Oligophenylenaminones as scaffolds for α-helix mimicry

Article abstract of DOI:10.1021/jo200917d

The design and synthesis of small molecule α-helix mimetics has been a productive field over the past decade. These compounds have performed well in a variety of biological systems as functional disruptors of α-helix- mediated protein-protein interactions. In our studies we have continued to develop novel, more biologically compatible scaffolds, which are often easier to assemble and capable of mimicking longer and/or more diverse helices. To this end, we have constructed a new series of i, i+4, i+7 α-helix mimics based on the enaminone scaffold. These molecules represent a step forward in the pursuit of idealized monofacial α-helix mimetics.

Full text of DOI:10.1021/jo200917d

ARTICLE
pubs.acs.org/joc
Oligophenylenaminones as Scaffolds for r-Helix Mimicry
Marc J. Adler and Andrew D. Hamilton*
University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom
Yale University, Department of Chemistry, 225 Prospect Street, P.O. Box 208107, New Haven CT 06520, United States
S Supporting Information
b
ABSTRACT: The design and synthesis of small molecule R-
helix mimetics has been a productive field over the past decade.
These compounds have performed well in a variety of biological
systems as functional disruptors of R-helix-mediated proteinꢀ
protein interactions. In our studies we have continued to
develop novel, more biologically compatible scaffolds, which
are often easier to assemble and capable of mimicking longer
and/or more diverse helices. To this end, we have constructed a
new series of i, i+4, i+7 R-helix mimics based on the enaminone
scaffold. These molecules represent a step forward in the pursuit
of idealized monofacial R-helix mimetics.
’ INTRODUCTION
R-Helices are the most commonly observed secondary struc-
ture in proteins. This important motif not only plays a large role
in the higher order structure of many proteins but also frequently
comprises key elements of the interfacing domains in proteinꢀ
protein interactions.1,2
Synthetic chemists have long been intrigued by the challenge of
developing synthetic R-helix mimetics not only as a tool to study
their properties outside of a larger protein but also for utilization as
potential therapeutic agents and/or biological probes. Strategies
for helix mimicry include helical β-peptides,3ꢀ5 covalently bonded
peptide helices,6ꢀ9 and nonpeptidic small molecules.10ꢀ13
Figure 1. Scaffolds for R-helix mimicry.
Work in our lab and others over the past decade has produced
nonpeptidic small molecules capable of imitating the structure
this type offer the potential for a more extendable synthesis of a
broader range of substrates with increased structural flexibility.
Our first example in this category was a simple enaminone
derivative (Figure 1B),23 which established the structural integ-
rity of the intramolecular hydrogen bond and the analogy to R-
helix structure.
We have further assembled and investigated a number of
benzoylurea compounds (Figure 1C), which, due to their facile
synthesis, allowed for the construction of R-helix mimics of
extended lengths. These oligobenzoylureas have been shown to
adopt conformationally biased structures that are able to project
peptidomimetic side chains with the distance and angular
projection similar to an R-helix19,20 and furthermore are able
to successfully mimic R-helical protein function in a biological
environment.18
and function of R-helices. Over time, these structures have
evolved from small, bicyclic indanes14 to elongated, rigid
terphenyls,15ꢀ17 to more easily assembled and biocompatible
structures such as benzoylureas.18ꢀ20
One crucial goal in the design of helix mimetics is the ease of
their synthesis. Ideally, readily accessible monomer units should
be linked together in a mild, direct manner, allowing for a variety
of mimics of different length and side-chain composition to be
synthesized directly.
The challenge of the synthetic accessibility of rod-like aryl
oligomers (such as the terphenyls) led us to develop scaffolds that
were not composed entirely of aryl subunits. Others have reported
helicomimetic molecules which feature six-membered covalently
bonded rings in lieu of one of the aryl constituents of the fundamental
helix-mimetic framework.21,22 These systems offer attractive options
to the previously developed methods of helix mimicry, especially in
regard to the increased ability of these scaffolds to conform to
induced-fit models of proteinꢀprotein interaction inhibition.
