Synthesis and characterization of a new tetradentate ligand for Cu(II) metal ions

Article abstract of DOI:10.1021/jo010661u

The synthesis and characterization of a tailor-made ligand 1 is described. Self-assembly of 1 on a GaAs surface was studied by FT-IR spectroscopy. The IR spectrum of the thin film points to the conclusion that the monolayer adsorbs to the surface via both carboxylates of the malonic acid derivative. The distinction between the possible binding modes is discussed.

Full text of DOI:10.1021/jo010661u

4040
J . Org. Chem. 2002, 67, 4040-4044
Syn th esis a n d Ch a r a cter iza tion of a New Tetr a d en ta te Liga n d for
Cu (II) Meta l Ion s
Ronnie Benshafrut,* Avner Haran, Dmitry Shvarts, and Benjamin Schneider
AMOS Ltd., 2 Pekeris Street, T.M.R-Rabin Science Park, Rehovot 76702, Israel
ronniebs@zahav.net.il
Received J une 27, 2001
The synthesis and characterization of a tailor-made ligand 1 is described. Self-assembly of 1 on a
GaAs surface was studied by FT-IR spectroscopy. The IR spectrum of the thin film points to the
conclusion that the monolayer adsorbs to the surface via both carboxylates of the malonic acid
derivative. The distinction between the possible binding modes is discussed.
The use of organic molecules as receptors for metal ions
Previously synthesized dicarboxylic ligands have uti-
lized the labile tartaric acid moiety. Due to the difficulties
of the group in surviving multistep synthetic manipula-
tions, a protected malonate was used in the synthesis of
1. The synthesis of the suitable ligand was envisioned to
begin at the anchor, utilizing suitably protected malonic
acid as shown in Scheme 1.
is well established.1 The majority of the reports describe
solution-state chelation of metal ions by various organic
ligands. Apart from high ligand-analyte affinities, che-
lation by a monolayer adsorbed on solid support demands
more complex prerequisites to succeed. These include
higher sensitivities, as concentration of adsorbed ligands
is small, and structural constraints that arise from the
contribution of surface interactions.1,2 Given the vast
spectrum of technological applications such as catalysis,
lithography, and molecular recognition, the interest in
chemistry and physics underlying these applications has
been on the rise in recent years.
Our synthetic aim was to prepare bifunctional ligand
molecules that contain receptor sites capable of binding
copper(II) metal ions and anchor moieties that can
specifically bind to the gallium arsenide (GaAs) surface.
Of the three structural features that make up a ligand
suitable for adsorption as an organic thin film, e.g.,
receptor, spacer, and anchor, it is the receptor site that
should be fitted to bind strongly and selectively to the
analyte. The spacer essentially acts to assist in securing
a stronger unhindered binding away from the surface
while the anchor allows strong and irreversible binding
to the solid surface. It has previously been demonstrated
that binding to GaAs can be achieved via thiols,2 disul-
fides,2 phosphates,3 or carboxyl groups.2 Disulfides were
found to bind relatively weakly to the GaAs surface, while
the phosphates and carboxylates are stronger binders.
The advantage of binding the ligand via a two-site
dicarboxylate lies in the greater strength of the bonding
as compared with sulfides or monocarboxylates.4
The tetradentate receptor site with the amide and
pyridyl donors as constructed for ligand 1, though previ-
ously determined to have a binding constant of only 3.41,
was found to be suitable for strainless binding of the Cu-
(II) ion.5 The higher stability of the copper complex as
compared to the stabilities of the other metal ion com-
plexes utilizing the same ligand was evident.5 It is in full
agreement with the larger flexibility of the copper ion
center toward tetrahedral distortions.
The synthesis of the ligand’s backbone started, accord-
ing to our preferred pathway, with the alkylation of tert-
butyl malonate6 2. Condensation of 2 with methyl
3-bromopropionate7 gave 3 as a slowly crystallizing solid.
