, our synthetic approach was proven to be
very efficient and hence valuable on a multi-gram preparative scale of enan-
tiopure 3,3a-dihydropyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones.
EXPERIMENTAL
Melting points were determined with a Buchi apparatus and are not
corrected. IR spectra were recorded with a Perkin-Elmer 1725 X spectro-
photometer. Mass spectra were determined with a VG-70EQ apparatus.
1H-NMR spectra (300 MHz) were taken with a Bruker AC 300 or a
Bruker AMX 300 instrument (in CDCl3 solutions). Chemical shifts are
given as ppm from tetramethylsilane and J values are given in Hz. Optical
rotations, [a]2D5 were recorded on a Perkin-Elmer Model 241 polarimeter at
the sodium D line.
Preparationof benzyl N-(2-nitrophenyl)methyl-L-alaninate (1). A solu-
tion of L-alanine benzylester (5.00 g, 27.9 mmol) in dry toluene (55 ml) was
added with KI (0.46 g, 2.8 mmol). 2-Nitrobenzyl chloride (2.21 g, 13.0 mmol)
in dry toluene (5 ml) was slowly added and the mixture was warmed to 75ꢀC
for 7 h under vigorous stirring. Toluene (35 ml) was added, the white pre-
cipitate was filtered off, and the solvent was evaporated under reduced press-
ure affording 1 (2.94 g, 73% yield) as undistillable oil; [a]2D5 ¼ –18.4 (MeOH,
1
c ¼ 0.14); IR (neat): 3340, 1740 (cmꢁ1); H-NMR d: 1.38 (3H, d, J ¼ 7.1),
2.10 (1H, br s), 3.42 (1H, q, J ¼ 7.1), 3.95 (1H, d, J ¼ 14.6), 4.10 (1H, d,
J ¼ 14.6), 5.12 (2H, s), 7.20–7.95 (9H, m); MS: m/z 310 (Mþ).
General procedure for the preparation of benzyl N-(2-nitrophenyl)-
methyl-N-(1-oxo-2-alkenyl)-L-alaninate(2).Asolutionof1(5.20 g,16.6 mmol)
in dry toluene (120 ml) was added with K2CO3 (4.58 g, 33.2 mmol). The
appropriate alkenyol chloride (16.6 mmol) in dry toluene (6.0 ml)
was added dropwise at 90ꢀC. The mixture was refluxed for 5 h, then the
undissolved material was filtered off. The organic layer was washed with
water (50 ml) and dried (Na2SO4). The solvent was removed under reduced
pressure and the residue was chromatographed on a silica gel column
with hexane-ethyl acetate 1:1 affording 2a–c as undistillable oils not analy-
tically pure.
2a (4.46 g, 73%) as pale yellow oil; [a]2D5 ¼ –52.3(MeOH, c ¼ 0.24); IR
1
(neat): 1660 (cmꢁ1); H-NMR d: 1.48 (3H, d, J ¼ 7.2), 4.63(1H, q, J ¼ 7.2),

ORDER
REPRINTS
L-ALANINE BENZYLESTER
2653
4.90 (1H, d, J ¼ 19.5), 5.17 (2H, s), 5.18 (1H, d, J ¼ 19.5), 5.70 (1H, d,
J ¼ 10.4), 6.24 (1H, dd, J ¼ 16.5, 10.4), 6.47 (1H, d, J ¼ 16.5), 7.25–8.20
(9H, m); MS: m/z 368 (Mþ).
2b (4.76 g, 75%) as pale yellow oil; [a]2D5 ¼ –35.5 (MeOH, c ¼ 0.50); IR
1
(neat): 1660 (cmꢁ1); H-NMR d: 1.46 (3H, d, J ¼ 7.1), 1.82 (3H, d, J ¼ 6.7),
4.57 (1H, q, J ¼ 7.1), 4.86 (1H, d, J ¼ 19.5), 5.13(2H, s), 5.15 (1H, d,
J ¼ 15.0), 5.17 (1H, d, J ¼ 19.5), 5.91 (1H, d, J ¼ 15.0), 7.00–8.10 (9H, m);
MS: m/z 382 (Mþ).