We have recently reported the use of a hydrogen-bonded ring
as an arene surrogate in R-helix mimetic scaffolds. Structures of
The success of the benzoylureas prompted us to pursue other
R-helix mimics of this type. A replacement of the acylurea with a
Received: May 13, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analyses of Enaminones
Figure 2. Representative examples of i, i+4, i+7 R-helix mimetics with
their respective logP values as calculated by MOE.
Figure 3. Lowest energy conformation of representative R-helix mi-
metic enaminone 23 as determined by MOE.
vinylogous amide would not only maintain planarity in the six-
membered hydrogen-bonded arene surrogate24 but also poten-
tially provide an even stronger noncovalent interaction due to its
electronically conjugated and dipolar nature. We herein explore
the scope and limitations of using an enaminone within R-helix
mimetic scaffolds.
Scheme 2. Synthesis of Terminal Monomer Unitsa
’ RESULTS AND DISCUSSION
Retrosynthetic Analysis and Modeling Studies. The design
of the enaminones was guided not only by synthetic accessibility but
also by the optimization of their physical properties. For example,
the calculated logP of the proposed structures indicated that they
would offer improved solubility over our earlier scaffolds (Figure 2).
Modeling studies performed using MOE (MMFF94, 10 000
iterations, default settings) suggest that the lowest energy con-
formation of nitroenaminone 23 possesses an intact intramole-
cular hydrogen bond, and places the three isopropyl groups on a
single face of the mimetic (Figure 3). The inter-side-chain
distances that the model predicts are in close agreement to those
of an idealized R-helix model.
A number of ways to approach the synthesis of helix mimetic
enaminones were explored (Scheme 1); however, route D
involving the conjugate addition of an aniline to an ynone was
deemed to be the simplest and thus was investigated.
Synthesis. The synthesis of both the terminal monomers
10ꢀ12 and the extending monomer units 16ꢀ18 began with the
bis-alkylation and subsequent ester hydrolysis of 2-hydroxy-4-
nitrobenzoic acid. Terminal segments 10ꢀ12 were obtained by
a a. oxalyl chloride, DMF, CH2Cl2; b. NH4OH, CH2Cl2; c. PtO2,
K2CO3, H2, MeOH.
conversion to the terminal amide via the acid chloride followed by
reduction of the nitrobenzene to the aniline (Scheme 2). Nitro-
benzamide 7 was significantly soluble in water; this was detrimental
to the obtained yield of this compound due to loss during workup.
Assembly of the extending monomers (Scheme 3) was also
achieved via the acid chlorides, which were converted to Weinreb
amides 13ꢀ15 before monoaddition of a lithiated alkyne. The
resulting ynone subunit (16ꢀ18) contains two groups which will
eventually mimic helix side chains and facilitate the elongation of
these i, i+4, i+7 R-helix mimetics.
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The two subunits were joined via a conjugate addition of an
aniline (10ꢀ12) to an ynone (16ꢀ18) (Scheme 4). A range of
solvents (including water, isopropanol, acetonitrile, dimethyl
sulfoxide, and dimethylformamide), additives (including K2CO3,
KHCO3, 1,4-diazabicyclo[2.2.2]octane, MgSO4, and silica gel),
and conditions (various temperatures using both conventional
heating and microwave irradiation for various periods of time)
were explored. The reported conditions were ultimately chosen
due to the rapid manner in which they could afford appreciable
amounts of product.
The final nitroenaminones (19ꢀ27) proved to be stable under
the reaction conditions. When the reactions were performed at
elevated temperatures in alcoholic solvent, the remaining ynone
was recovered as the enolone ether (37). Isolation of this
material and exposure to the aniline under the same conditions
led to the generation of more product, while the nitroenaminone
was unaffected after re-exposure to the original reaction condi-
tions (Scheme 5).
Reduction with Adams’ catalyst afforded the final aminoena-
minones (28ꢀ36). While these products proved to be acid-
sensitive, they could be purified by flash column chromatography
using untreated commercially available silica gel (or via HPLC).