Compound 3 consists of both the binding groups (the
protected 1,3-dicarboxylic acid) that are later transformed
to adsorb to the GaAs surface and the alkyl ester spacers
to which the receptor center is to be attached. Basic
saponification of the methyl esters in 3 gave the desired
diacid 4 in 58% yield (over two steps). Carbodiimide-
catalyzed coupling of the diacid with 2-picolylamine
* To whom correspondence should be addressed. Fax: +972-8-
9365092.
(1) (a) Go¨pel, W., Hesse, J ., Zemel J . N., Eds. Sensors: Chemical
and Biochemical Sensors; VCH Publishers: Weinheim, 1991-1992;
Vols. 2 and 3. (b) Prodi, L.; Bolletta, F.; Zaccheroni, N.; Watt, C. I. F.;
Mooney, N. J . Chem. Eur. J . 1998, 4, 1090-1094. (c) de Silva, A. P.;
Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A. J . M.; McCoy, C.
P.; Rademacher, J . T.; Rice, T. E. Chem. Rev. 1997, 97, 1515-1566.
(2) (a) Vilan, A.: Ussyshkin, R.; Gartsman, K.; Cahen, D.; Naaman,
R.; Shanzer, A. J . Phys. Chem. B 1998, 102, 207-209. (b) Bastide, S.;
Butruille, R.; Cahen, D.; Dutta, A.; Libman, J .; Shanzer, A.; Sun, L.;
Villan, A. J . Phys. Chem. B 1997, 101, 2678.
(3) Artzi, R. MSc. Dissertation, The Weizmann Institute of Science,
December 1999.
(4) Vilan, A. MSc. Dissertation, The Weizmann Institute of Science,
November 1996.
(5) Comba, P.; Goll, W.; Nuber, B.; Va´rnagy, K. Eur. J . Inorg. Chem.
1998, 2041-2049.
(6) Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, pp
263-266.
(7) Methyl acrylate may be used instead.
10.1021/jo010661u CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/14/2002

Tetradentate Ligand for Cu(II) Metal Ions
J . Org. Chem., Vol. 67, No. 12, 2002 4041
Sch em e 1. BOC-m a lon a te P a th w a ya
a
Key: (a) methyl bromopropionate, NaH, THF, 5 h, rt, 89%; (b) NaOH, MeOH, 8 h, rt, 65%; (c) PCP-DCC complex, EtOAc, 3 h, rt,
83%; (d) 2-picolylamine, triethylamine, CH2Cl2, 8 h, rt, 92%; (e) TFA, CH2Cl2, 8 h, rt, 93%.
Sch em e 2a
Sch em e 3. Alloc-m a lon a te P a th w a ya
a
Key: (a) amine of choice, triethylamine, CH2Cl2, 5-12 h, rt,
65-90% yield.
under DCC/HOBT conditions gave only low yields of the
desired product 6 and a larger yield of an unidentified
product, probably resulting from intramolecular DCC-
mediated cyclization. Activation of the diacid toward
amide formation was best achieved by the reaction of
diacid 4 with a solid pentachlorophenol-dicyclohexyl-
carbodiimide complex (PCP-DCC complex).8 Under these
conditions, the organic acid is added to a suspension of
excess complex in ethyl acetate and stirred for 3 h.
The active diester 5 was separated from the urea and
pentachlorophenol side products as white solid in 83%
yield. This reactive intermediate, prepared in gram
quantities, is quite stable and could be stored with out
degradation for extended periods of time. It has been used
in our laboratory in the synthesis of various other ligands
such as those shown in Scheme 2.9
Treatment of 5 with 2-picolylamine, in the presence of
triethylamine, gave diamide 6 in a very good yield, i.e.,
77% yield over two steps as compared with yields lower
than 40% obtained for the direct conversion of 4 to 6.
