1,3,5-Trisubstituted 1,4-diazepin-2-ones

Article abstract of DOI:10.1021/jo701467d

(Chemical Equation Presented) Six 1,3,5-trisubstituted 1,4-diazepin-2-ones were synthesized by a sequence featuring the cascade addition of vinyl Grignard to N-[Boc-aminoacyl]-N-alkyl-β-amino esters, followed by Boc group removal and annulation by a reduc

Full text of DOI:10.1021/jo701467d

1,3,5-Trisubstituted 1,4-Diazepin-2-ones
Hassan S. Iden and William D. Lubell*
De´partement de Chimie, UniVersite´ de Montre´al, C.P. 6128,
Succursale Centre Ville, Montre´al, Que´bec, Canada H3C 3J7
FIGURE 1. Structural relationship of γ-turns and 1,4-diazepin-2-ones.
lubell@chimie.umontreal.ca
methodology for the synthesis of 1,4-diazepin-2-ones is thus
well merited with potential for creating new biologically active
peptide mimics.
ReceiVed July 16, 2007
The diazepinone ring has been typically formed from linear
precursors by intramolecular reductive amination,12 lactam
formation,13,14 and transamidation reactions.15 For example, a
library of 1,4-diazepinones was generated by a solid-phase
reductive-amination approach.16 A sequence employing Ugi
multicomponent and Mitsunobu annulation reactions has also
delivered libraries of 1,4-diazepin-1- and -5-ones.17 We have
reported the synthesis of enantiopure 3,5-disubstituted 1,4-
diazepin-2-ones from inexpensive amino acids5 by a process
involving cascade addition of vinyl magnesium bromide to an
R-aminoacyl â-amino ester to provide a γ,δ-unsaturated ketone
intermediate.18 Nitrogen deprotection and intramolecular reduc-
tive amination provided the 1,4-diazepinone.5 In light of the
relationship of 1,4-diazepin-2-ones and γ-turn conformations,
the display of substituents on the 1-, 3-, and 5-positions of the
heterocycle could respectively mimic the pharmacophores at
the i, i + 1, and i + 2 residues in the γ-turn (Figure 1).
Methodology for introducing substituents at the 3- and 5-posi-
tions was achieved by the employment of different R-amino
acid starting materials and by the modification of the olefin of
the γ,δ-unsaturated ketone, respectively.5 Employing R-ami-
noacyl â-amino esters possessing N-alkyl substituents, we have
now elaborated our synthesis methodology to introduce func-
tionality at the N1-position of the 1,4-diazepin-2-one. Moreover,
the presence of the N-alkyl substituent was noted to accelerate
ring closure in the reductive amination step and improve the
yield of diazepinone.
Six 1,3,5-trisubstituted 1,4-diazepin-2-ones were synthesized
by a sequence featuring the cascade addition of vinyl
Grignard to N-[Boc-aminoacyl]-N-alkyl-â-amino esters, fol-
lowed by Boc group removal and annulation by a reductive
amination. Relative to the parent sequence employing N-Boc-
aminoacyl â-amino esters to make 3,5-disubstituted hetero-
cycle, the additional N-alkyl substituent caused a noticeable
acceleration and gave relatively higher yield in the 1,4-
diazepin-2-one annulation.
Mimicry of peptide conformations by privileged organic
structures has proven effective for identifying candidates for
drug development.1 For example, 1,4-diazepin-2-ones have been
suggested to function as privileged structures in medicinal
chemistry,2 because the seven-member diazepinone ring may
mimic â- and γ-turn secondary structures.3,4 In X-ray structural
analyses of 1,4-diazepinones,5 the dihedral angle geometry of
the R-amino acid moiety mimicked that of an ideal reverse
γ-turn (Figure 1).6 γ-Turn conformations have been suggested
to be populated by many biologically active peptides.7,8
Furthermore, biologically active 1,4-diazepinones include an-
tagonists of the lymphocyte function-associated antigen-1/
immunoglobulin superfamily ICAM-1 interaction,9 the liposi-
domycin family of antibiotic inhibitors of bacterial peptidoglycan
synthesis,10 as well as anticonvulsants.11 The development of
R-Aminoacyl â-amino esters possessing N-alkyl substituents
were prepared from the coupling of N-Boc-R-amino acids to
N-alkyl â-amino esters. Methyl N-alkyl â-aminopropionate
derivatives 2a-d were made by reductive amination of the imine
generated from methyl â-alaninate 1 and the respective aldehyde
with sodium triacetoxy borohydride and 1% acetic acid in
DMF.19 N-Alkyl â-amino esters 2a-d were then isolated by
(1) (a) Evans, B. E.; et al. J. Med. Chem. 1988, 31, 2235-2246. (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-
930. (c) Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35,
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G.; Aube´, J. Org. Lett. 2005, 7, 1059-1062.