These derivatives were characterized by NMR spectroscopy
and mass spectrometry. The structure-stabilizing intramolecular
hydrogen bond is evident in solution, as the NH proton of the
enaminone portion invariably displayed a chemical shift near 13
ppm in chlorinated solvents; non-hydrogen bonded protons of
similar nature have been observed in CDCl3 near 11.5 ppm.
Unchanging shifts of the enaminone NH proton during dilution
studies in CDCl3 over 3 orders of magnitude (1 mM to 100 mM)
and small upfield chemical shift during titration of d6-DMSO into
a 10 mM solution of nitroenaminone 23 in CDCl3 supported the
presence of an intramolecular hydrogen (Figure 4).
Additional evidence for the existence of this intramolecular
hydrogen bond in solution was provided by a variable tempera-
ture 1H NMR study performed in d6-DMSO. This investigation
showed the temperature-dependent coefficient (Δδ/ΔK) of the
enaminone proton to be ꢀ0.8 ppb/K, which compares favorably
to the result of a similar study on the benzoylureas (ꢀ2.9 ppb/K
for the hydrogen-bonded proton).19,20
A single-crystal of nitroenaminone 23 was obtained by slow
evaporation of CH2Cl2 at 4 °C, and a crystal structure was
subsequently obtained (Figure 5). This confirmed that the
hydrogen-bond-stabilized six-membered ring was intact in the
solid state; the interatomic distance between the ketone oxygen
and the aniline proton (1.88 Å) was significantly less than the
sum of their respective van der Waals radii (2.72 Å). Also
noteworthy is the presence of a hydrogen bond, with an
interatomic distance of 2.00 Å, between one of the NH protons
of the terminal amide and the oxygen of the alkoxy substituent
that is ortho to that amide.
Comparison to a crystal structure of a terphenyl species
showed the general size and shape of the enaminone portion
of the molecule to be a fine arene surrogate, and suggested that
the enaminone scaffold is indeed a viable one for helix mimicry.
The distances between the groups that serve as side chain mimics
for the i, i+4, and i+7 residues of a helix (5.45, 4.83, and 9.17 Å, as
depicted in Figure 5) are comparable to those of an idealized
Scheme 5. Conversion of Recovered Enolone Ether to the
Desired Nitroenaminonea
Scheme 3. Synthesis of Extending Monomer Unitsa
a a. oxalyl chloride, DMF, CH2Cl2; b. HNOCH3CH3 HCl, Et3N,
CH2Cl2; c. 4-methyl-1-propyne, nBuLi, THF.
3
a (R, R0 = Me, iPr, Bn) a. Δ, 10/11/12, MeOH; b. Δ, MeOH.
Scheme 4. Synthesis of Final Aminoenaminones 28ꢀ36a
a a. Δ, MeOH; b. PtO2, K2CO3, H2, MeOH.
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sequentially 1 mmol of 2-hydroxy-4-nitrobenzoic acid, 2.5 mL of N,N-
dimethylformamide, 2.5 mmol of K2CO3, and 2.5 mmol of the appro-
priate alkyl halide (1, methyl iodide; 2, 2-iodopropane; 3, benzyl
bromide). The vessel was then sealed and stirred at 80 °C for 16 h.
After being allowed to cool to room temperature, the mixture was
diluted with ethyl acetate and washed with distilled water twice followed
by an aqueous saturated sodium chloride solution. The organic layer was
dried over magnesium sulfate, filtered, and then concentrated. This
material was taken up in 1 mL tetrahydrofuran, to which was added 2 mL
of ethanol and 2 mL of a 45% aqueous NaOH solution. This mixture was
allowed to stir at 80 °C for 15 h. The resulting solution was allowed to
cool to ambient temperature and then diluted with distilled water and
washed twice with ethyl acetate. The aqueous solution was then acidified
using 1 M aqueous HCl and extracted twice with diethyl ether. The
combined organic layers were washed with an aqueous saturated sodium
chloride solution, dried over magnesium sulfate, filtered, and concen-
trated as pure product.
Figure 4. 1H NMR titration study data, performed on compound 23.