Removal of the tert-butyl groups with trifluoroacetic acid
in methylene chloride gave the desired ligand 1 as a
viscous, colorless oil in nearly quantitative yield (41%
yield over five steps).
a
Key: (a) tert-butyl bromoacetate, NaH, THF, 5 h, rt, 89%; (b)
TFA, CH2Cl2, 5 h; (c) PCP-DCC complex, EtOAc, 3 h, rt; (d)
2-picolylamine, triethylamine, CH2Cl2, 8 h, rt, 75%.
Alternatively, we used diallyl malonate (Alloc ester)
as the protected diacid for step 1 of the synthesis (Scheme
3). Alkylation with tert-butyl bromoacetate and depro-
tection of the resulting di-tert-butyl diester 7 with TFA
gave the diacid 8 that was, similar to 4, converted to the
diamide compound via the PCP-DCC approach. Pal-
ladium-catalyzed removal of the Alloc groups in the
presence of potassium ethyl hexanoate10 afforded 1 in a
low yield.
Attempts to grow and isolate a single crystal of the
1-Cu 2+ complex were difficult as the formation of car-
boxylate-Cu2+ salts was interfering. To evade the car-
boxylate interferences in the binding and be able to study
the complexation, we prepared the complex of 6, where
ligation occurs exclusively through the receptor site.
Stable white powdery complex 6-Cu 2+ was obtained upon
stirring 6 in a two-phase water-methylene chloride
(8) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis,
2nd ed.; Springer-Verlag: Berlin, 1994.
(9) Benshafrut, R. Unpublished results.
(10) J effrey, P. D.; McCombie, S. W. J . Org. Chem. 1982, 47, 587.

4042 J . Org. Chem., Vol. 67, No. 12, 2002
Benshafrut et al.
F igu r e 1. (a) 1H NMR spectra of free 6; (b) 6-Cu 2+ complex; (c) enhancement (×6) of the aromatic region showing the broad peak
at 8.52 ppm. Signals marked with an asterisk are due to MeOH and THF solvent impurities.
F igu r e 2. (a) 13C NMR spectra of free 6 and (b) 6-Cu 2+ complex. Signals marked with an asterisk are due to MeOH and CHCl3
solvent impurities.
1
mixture containing CuSO4. The H NMR and 13C NMR
spectra of the complex, obtained after evaporation of the
organic phase, provided direct evidence of the successful
complexation at the receptor site (Figures 1 and 2).
The largest shift (downfield shift of ∆δ ) 1.5 ppm) was
observed in the 13C NMR spectra for the R pyridyl carbon
situated next to the chelating pyridyl-nitrogen atom.
Smaller yet similar downfield shifts were observed for
the remaining pyridyl carbons. While complexation with
the paramagnetic ion did not result in any significant
shifts, both the proton and carbon NMR signals for the
atoms situated at or near the receptor site suffered from
intensive broadening. The benzyl methylene protons, for
example, that appeared as a doublet at 4.53 ppm in the
1H NMR spectrum of free 6, came into view as a broad
singlet at 4.47 ppm in the spectrum of the copper
complex. On the other hand, the terminal tert-butyl
F igu r e 3. Infrared spectra of ligand 1: (a) neat on a NaCl
pellet, (b) excess ligand on a GaAs surface prior to washing,
groups and the methylene groups exhibited no broaden-
ing, suggesting that they were unaffected by the forma-
tion of the complex. Furthermore, this supports the
conclusion that this host-guest interaction at the inter-
nal receptor cavity of 6 closely resembles the host-guest
interaction expected in 1.
and (c) adsorbed ligand after washing in 1:1 hexane/2-propanol
for 15 s. Only the 1800-1000 cm-1 region is shown. Note: the
spectra of neat 1 and excess (a and b) are scaled down by 10
for clarity.
indicated that the monolayer of 1 was successfully formed
(Figure 3).