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Hommel, U.; Welzenbach; Weitz-Schmidt, G. Biorg. Med. Chem. Lett. 2003,
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J. Org. Chem. 2007, 72, 2151-2160.
(18) Hansford, K. A.; Dettwiler, J. E.; Lubell, W. D. Org. Lett. 2003, 5,
4887-4890.
10.1021/jo701467d CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/10/2007
8980
J. Org. Chem. 2007, 72, 8980-8983

TABLE 1. Isolated Product Yields
SCHEME 1. 1,3,5-Trisubstituted Diazepin-2-one Synthesis
% yields
a
b
c
d
amide
3
4
77
55
82
63
90
77
ketone
5
6
66
62
50 (78)a
70
60
65
35
66
diazepine
7
8
68
71
85
78
a Yield in parentheses accounts for recovered starting material.
removal with a 1:1 TFA:DCM solution, free-basing neutraliza-
tion of the amine TFA salt with Amberlyste A-21 ion-exchange
resin,26 and reductive amination of the imine intermediate with
sodium cyanoborohydride in THF (Scheme 1).
Only one diastereoisomer was observed by LCMS analysis
of diazepinones 7a,b,d and 8a,b; diazepinone 7b was observed
to consist of a 30:1 mixture of diastereoisomers measured by
HPLC. The cis relative configuration of the newly formed chiral
center in diazepinones 7a-d and 8a,b was initially assigned
based on our previous study,5 and confirmed by a NOESY
experiment on 7b, which indicated strong NOE between the
C3 and C5 protons.
chromatography on silica gel in 70-93% yields (Scheme 1).
Some requisite aldehydes were obtained from commercial
sources. Benzylthioacetaldehyde was prepared by oxidation of
2-benzylthioethanol.20 Benzyl and phenylthioacetaldehydes were
prepared by alkylation of the respective thiol with 3-bromo-
1,1-dimethoxyethane, followed by acetal hydrolysis with 2 N
HCl at 80 °C for 24 h.21 2,4-Dimethoxy- and 4-benzyloxybenzyl
amino esters 2a and 2b exhibited identical spectra as previously
described.22,23
Dipeptides 3a-d and 4a,b were respectively prepared by
coupling either Boc-Phe or R-Boc-(ꢀ-Cbz)-Lys to secondary
amino esters 2 with HATU in DMF,24 and isolated by silica
gel chromatography in 55-90% yield. Lysine was employed
because of the importance of constrained ꢀ-amino alkyl amino
acids,25 and to examine the influence of a remote carbamate
group on the synthesis method. Homoallylic ketones 5a-d and
6a,b were synthesized in 35-60% yields by respectively treating
R-aminoacyl â-amino esters 3a-d and 4a,b with an excess of
freshly prepared vinyl magnesium bromide in the presence of
a catalytic amount of CuCN in THF at -45 °C followed by
warming to rt.18 Amides 3-6 were typically observed to exist
as conformational isomers causing a doubling of NMR signals
for the cis and trans isomers. Spectral data for the minor amide
isomer are recorded with an asterisk in the Experimental Section.