2-Methoxy-4-nitrobenzoic Acid (1) (88%). 1H NMR (500 MHz, d6-
DMSO) δ 13.36 (bs, 1H), 7.87ꢀ7.80 (m, 3H), 3.95 (s, 1H); 13C NMR
(125 MHz, d6-DMSO) δ 166.3, 157.9, 149.9, 130.9, 128.1, 115.1, 107.2,
56.5; HRMS (ESI) m/z calculated for C8H7NO5Na [NaM+] 220.0216,
found 220.0216.
1
2-Isopropoxy-4-nitrobenzoic Acid (2) (72%). H NMR (500 MHz,
d6-DMSO) δ 13.30 (bs, 1H), 7.85 (d, J = 2.0, 1H), 7.81 (dd, J = 2.0, 8.4,
1H), 7.76 (d, J = 8.4), 4.84 (septet, J = 6.0, 1H), 1.30 (d, J = 6.0, 6H); 13C
NMR (125 MHz, d6-DMSO) δ 166.6, 155.9, 149.7, 130.7, 129.7, 115.0,
109.4, 71.8, 21.6; HRMS (ESI) m/z calculated for C10H11NO5Na
[NaM+] 248.0529, found 248.0529.
2-(Benzyloxy)-4-nitrobenzoic Acid (3) (83%). 1H NMR (500 MHz,
d6-DMSO) δ 13.39 (bs, 1H), 7.97 (d, J = 1.8, 1H), 7.87 (dd, J = 1.9, 8.4,
1H), 7.84 (d, J = 8.4, 1H), 7.51 (d, J = 7.4, 2H), 7.41 (t, J = 7.5, 2H), 7.34
(t, J = 7.3, 1H), 5.35 (s, 2H); 13C NMR (125 MHz, d6-DMSO) δ 166.4,
156.8, 149.7, 136.2, 131.0, 128.6, 128.5, 128.0, 127.2, 115.4, 108.5, 70.3;
HRMS (ESI) m/z calculated for C14H11NO5Na [NaM+] 296.0529,
found 296.0527.
Figure 5. Crystal structure of nitroenaminone 23.
helix (6.21, 5.40, 10.15 Å) and a crystalographically analyzed
terphenyl compound (6.28, 5.10, and 8.83 Å).17
General Method for the Synthesis of Terminal Nitroa-
mides (7ꢀ9). To a flame-dried round-bottomed flask containing a
magnetic stirbar and under an atmosphere of argon was sequentially
added 1 mmol benzoic acid, 2 mL CH2Cl2, 2 mmol oxalyl chloride,
and 2 drops (∼100 μL) of N,N-dimethylformamide. This mixture
was stirred at ambient temperature for 1 h, upon which it was
concentrated. The resulting material was taken up in 10 mL CH2Cl2
and added slowly to a round-bottomed flask containing 15 mL
CH2Cl2 and 15 mL ammonium hydroxide stirring vigorously. The
mixture was diluted with CH2Cl2 and washed twice with distilled
water and once with an aqueous saturated sodium chloride solution,
then dried over magnesium sulfate. Filtration and concentration gave
pure products.
’ CONCLUSIONS
This paper describes the synthesis of a series of R-helix
mimetics based on the enaminone scaffold. The reported com-
pounds, which are assembled via a facile and mild conjugate
addition of an aniline to an ynone, are structurally reliant on
intramolecular hydrogen bonds. Work on assessing the biological
activity of helix mimics based on this scaffold is ongoing.
’ EXPERIMENTAL SECTION
1
General Notes. All air- and/or moisture-sensitive reactions were
carried out under a positive pressure of argon in flame-dried glassware.