Self-assembly of 1 on 5 × 5 mm GaAs slides was
achieved by immersing the slides for 12 h in a DMF
solution having a concentration of 38 mM of the adsor-
bate 1. Examination of the infrared spectra of the slides
In the process of adsorbing the ligand molecules onto
the GaAs surface two basic modes of adsorption may be
considered (shown below): mode 1 in which all of the
adsorbate molecules bind through the carboxylic acid

Tetradentate Ligand for Cu(II) Metal Ions
J . Org. Chem., Vol. 67, No. 12, 2002 4043
groups and mode 2 in which the preferred adsorption is
through a single carboxylic arm keeping the second arm
unbound and away from the surface. It is, however,
reasonable to assume that a mixture of the two modes
could be present and that parameters such as adsorbate
concentration, solvent interactions, intermolecular ef-
fects, and the distance of one carboxylic group from the
surface relative to the other could favor the existence of
one mode over the other.
Exp er im en ta l Section
Gen er a l Com m en ts. All chemicals were analytical grade
and were used without further purification. All glassware was
washed with acetone and dried in an oven at 120 °C before
use. 1H NMR spectroscopy was performed on a 250 MHz
spectrometer or on a 400 MHz spectrometer as indicated. All
13C and 1H NMR spectra were obtained in CHCl3-d, except
where noted. Column chromatography was performed with
silica gel 60 (230-240 mesh). Melting points are uncorrected.
All reactions were carried out in a nitrogen atmosphere.
Standard workup means that the organic layers were pooled
after extraction, washed with water, dried over MgSO4,
filtered, and evaporated under reduced pressure.
Liga n d Ad sor p tion . GaAs slides were immersed in a 38
mM DMF solution of the ligand for a period of 12 h, under an
atmosphere of nitrogen. The slides were then taken out of the
solution, rinsed with a 1:1 solution of hexane and 2-propanol,
and dried with N2.
Tetr a Ester 3. A 13.06 g (60.4 mmol) portion of malonate
2 and 22.21 g (132.9 mmol, 2.2 equiv) methyl bromopropionate
were introduced into a one-neck 200 mL round-bottom-flask
containing 75 mL of THF. Into the well-stirred solution was
added NaH (60% in oil) in small portions in such a way that
the evolution of hydrogen gas ceases before the next portion
is added. The solution was allowed to stir at room temperature
for 5 h before it was quenched with water and extracted with
ether (3 × 75 mL). Workup afforded nearly colorless oil that
solidified slowly into a white mass. Recrystallization from
methanol-hexane gave 20.97 g of the desired solid (89.5%
yield). Mp: 66.5 °C. 1H NMR (250 MHz, CDCl3, δ): 1.46 (s,
18H), 2.15 (t, 4H), 2.35 (t, 4H), 3.79 (s, 6H). 13C NMR (62 MHz,
CDCl3, δ): 25.9, 26.4, 27.6, 29.5, 51.3, 81.3, 169.8, 170.1. GC-
MS (EI): 388 (M+, 1), 277 (100). IR (CCl4, NaCl): 2981, 1725,
Neat 1 exhibites an FT-IR spectrum consistent with
internal hydrogen bonding. Apart from the CdO stretch-
ing corresponding to the carboxylic acids (νCdO ) 1717
cm-1), two other stretching frequencies contribute to the
broadening of the peak between 1600 and 1750 cm-1, i.e.,
amide CdO bands (νCdO ) 1676 and 1631 cm-1) and
pyridine skeletal bands (νCdN ) 1600 cm-1). The position
of the bands corresponding to the amide and pyridine
groups in the IR spectrum of the adsorbed 1 should not
change, as these groups do not participate in the adsorp-
tion to the GaAs surface. Quenching the hydrogen
bonding effect in 1 by means of salt formation or by
adsorption to the GaAs surface, according to mode 1,
should result in the disappearance of the 1717 cm-1
shoulder and the emergence of a carboxylate band at νCd
1655, 1618, 1446, 1146 cm-1
.