Diazepinones 7a-d and 8a,b were respectively synthesized
from γ,δ-unsaturated ketones 5a-d and 6a,b by Boc group
In our previous synthesis of 3,5-disubstituted 1,4-diazepin-
2-ones from R-aminoacyl â-amino esters, the final amine
deprotection/free-basing neutralization/reductive amination se-
quence gave at best 50% overall yield.5 Improved overall yield
was obtained from performing this sequence on tertiary amides
5 and 6 to form 1,3,5-trisubstituted 1,4-diazepin-2-ones 7 and
8. For example, a 45% augmentation in overall yield was
obtained from performing the Boc removal/reductive amination
sequence on N-(4-benzyloxylbenzyl) amide 5b instead of the
corresponding secondary amide. The increase in yield was
accompanied by a noticeable acceleration in the reductive-
amination step, which had usually occurred in 3 to 7 days in
the absence of the N-alkyl substituent.5 In the presence of
N-alkyl substituent, the reductive amination was typically
complete after 24 h. The steric effects of N-alkylation likely
destabilized the trans and augmented the population of the cis
amide isomer, which was necessary for ring formation.27,28
Tertiary amides exhibited multiple signals indicative of cis and
trans isomers under slow isomerization on the NMR time scale.
In addition, the trisubstituted diazepinones 7 and 8 were less
polar than their disubstituted counterparts and easier to purify
by silica gel chromatography, which may also account for the
better yields in the annulation sequence.
The removal of the 1-position substituent was explored by
using trisubstituted diazepinone 7 as an alternative strategy for
making 3,5-disubstituted diazepinone 10 (Scheme 2). The
presence of olefin and secondary amine groups in diazepinones
7c and 7d prevented attempts to remove the mercaptoethyl
moieties by oxidation of the sulfur to the sulfone,29-31 followed
(19) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. J.
Org. Chem. 1997, 62, 1240-1256.
(20) Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad, M. M.; Von
Langen, D.; Cushman, D. W. J. Med. Chem. 1988, 31, 2199-2211.
(21) Bitan, D.; Muller, D.; Kasher, R.; Gluhov, E. V.; Gilon, C. J. Chem.
Soc., Perkin Trans. 1 1997, 10, 1501-1509.
(22) Muhuhi, J.; Spaller, M. J. Org. Chem. 2006, 71, 5515-5526.
(23) Tattersall, P. I.; Breslin, D.; Grayson, S. M.; Heath, W. H.; Lou,
K.; McAdams, C. L.; McKean, D.; Rathsack, B. M.; Willson C. G. Chem.
Mater. 2004, 16, 1770 - 1774.
(26) Natarajan, S.; Yurek-George, A.; Ganesan, A. Mol. DiVersity 2005,
9, 291-293.
(27) Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995,
60, 4175-4720.
(28) Kaul, R.; Surprenant, S.; Lubell, W. D. J. Org. Chem. 2005, 70,
3838-3844.
(24) Fader, L. D.; Boyd, M.; Tsantrizos, Y. S. J. Org. Chem. 2001, 66,
3372-3379.
(25) Feng, Z.; Lubell, W. D. J. Org. Chem. 2001, 66, 1181-1185 and
references cited therein.
(29) Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura,
S. J. Org. Chem. 2004, 69, 7949-7959.
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1290.
J. Org. Chem, Vol. 72, No. 23, 2007 8981

SCHEME 2. 4-Benzyloxybenzylamide Cleavage under
Acidic Conditions
evaporated to a residue, which was purified on silica gel by using
the specified solvent as eluant to afford respectively tertiary amide
3a-d, 4a, or 4b.
(2S)-Methyl N-(2,4-dimethoxybenzyl)-N-[(Boc)phenylalani-
nyl]-â-alaninate (3a). A colorless oil was prepared from amine
2a (2 mmol, 0.506 g) according to the general protocol 2 and
isolated in 77% yield after purification on silica gel eluting with
1
40% EtOAc in hexane (Rf 0.4, 40% EtOAc in hexane). H NMR
(1.6:1 isomer ratio, 400 MHz, CD3OD) δ 1.39 (s, 9H), 1.4* (s,
9H), 2.4* (m, 2H), 2.45 (m, 2H), 2.90-2.93 (m, 2H), 2.95-2.95*
(m, 2H), 3.42-3.50 (m, 3H), 3.59* (s, 3H), 3.60 (s, 3H), 3.74 (s,
6H), 3.78* (s, 6H), 4.24-4.70 (m, 2H), 5.0 (br d, 1H), 6.41-7.20
(m, 8H). 13C NMR (2:1 isomer ratio, 100 MHz, CD3OD) δ 172.4*,
172.0, 171.9, 171.3*, 160.7, 160.2*, 158.2, 158.1*, 155.6*, 155.2,
136.7*, 136.5, 129.5, 129.3, 128.9, 126.2, 126.0*, 116.4*, 115.8,
103.9*, 103.8, 97.9, 97.4*, 78.8, 78.7, 54.2, 51.7, 46.7, 42.6*, 42.2*,
41.4, 38.8*, 38.2, 32.2, 31.1, 27.1. [R]20D -7.1 (c 0.008 M, CHCl3).