Dichloromethane (DCM), tetrahydrofuran (THF), and dimethylforma-
mide (DMF) were obtained from commercial sources and dried on an
MB-SPS-800 dry solvent system. Column chromatography was per-
2-Methoxy-4-nitrobenzamide (7) (38%). H NMR (500 MHz, d6-
DMSO) δ 7.87ꢀ7.85 (m, 3H), 7.81 (s, 1H), 7.78 (s, 1H), 3.98 (s, 3H);
13C NMR (125 MHz, d6-DMSO) δ 165.4, 157.1, 149.4, 131.0, 130.3,
115.3, 106.9, 56.6; HRMS (EI) m/z calculated for C8H8N2O4Na
[NaM+] 219.0376, found 219.0375.
formed using silica gel (400ꢀ600 mesh). H and 13C NMR data were
2-Isopropoxy-4-nitrobenzamide (8) (90%). 1H NMR (500 MHz, d6-
DMSO) δ 7.87 (d, J = 8.4, 1H), 7.85 (d, J = 2.0, 1H), 7.82 (dd, J = 2.1,
8.4, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 4.89 (septet, J = 6.0, 1H), 1.35 (d, J =
6.1, 6H); 13C NMR (125 MHz, d6-DMSO) δ 165.5, 155.3, 149.4, 131.3,
131.0, 115.1, 108.9, 72.2, 21.4; HRMS (EI) m/z calculated for
C10H12N2O4Na [NaM+] 247.0689, found 247.0690.
1
1
recorded at 500 and 125 MHz, respectively, at room temperature. H
chemicalshiftsarereported relativetoresidualCHCl3 (δ7.24 ppmfor 1H,
δ 77.23 ppm for 13C), DMSO (δ 2.50, 39.52 ppm), or CH2Cl2 (δ 5.32,
53.80 ppm). Coupling constants (J) are reported in Hz. Purification by
reverse phase HPLC was performed using a dual λ UV detector (254 and
365 nm) with a binary pump using a 5 μ C18(2) 250 ꢁ 21.2 mm column
run at 10 mL/minute using gradient mixtures of water with 0.1% tri-
ethylamine and methanol with 0.1% triethylamine.
2-(Benzyloxy)-4-nitrobenzamide (9) (90%). 1H NMR (500 MHz, d6-
DMSO) δ 7.96 (d, J = 2.0, 1H), 7.88 (dd, J = 2.0, 8.4, 1H), 7.83 (d, J =
8.4, 1H), 7.81 (s, 1H), 7.79 (s, 1H), 7.53 (d, J = 7.2, 2H), 7.42 (t, J = 7.4,
2H), 7.36 (t, J = 7.3, 1H), 5.37 (s, 2H); 13C NMR (125 MHz, d6-
DMSO) δ 165.7, 155.9, 149.1, 136.0, 131.3, 130.8, 128.6, 128.2, 127.7,
General Method for the Synthesis of Alkoxybenzoic Acids
(1ꢀ3). To a pressure vessel containing a magnetic stirbar was added
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115.6, 108.1, 70.6; HRMS (EI) m/z calculated for C14H12N2O4Na
[NaM+] 295.0689, found 295.0690.
containing a magnetic stirbar was added 3 mL tetrahydrofuran and 1.05
mmol 4-methyl-1-propyne via syringe. While stirring, the solution was
cooled to ꢀ78 °C, at which time 0.72 mL of a 1.45 M solution of nBuLi
(1.05 mmol) was added dropwise via syringe. The solution was stirred at
ꢀ78 °C for 10 min, then the dry ice/acetone bath was removed and the
solution was stirred and allowed to warm for an additional 15 min. The flask
was then again cooled to ꢀ78 °C, and then 1 mmol of the Weinreb amide in
3 mL tetrahydrofuran was added to the mixture dropwise via syringe. The
solution was stirred at ꢀ78 °C for 15 min, at which point it was allowed
to return to ambient temperature over a period of 1 h while stirring
continued. The reaction was quenched by addition of a saturated
aqueous NaHCO3. This mixture was then extracted with ethyl acetate,
which was subsequently washed with aqueous saturated sodium chloride
solution and dried over magnesium sulfate. Filtration, concentration,
and flash column chromatography using 5:1 hexane/ethyl acetate as the
eluent afforded the desired ynone.
1-(2-Methoxy-4-nitrophenyl)-5-methylhex-2-yn-1-one (16) (76%).