Dia cid 4. A 3.06 g (7.88 mmol) portion of 2 in 75 mL of
methanol was treated with 5 mL of a 2 N NaOH solution. The
solution was stirred overnight before its volume was reduced
in half in vacuo. The thick solution was acidified to pH 5 with
dilute HCl and extracted with chloroform (3 × 75 mL). Workup
gave 4 as a white solid in 65.0% yield. Mp: 140.5 °C. 1H NMR
(250 MHz, CDCl3, δ): 1.42 (s, 18H), 2.09 (t, 4H), 2.32 (t, 4H),
8.30 (br s, 2H). 13C NMR (62 MHz, CDCl3, δ): 26.4, 27.6, 28.9,
57.0, 81.8, 169.5, 178.3. MS (ESI-MS, m/z): 359 (M - H, 100).
IR (CCl4, NaCl): 3395, 3075, 1721, 1701, 1434, 1253, 1142
) ∼1650 cm-1. However, if mode 2 is preferred, the
O
interruption in the hydrogen bonding should give rise to
a carboxylic acid band at a higher frequency, ∼1750
cm-1 11 and a carboxylate band at or around 1650 cm-1
.
,
After an adsorption process of 12 h and withdrawal of
the slide from the solution, excess unbound ligand covers
the bound monolayer. The characteristic infrared bands
of this bulk are closely similar to the IR characteristics
of the neat material (Figure 3a,b). The bound monolayer
uncovered by rinsing the device in a 1:1 solution of
hexane and 2-propanol exhibits carboxylate adsorptions
that are indicative of mode 1. On binding to the surface
(Figure 3c), a Ga-carboxylate species forms giving rise
to the carboxylate bands at 1652 (strong and asym-
metrical) and a weaker and symmetrical band at a lower
frequency. A trace of excess adsorbate is seen in Figure
3c at 1717 cm-1. The bands that should appear if mode
2 were to prevail are clearly absent.
No change was observed for the amide bands at 1676
and 1631 cm-1 and the pyridine rings at 1600 cm-1. This
indicates that there is no detectable effect on the receptor
site that can arise either from some surface interaction
or from complexation of contaminants that may be
present on the GaAs surface or in the solution, prior to
or during monolayer formation. Continuous rinsing of the
GaAs slice with the organic solution mentioned above
does not further affect the stability of the bound mono-
layer.
cm-1
.
Active Diester 5. A 50 mL portion of ethyl acetate and 7.00
g (6.96 mmol) of the PCP-DCC complex were introduced into
a 100 mL flask. The nearly homogeneous solution was then
treated with 1.0 g (2.77 mmol) of diacid 4 in 15 mL of ethyl
acetate, added in one portion. Within 10 min of the addition,
the solution was clear and the urea started to precipitate. The
mixture was stirred at room temperature for an additional 3
h, after which time the urea was filtered off and the solvents
were evaporated in vacuo to afford a thick mass. The residue
was chromatographed twice on silica (eluted with 5:1 hexane/
ethyl acetate) to yield 1.95 g of the active ester as a white solid
1
in 82.8% yield. Mp: 165.4 °C. H NMR (250 MHz, CDCl3, δ):
1.53 (s, 18H), 2.35 (t, 4H), 2.79 (t, 4H). 13C NMR (62 MHz,
CDCl3, δ): 27.8, 27.9, 28.9, 57.0, 82.5, 127.6, 131.6, 132.0,
143.9, 168.6, 169.4. MS (FAB-): 856, 264 (100). IR (CCl4,
NaCl): 2982, 1784, 1718, 1265, 1152 cm-1
.
Dia m id e 6. A 15.0 mL portion of methylene chloride in a
50 mL round-bottom flask was treated with 0.240 g (2.22
mmol) of 2-picolylamine and 0.5 mL of triethylamine. The
solution was stirred at room temperature for 10 min prior to
the addition of 0.857 g (1.0 mmol) of the active ester 5 in 5
mL of methylene chloride. After the solution was stirred for 8
h, the solvents were evaporated and the residue was chro-
matographed on silica (9.5:0.5 CH2Cl2/MeOH). The protected
ligand 6 was obtained as a white solid in 92.5% yield (0.50 g).