HRMS (EI) m/z 523.2425 [M + Na]+; calcd for C27H36N2O7Na
523.2429.
General Protocol 3, Synthesis of Ketones 5a-d and 6a,b. A
suspension of CuCN (0.3 mmol, 60 mol %) in THF (2 mL of THF
per 1 mmol of CuCN) was cooled to -45 °C, treated with vinyl
magnesium bromide (3 mmol, 600 mol %, 1 M) over 10 min, stirred
for 1 h, treated with a solution of the corresponding ester 3a-d,
4a, or 4b (0.5 mmol, 100 mol %) in THF (0.1 M), stirred for 2 h
at -45 °C, and warmed to room temperature for an additional 30
min. The reaction mixture was cooled to 0 °C, treated with a
saturated ammonium chloride solution (30 mL), and shaken
vigorously for 20 min. The layers were separated, and the aqueous
phase was extracted with Et2O (3 × 50 mL) or EtOAc. The
combined extracts were washed with saturated sodium bicarbonate
solution (50 mL), pH 6.8 phosphate buffer (50 mL), and brine (2
× 50 mL), dried over magnesium sulfate, and concentrated under
vacuum. The crude product was purified by column chromatography
with an eluant of EtOAc in hexane as specified for each compound.
Evaporation of the collected fractions afforded the respective ketone
5a-d, 6a, or 6b.
by â-elimination. Employing diazepinone 7b, oxidative condi-
tions32,33 failed similarly to remove the 4-benzyloxybenzyl group
and gave back starting material at rt. By using CAN in
acetonitrile:water at 100 °C, trace amounts of diazepinone 10
and 1-hydroxybenzyl diazepinone 9 were detected by LCMS
analysis; however, decomposition ensued on prolonged exposure
of 7b to these conditions. Alternatively, deprotection of the
4-benzyloxybenzyl group was successful under acidic condi-
tions. Employing a 95:5 TFA/triethylsilane (TES)34 mixture at
rt for 1 day gave some diazepinone 10 and its 1-hydroxybenzyl
counterpart 9. After heating at 80 °C for 3 d, and purification
by chromatography, diazepinones 9 and 10 were isolated in 25%
and 70% yields.
1,4-Diazepin-2-ones with substituents at the 1-, 3-, and
5-positions of the heterocycle have been synthesized by an
effective method featuring the copper-catalyzed cascade addition
of vinyl Grignard reagent to N-alkyl N-Boc-R-aminoacyl
â-amino esters 3a-d and 4a,b. Trisubstituted diazepinones
7a-d and 8a,b were respectively synthesized from phenylala-
nine and lysine to provide diversity at the 3-position. Further-
more, a variety of 1-position substituents were introduced by
reductive aminations of different aldehydes onto the â-amino
ester precursor. A cursory study of the removal of the 1-position
thioethyl and benzyl amide substituents demonstrated that the
4-benzyloxybenzyl group may be cleaved under acid conditions
to provide an alternative route to 3,5-disubstituted 1,4-diazepin-
2-ones. A study to extend this approach for generating a library
of diazepinones is currently in progress in our laboratory.