2c (6.12 g, 83%) as yellow oil; [a]2D5 ¼ ꢁ42.3(MeOH, c ¼ 0.28); IR
(neat): 1650 (cmꢁ1); 1H-NMR d: 1.50 (3H, d, J ¼ 7.0), 4.60 (1H, q,
J ¼ 7.0), 4.95 (1H, d, J ¼ 18.0), 5.18 (2H, s), 5.22 (1H, d, J ¼ 16.2), 5.24
(1H, d, J ¼ 18.0), 6.50 (1H, d, J ¼ 16.2), 7.25–7.90 (14H, m); MS: m/z 444
(Mþ).
General procedure for the preparation of benzyl N-(2-aminophenyl)-
methyl-N-(1-oxo-2-alkenyl)-L-alaninate (3). A solution of 2 (10.0 mmol)
in EtOH (40 ml) was treated with iron dust (4.80 g, 83.0 mmol) and 20%
aqueous AcOH (1.7 ml), and then refluxed for 3h under vigorous stirring.
The mixture was taken up with AcOEt (50 ml) and filtered over celite.
The organic layer was washed firstly with 5% aqueous NaHCO3 (50 ml),
then with water (2 ꢂ 50 ml), and dried Na2SO4). Evaporation of the solvent
gave 3 as undistillable oils not analytically pure.
3a (2.73g, 81%) as yellow oil; [ a]2D5 ¼ –32.3 (MeOH, c ¼ 0.17); IR
1
(neat): 3430, 3360, 3240, 1645 (cmꢁ1); H-NMR d: 1.45 (3H, d, J ¼ 7.0),
3.58 (2H, br s), 4.25 (1H, q, J ¼ 7.0), 4.80 (1H, d, J ¼ 18.0), 5.20 (2H, s),
5.22 (1H, d, J ¼ 18.0), 5.60–6.40 (3H, m), 6.90–7.30 (9H, m); MS: m/z 338
(Mþ).
3b (2.60 g, 74%) as yellow oil; [a]2D5 ¼ ꢁ14.3(MeOH, c ¼ 0.15); IR
1
(neat): 3430, 3360, 3235, 1660 (cmꢁ1); H-NMR d: 1.37 (3H, d, J ¼ 7.2),
1.80 (3H, d, J ¼ 6.8), 3.80 (2H, br s), 4.25 (1H, q, J ¼ 7.2), 4.70 (1H, d,
J ¼ 18.5), 5.18 (2H, s), 5.20 (1H, d, J ¼ 18.5), 5.50–6.20 (2H, m), 6.80–7.45
(9H, m); MS: m/z 352 (Mþ).
3c (3.02 g, 73%) as yellow oil; [a]2D5 ¼ –10.8 (MeOH, c ¼ 0.12); IR
1
(neat): 3440, 3355, 3245, 1650 (cmꢁ1); H-NMR d: 1.48 (3H, d, J ¼ 7.0),
3.85 (2H, br s), 4.45 (1H, q, J ¼ 7.0), 4.68 (1H, d, J ¼ 17.8), 5.12 (2H, s),
5.18 (1H, d, J ¼ 17.8), 5.60–6.00 (2H, m), 6.90–97.40 (14H, m); MS: m/z 414
(Mþ).
General procedure for the conversion of 3 into 6,7. A solution of 3
(5.0 mmol) in 6M aqueous hydrochloric acid (3.0 ml) and MeOH (2.5 ml)
was cooled to 0ꢀC. Sodium nitrite (0.69 g, 10.0 mmol) was added portion-
wise keeping the temperature between 0 and 5ꢀC. After 15 min, the pH was
adjusted to 5 by adding sodium acetate, and a solution of methyl-2-chloro-
acetoacetate (0.75 g, 5.0 mmol) in MeOH (1.5 ml) was added under vigorous

ORDER
REPRINTS
2654
BROGGINI ET AL.
stirring and ice-cooling. The mixture was allowed to stand overnight under
stirring at room temperature. The solvent was partly removed under
reduced pressure and the resulting mixture was extracted with Et2O
(50 ml). The organic layer was washed firstly with 5% NaHCO3 (15 ml),
then with water (50 ml), and dried (Na2SO4). The solvent was removed
under reduced pressure to give an oily residue that was dissolved in dry
dioxane (225 ml). Silver carbonate (2.48 g, 9.0 mmol) was added and the
mixture was stirred in the dark at room temperature for the time indicated
in the Table. After evaporation of the solvent, the crude was chromato-
graphed on a silica gel column with the eluents indicated in the Table
affording the 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones
6 and 7. Major diastereoisomers 6 was eluted first, followed by minor dia-
stereoisomers 7.