1
Mp: 134.2 °C. H NMR (250 MHz, CDCl3, δ): 1.47 (s, 18H),
(11) (a) Meloan, C. F. Elementary Infrared Spectroscopy; Macmillan
Publishers: New York, 1963. (b) Lambert, J . B.; Shurvell, H. F.;
Lightner, D. A.; Cooks, R. G. Introduction to Organic Spectroscopy;
Macmillan Publishers: New York, 1987.
2.22 (m, 4H), 2.26 (m, 4H), 4.57 (d, 4H, J ) 5.0 Hz), 4.95 (br
t, 2H, NH), 7.28 (m, 4H), 7.72 (t, 2H), 8.54 (d, 2H, J ) 4.25
1
Hz). H NMR (250 MHz, D2O, δ): 1.47 (s, 18H), 2.22 (m, 4H),

4044 J . Org. Chem., Vol. 67, No. 12, 2002
Benshafrut et al.
2.26 (m, 4H), 4.53 (d, 4H), 7.44 (m, 4H), 7.89 (t, 2H), 8.53 (d,
2H, J ) 4.25 Hz). 13C NMR (62 MHz, CDCl3, δ): 27.8, 27.9,
31.3, 44.1, 57.5, 81.7, 122.5, 122.6, 137.7, 148.1, 156.3, 170.1,
172.5. MS (ESI+): 541 (M + 1), 563 (M + Na). IR (CCl4): 3265,
a gray wet solid. The solid was chromatographed on silica
eluted with a 9.5:0.5 mixture of CH2Cl2 and methanol (TLC ∼
Rf ) 0.5) to give 0.48 g of the product, 65% yield. 1H NMR
(250 MHz, CDCl3, δ): 3.0 (s, 4H), 4.65 (m, 8H), 5.25 (dd, 4H),
5.90 (m, 2H), 7.26 (m, 6H), 7.71 (t, 2H), 8.52 (d, 2H). 13C NMR
(62 MHz, CDCl3, δ): 38.7, 43.4, 54.2, 65.8, 117.7, 122.1, 122.2,
131.4, 137.0, 147.6, 157.5, 168.9, 169.9. MS (FAB+): 481
(MH+, 100), 423 (34), 373 (35.7).
Liga n d 1. Dep r otection of BOC Ester . A 0.210 g (0.41
mmol) portion of 6 was added to a 1:1 mixture of TFA and
CH2Cl2 (3 mL) in a 25 mL round-bottom flask, under an
atmosphere of nitrogen. The solution was stirred overnight,
reduced in volume in vacuo, and washed four times with
methylene chloride (5 mL). The viscous colorless oil amounted
to 0.150 g, 92.5% yield.
2977, 1721, 1647, 1245, 1163 cm-1
.
Com p lex 6-Cu 2+. In a two-phase mixture made of 50 mL
of a 0.1 M Tris buffer (pH 7.5) and 50 mL methylene chloride
were dissolved 65 mg of CuSO4 pentahydrate followed by 31
mg of ligand 6. The two-phase mixture was stirred vigorously
at room temperature for 10 min. The aqueous phase was then
separated and the organic phase dried and evaporated to afford
a white crystalline complex. 1H NMR (400 MHz, MeOD-d3,
δ): 1.49 (s, 18H), 2.12 (m, 4H), 2.26 (m, 4H), 4.47 (s, 4H), 7.33
(br s, 2H), 7.40 (br s, 2H), 7.81 (t, 2H), 8.52 (br s, 2H). 13C
NMR (100 MHz, MeOD-d3, δ): 28.1 (CH3), 28.9 (CH2), 31.7
(CH2CON), 45.7 (CH2-Py), 58.6 (quaternary C-malonate), 83.0
(quaternary tert-butyl), 123.0 (aryl H4), 123.9 (aryl H2), 138.8
(aryl H3), 149.6 (aryl H1), 159.3 (aryl ipso), 171.5 (CO tert-
butyl), 175.1 (CON).