(2S)-N′-(2,4-Dimethoxybenzyl)-N′-1-(3-oxohept-6-enyl)-N-
(Boc)phenylalaninamide (5a). A colorless oil was prepared from
ester 3a (0.5 mmol, 0.25 g) according to the general protocol 3,
purified on silica gel eluting with 30% EtOAc:hexane (Rf 0.2, 30%
EtOAc:hexane), and isolated in 66% yield: 1H NMR (1.3:1 isomer
ratio, 400 MHz, CD3OD) δ 1.39 (s, 9H), 1.42* (s, 9H), 2.16-2.53
(m, 6H), 2.89-2.92 (m, 2H), 3.33-3.41 (m, 2H), 3.42-3.76* (m,
2H), 3.77 (s, 6H), 4.86 (s, 2H), 4.93-5.03 (m, 3H), 5.76-5.80
(m, 1H), 6.41-7.23 (m, 8H). 13C NMR (2:1 isomer ratio, 100 MHz,
CD3OD) δ 210.0, 209.2*, 173.7*, 173.2, 161.9, 161.4*, 159.4,
159.2*, 156.8, 156.5*, 137.9, 137.8*, 130.5, 130.4*, 130.2, 130.1*,
129.8, 129.0, 128.9, 127.4, 127.2, 117.6, 117.0, 115.1, 99.0*, 98.6,
80.0*, 79.9, 55.4*, 55.3, 47.6, 42.5, 42.2, 41.9, 41.6, 40.7, 39.9*,
Experimental Section
General Protocol 2, Synthesis of Tertiary Amides 3a-d and
4a,b. N-Boc-R-Amino acid (N-(Boc)Phe or N-(Boc)-ꢀ-(Cbz)Lys,
2.2 mmol) and HATU (2.2 mmol) were placed in a 100-mL round-
bottomed flask, dissolved in DMF (0.4 M), cooled to 0 °C, treated
with DIEA (4.4 mmol), stirred for 10 min under argon, and treated
with a solution of secondary amine 2 (2 mmol) in DMF (0.8 M).
The reaction mixture was stirred overnight at room temperature.
The solvent was concentrated on a rotary evaporator, and the
reduced volume was partitioned between an aqueous HCl solution
(10%, 50 mL) and ether (50 mL). The aqueous phase was separated
and extracted with ether (3 × 20 mL). The combined organic phase
was washed with saturated aqueous NaHCO3 (2 × 30 mL) and
brine (2 × 50 mL), dried over magnesium sulfate, filtered, and
28.2, 28.1*. [R]20 -7.82 (c 0.011 M, CHCl3). HRMS (EI) m/z
D
525.2957 [M + H]+; calcd for C30H40N2O6 525.2959.
General Protocol 4, Synthesis of 1,3,5-Trisubstituted 1,4-
Diazepinones 7a-d and 8a,b. Ketone 5a-d, 6a, or 6b (0.095
mmol, 100 mol %) was dissolved in a 1:1 TFA/DCM solution (4
mL), stirred for 10 min, and evaporated to a residue. The residue
was dissolved in THF (5 × 10-3 M), treated with supported free
tertiary amine Amberlyste A-21 resin (1.9 mmol, 2000 mol %,
prewashed with methanol, THF, DCM, and dried under high
vaccum for 2 h), stirred for 2 h, filtered, and treated with a sodium
cyanoborohydride solution in THF (0.475 mmol, 500 mol %, 1
M). The reaction mixture was stirred overnight under argon
atmosphere. After completion of the reaction was indicated by TLC,
the solvent was concentrated on a rotary evaporator, and the
remainder was partitioned between a saturated NaHCO3 solution
(20 mL) and ethyl acetate (20 mL). The aqueous phase was
separated and extracted with ethyl acetate (3 × 10 mL). The
(31) Wade, W. S.; Yang, F.; Sowin, T. J. J. Comb. Chem. 2000, 2, 266-
275.
(32) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
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Zhai, H. J. Org. Chem. 2006, 71, 9495-9498.
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8982 J. Org. Chem., Vol. 72, No. 23, 2007

combined organic phase was dried over magnesium sulfate, filtered,
and evaporated to a residue, which was purified further as specified
below.