6a (1.18 g, 56%) m.p. 140ꢀC (from hexane-CH2Cl2); [a]2D5 ¼ þ178.0
1
(MeOH, c ¼ 0.33); IR (nujol): 1730, 1645 (cmꢁ1); H-NMR d: 1.43(3H, d,
J ¼ 7.4), 3.27 (3H, dd, J ¼ 18.1, 13.5), 3.90 (3H, s), 4.02 (1H, d, J ¼ 17.2),
4.13(1H, dd, J ¼ 18.1, 8.3), 5.18 (1H, d, J ¼ 12.3), 5.23 (1H, d, J ¼ 12.3),
5.38 (1H, d, J ¼ 17.2), 5.47 (1H, q, J ¼ 7.4), 5.66 (1H, dd, J ¼ 13.5,
8.3), 6.90–7.60 (9H, m); MS: m/z 421 (Mþ) (30%). Anal. Calcd for
C23H23N3O5: C, 65.55; H, 5.50; N, 9.97. Found: C, 65.61; H, 5.53; N,
10.04.
7a (0.29 g, 14%) m.p. 89ꢀC (from diisopropyl ether); [a]2D5 ¼ ꢁ54.2
(MeOH, c ¼ 0.05); IR (nujol): 1730, 1660 (cmꢁ1); dH: 1.48 (3H, d, J ¼ 7.1),
3.26 (1H, dd, J ¼ 18.1. 13.5), 3.90 (3H, s), 3.97 (1H, d, J ¼ 16.8), 4.12 (1H,
dd, J ¼ 18.1, 8.5), 4.51 (1H, d, J ¼ 12.3), 4.98 (1H, d, J ¼ 12.3), 5.22 (1H, q,
J ¼ 7.1), 5.32 (1H, d, J ¼ 16.8), 5.67 (1H, dd, J ¼ 13.5, 8.5), 6.85–7.60 (9H,
m); MS: m/z 421 (Mþ) (29%). Anal. Calcd for C23H23N3O5: C, 65.55; H,
5.50; N, 9.97. Found: C, 65.50; H, 5.53; N, 9.91.
6b (0.94 g, 43%) m.p. 150ꢀC (from diisopropyl ether); [a]2D5 ¼ þ147.0
1
(MeOH, c ¼ 0.33); IR (nujol): 1740, 1670 (cmꢁ1); H-NMR d: 1.36 (3H, d,
J ¼ 7.4), 1.38 (3H, d, J ¼ 7.1), 3.86 (3H, s) 4.01 (1H, d, J ¼ 17.4), 4.37 (1H,
dq, J ¼ 7.1, 6.7), 5.17 (2H, s), 5.21 (1H, d, J ¼ 6.7), 5.32 (1H, d, J ¼ 17.4),
5.36 (1H, q, J ¼ 7.4), 6.80–7.60 (9H, m); MS: m/z 435 (Mþ) (36%). Anal.
Calcd for C24H25N3O5: C, 66.19; H, 5.79; N, 9.65. Found: C, 66.12; H, 5.74;
N, 9.58.
7b (0.80 g, 37%) m.p. 125ꢀC (from diisopropyl ether); [a]2D5 ¼ ꢁ214.5
1
(MeOH, c ¼ 0.33); IR (nujol): 1740, 1660 (cm–1); H-NMR d: 1.38 (3H, d,
J 7.2), 1.44 (3H, d, J ¼ 7.1), 3.87 (3H, s), 4.01 (1H, d, J ¼ 17.0), 4.38 (1H, dq,
J ¼ 7.1, 6.9), 4.47 (1H, d, J ¼ 12.3), 4.92 (1H, d, J ¼ 12.3), 5.15 (1H, d,
J ¼ 6.9), 5.18 (1H, d, J ¼ 71), 5.25 (1H, d, J ¼ 17.0), 6.80–7.60 (9H, m);
MS: m/z 435 (Mþ) (30%). Anal. Calcd for C24H25N3O5: C, 66.19; H,
5.79; N, 9.65. Found: C, 66.24; H, 5.84; N, 9.60.