Dep r otection of Alloc Ester . A premade solution of 2 mL
of ethylhexanoic acid in 5 mL of THF was treated with small
pieces of potassium metal (10% excess) and was stirred until
all the metal was consumed. Then, the solvent was removed
under vacuum and the residue was dissolved in 5 mL of
methylene chloride. In a separate 100 mL round-bottom flask,
maintained under an inert atmosphere, were dissolved 0.20 g
of Alloc 8, 20 mg of triphenylphosphine, and 50 mg of tetrakis-
(triphenylphosphine)palladium(0) in 70 mL of methylene
chloride. The mixture was allowed to stir for 5 min before the
hexanoate solution prepared separately was added in one
portion. After 12 h, the dark solution was treated with 50 mL
of ether. The oil, which separated, was acidified, extracted into
CH2Cl2, and dried over MgSO4. Evaporation of the dried
organic solvent gave light brown oil that was identical with
the product obtained from the BOC pathway. 1H NMR (250
MHz, MeOD-d3, δ): 1.72 (t, 4H), 1.94 (t, 4H), 4.26 (s, 4H), 7.50
Alloc 7. Into a 50 mL round-bottom flask fitted with a
nitrogen inlet were added 10 mL of THF, 1.00 g (5.4 mmol) of
Alloc-malonate ester, and 2.21 g (11.3 mmol, 2.1 equiv) of tert-
butyl bromoacetate. The solution was stirred under nitrogen
while NaH (60% suspension) was added in small portions in
such a way that hydrogen gas evolution ceased before the next
portion was added. The thick gray solution was allowed to stir
at room temperature for 5 h before it was quenched with water
and brine (50%). The solution was extracted with ether (3 ×
50 mL), dried over MgSO4, and evaporated to yield light yellow
oil. Chromatography on silica and elution with a 5:1 mixture
of hexane/ethyl acetate afforded the product as a nearly
colorless oil in 89% yield. 1H NMR (250 MHz, CDCl3, δ): 3.32
(s, 4H), 4.67 (d, J ) 5.8 Hz), 5.30 (dd, 4H), 5.86 (m, 2H), 10.12
(br s, 2H). 13C NMR (62 MHz, CDCl3, δ): 36.9, 53.1, 66.9, 119.0,
131.0, 168.3, 176.4. IR (neat oil, NaCl): 3228, 2951, 2664, 1743,
1
(m, 4H0, 8.09 (t, 2H), 8.30 (d, 2H, J ) 4.0 Hz). H NMR (250
MHz, DMSO-d6, δ): 2.20 (m, 4H), 2.13 (m, 4H), 4.51 (d, 4H, J
) 5.45 Hz), 7.72 (m, 4H), 8.29 (t, 2H), 8.69 (m, 4H, aryl H’s +
amide H’s). 13C NMR (62 MHz, MeOD-d3, δ): 29.2, 31.4, 41.8,
57.1, 126.5, 126.7, 142.3, 147.7, 155.5, 174.1, 175.9. MS
(FAB-): 427 (M - H), 266 (100). HRMS (FAB+): found
429.1764, calcd for C21H25N4O6 429.1774. IR (neat oil, NaCl):
1714, 1411, 1262 cm-1
.
Alloc 8. A solution of the activated Alloc-malonate ester in
10 mL of chloroform was added in one portion to a stirring
solution of 0.250 g (2.31 mmol, 4 equiv) of 2-picolylamine and
350 µL of triethylamine in 15 mL of chloroform under a
nitrogen atmosphere. The yellow solution was stirred at room
temperature for 5 h and then evaporated under vacuo to yield
3403, 3070, 2943, 1708, 1672, 1202, 1134 cm-1
.
J O010661U