temperature, and concentrated under vacuum to a residue, which
was purified on silica gel with 50% EtOAc:hexane as eluent, to
afford diazepinone 9 (2.4 mg, 25% yield) as a colorless oil: Rf
1
(3S,5S)-3-Benzyl-5-but-3-enyl-1-(2,4-dimethoxybenzyl)[1,4]-
diazepin-2-one (7a). A colorless oil was prepared from ketone 5a
(0.095 mmol, 0.05 g) according to the general protocol 4, purified
on silica gel eluting with 20% EtOAc:hexane (Rf 0.22, 20% EtOAc:
hexane), and isolated in 68% yield. 1H NMR (400 MHz, CDCl3) δ
1.18-1.34 (m, 3H), 1.62 (m, 1H), 1.78 (m, 2H), 2.50 (m, 1H),
2.83-2.89 (q, J ) 8, 1H), 3.28-3.33 (m, 2H), 3.57-3.60 (m, 2H),
3.81 (s, 6H), 4.51-4.68 (q, J ) 16, 2H), 4.7-4.84 (m, 2H), 5.56-
5.57 (m 1H), 6.46-6.49 (m, 2H), 7.25-7.35 (m, 6H). 13C NMR
(100 MHz, CDCl3) δ 174.4, 159.8, 158.1, 138.9, 137.5, 130.8,
129.0, 128.1, 126.0, 118.0, 114.4, 103.9, 97.9, 60.6, 59.8, 55.0,
0.25 (50% EtOAc in hexanes). H NMR (400 MHz, CDCl3) δ
1.29-1.47 (m, 2H), 1.6-1.93 (m, 4H), 2.02-2.22 (m, 4H), 3.20-
3.24 (br d, 1H), 3.75-3.82 (br q, 1H), 4.50-4.62 (m, 2 H), 5.02-
5.10 (m, 2H), 5.75-5.83 (m, 1H), 6.70-7.39 (m, 9H). 13C NMR
(100 MHz, CDCl3) δ 174.3, 165.7, 156.5, 135.8, 135.6, 129.0,
128.8, 127.8, 126.5, 126.2, 114.8, 114.6, 60.4, 58.6, 43.9, 34.7,
32.0, 30.1, 28.6. HRMS (EI) m/z 365.2228 [M + H+; calcd for
C23H28N2O23 365.2224]. [R]20 -7.0 (c 0.014, CHCl3). Second to
D
elute was diazepinone 105 on changing the solvent system to 5%
methanol in DCM. After evaporation of the combined collected
fractions, the residue was dissolved in 10% HCl solution followed
by freeze drying to afford diazepinone 105 (5.0 mg, 70% yield):
mp 138-140 °C; Rf 0.32 (5% MeOH/DCM), [R]20D -35.0 (c 0.008,
DMF). HRMS (EI) m/z 259.1808 [M + H]+; calcd for C16H23N2O
55.9, 46.9, 45.2, 37.8, 35.7, 35.3, 29.4. [R]20 -7.6 (c 0.018,
D
CHCl3). HRMS (EI) m/z 409.2491 [M + H]+; calcd for C25H32N2O3
409.2486.
(3S,5S)-3-Benzyl-5-(but-3-enyl)-1,4-diazepin-2-one (10) and
3-Benzyl-5-(but-3-enyl)-1-(4-hydroxybenzyl)-1,4-diazepin-2-
one (9). 4-Benzyloxybenzyl amide 7b (12 mg, 0.026 mmol) was
placed into a 10-mL three-necked flask, equipped with a water
condenser, treated with 3 mL of a mixture of TFA/TES (95:5),
and heated with an oil bath to a bath temperature of 80 °C for 72
h. The progress of the reaction was followed by LCMS analysis,
by removing aliquots from the mixture and injecting directly onto
a Gemini column (C18 110 A, 50 × 4.60 mm, 5 µm) with an eluant
of 20-80% acetonitrile:H2O buffered with 0.1% TFA. After 72 h,
a 75:25 ratio was observed of two peaks eluting at retention times
of 3.49 and 4.24 min corresponding to 3,5-disubstituted diazepinone
10 and 4-hydroxybenzylamide 9. The solution was cooled to room
259.1804. Lit.5 mp 138-140 °C; [R]20 -35.6 (c 0.008, DMF).
D
Acknowledgment. The authors gratefully acknowledge
financial support from the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Fonds Que´be´cois
de la Recherche sur la Nature et les Technologies (FQRNT).
Supporting Information Available: Experimental details and
spectroscopic characterization for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO701467D
J. Org. Chem, Vol. 72, No. 23, 2007 8983