ORDER
REPRINTS
L-ALANINE BENZYLESTER
2655
6c (1.04 g, 42%) m.p. 155ꢀC (from diisopropyl ether); [a]2D5 ¼ þ217.0
1
(MeOH, c ¼ 0.36); IR (nujol): 1740, 1670 (cmꢁ1); H-NMR d: 1.35 (3H, d,
J ¼ 7.3), 3.73 (3H, s), 3.97 (1H, d, J ¼ 17.5), 5.15 (2H, s), 5.21 (1H, d,
J ¼ 17.5), 5.38 (1H, q, J ¼ 7.3), 5.49 (1H, d, J ¼ 6.3), 5.54 (1H, d, J ¼ 6.3),
6.80–7.50 (14H, m); MS: m/z 497 (Mþ) (54%). Anal. Calcd for C29H27N3O5:
C, 73.77; H, 5.74; N, 9.57. Found: C, 73.83; H, 5.80; N, 9.66.
7c (0.70 g, 28%) m.p. 95ꢀC (from diisopropyl ether); [a]2D5 ¼ ꢁ445
1
(MeOH, c ¼ 0.15); IR (nujol): 1740, 1670 (cmꢁ1); H-NMR d: 1.42 (3H, d,
J ¼ 7.2), 3.93 (3H, s) 3.99 (1H, d, J ¼ 17.1), 4.46 (1H, d, J ¼ 12.3), 4.93 (1H,
d, J ¼ 12.3), 5.18 (1H, d, J ¼ 17.1), 5.21 (1H, q, J ¼ 7.2), 5.51 (2H, s),
6.90–7.80 (14H, m); MS: m/z 497 (Mþ) (54%). Anal. Calcd for C29H27
N3O5: C, 73.77; H, 5.74; N, 9.57. Found: C, 73.80; H, 5.68; N, 9.53.
X-ray structure determination of 6a. Crystal data were collected using
graphite monochromated Mo-Ka radiation ꢀ ¼ 0.71073A . The structures
was solved by SIR92,8 and refined on F2 by full-matrix least-squares
using SHELX97;9 heavy atoms were anisotropic, H atoms isotropic.
Absolute configurations was based on the reactants knowledge. Data of
6a. C23H23N3O5, Mr ¼ 421.44, triclinic, space group P1, a ¼ 7.3469(6),
b ¼ 8.6967(8), c ¼ 8.8671(9) A, a ¼ 95.540(7), b ¼ 107.008(7), g ¼ 98.187(7)ꢀ,
V ¼ 530.51(8) A3, T ¼ 291(1) K, Z ¼ 1, dcalc ¼ 1.319 g cmꢁ1, m(Mo-Ka) ¼
0.094 mmꢁ1; o/2y scans, 4 < 2y<60ꢀ; 6169 reflection collected, 3094
unique (Rav ¼ 0.0149) used for all calculations. Final R ¼ 0.0350 and
wR ¼ 0.0859, g.o.f. 0.926, –0.14<Ár;<0.23eA -3. Detailed crystallographic
data were deposited (as CCDC 147229) with the Cambridge crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
ACKNOWLEDGMENTS
We are grateful to CNR and MURST for financial support.
REFERENCES
1. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron:
Asymmetry 1999, 10, 487.
2. Broggini, G.; Garanti, L.; Molteni, G.; Pilati, T.; Ponti, A.; Zecchi, G.
Tetrahedron: Asymmetry 1999, 10, 2203.
3. Molteni, G.; Pilati, T. Tetrahedron: Asymmetry 1999, 10, 3873.
4. Broggini, G.; Casalone, G.; Garanti, L.; Molteni, G.; Pilati, T.;
Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 4447.

ORDER
REPRINTS
2656
BROGGINI ET AL.
5. Broggini, G.; Molteni, G.; Pilati, T. Tetrahedron: Asymmetry 2000,
11, 1975.
6. Personal communication from the National Institute of Health
(Bethesda, Maryland, USA) to the Senior Author.
7. The IR spectra of crude 4a–c exhibited the typical N–H strech band of
hydrazonoyl chlorides at 3240–3250 cm–1.
8. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.;
Burla, M.C.; Polidori, G.; Camalli, G. J. Appl. Crystallogr. 1994, 27,
435.
9. Sheldrick, G.M. SHELX97. Program for the Refinement of Crystal
Structures, 1997, University of Goettingen Germany.
Received in the UK August 2, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC100105392