1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 8.5, 1H), 7.84 (dd, J = 2.0,
8.5, 1H), 7.80 (d, J = 2.0, 1H), 3.99 (s, 3H), 2.36 (d, J = 6.5, 2H),
2.00ꢀ1.91 (m, 1H), 1.04 (d, J = 6.7, 6H); 13C NMR (125 MHz, CDCl3)
δ 175.9, 159.7, 151.3, 132.9, 132.2, 115.2, 107.4, 97.2, 82.7, 56.7, 28.6,
28.0, 22.3; HRMS (EI) m/z calculated for C14H15O4Na [NaM+]
284.0893, found 284.0894.
General Method for the Synthesis of Aminobenzamides
(10ꢀ12). To a round-bottomed flask containing a magnetic stirbar and
1 mmol of the nitrobenzamide was sequentially added 40 mg of K2CO3,
40 mg of PtO2, and 40 mL of methanol. The flask was sealed and flushed
with hydrogen three times using a balloon filled with hydrogen and a
vacuum. The mixture was then stirred vigorously under an atmosphere
of hydrogen for 45 min. Filtration through Celite and concentration
afforded the target aniline in quantitative yield.
4-Amino-2-methoxybenzamide (10). 1H NMR (500 MHz, d6-
DMSO) δ 7.62 (d, J = 8.5, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.22 (d,
J = 1.9, 1H), 6.18 (dd, J = 1.9, 8.5, 1H), 3.80 (s, 3H); 13C NMR (125
MHz, d6-DMSO) δ 166.2, 159.3, 153.5, 132.9, 108.7, 106.0, 95.9, 55.3;
HRMS (EI) m/z calculated for C8H10N2O2Na [NaM+] 189.0634,
found 189.0632.
1
4-Amino-2-isopropoxybenzamide (11). H NMR (500 MHz, d6-
DMSO) δ 7.64 (d, J = 8.5, 1H), 6.25 (d, J = 1.9, 1H), 6.17 (dd, J = 1.9,
8.5, 1H), 4.60 (septet, J = 6.0, 1H), 3.16 (s, 1H), 1.33 (d, J = 6.0, 6H);
13C NMR (125 MHz, d6-DMSO) δ 166.3, 157.4, 153.3, 132.9, 109.5,
106.2, 97.9, 70.6, 21.9; HRMS (EI) m/z calculated for C10H14N2O2Na
[NaM+] 217.0947, found 217.0944.
1
4-Amino-2-(benzyloxy)benzamide (12). H NMR (500 MHz, d6-
DMSO) δ 7.64 (d, J = 8.5, 1H), 7.49 (d, J = 7.1, 2H), 7.42 (dd, J = 7.1,
7.3, 2H), 7.37 (d, J = 7.3, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 6.32 (d, J = 1.9,
1H), 6.20 (dd, J = 1.9, 8.5, 1H), 5.14 (s, 2H); 13C NMR (125 MHz, d6-
DMSO) δ 166.2, 158.3, 153.4, 136.5, 132.9, 128.7, 128.2, 127.9, 109.0,
106.4, 97.1, 69.7; HRMS (EI) m/z calculated for C14H14N2O2Na
[NaM+] 265.0947, found 265.0946.
1-(2-Isopropoxy-4-nitrophenyl)-5-methylhex-2-yn-1-one (17) (74%).
1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 9.1, 1H), 7.78ꢀ7.75 (m, 2H),
4.73 (septet, J = 6.1, 1H), 2.32 (d, J = 6.6, 2H), 1.98ꢀ1.90 (m, 1H), 1.42
(d, J = 6.1, 6H), 1.01 (d, J = 6.7, 6H); 13C NMR (125 MHz, CDCl3) δ
176.4, 158.0, 151.1, 133.5, 132.4, 114.9, 109.2, 96.9, 83.0, 72.5, 28.7, 28.0,
22.4, 22.0; HRMS (EI) m/z calculated for C16H19NO4Na [NaM+]
312.1206, found 312.1204.
1-(2-(Benzyloxy)-4-nitrophenyl)-5-methylhex-2-yn-1-one (18) (77%).
1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.5, 1H), 7.85 (d, J = 2.0, 1H),
7.83 (dd, J = 2.0, 8.4, 1H), 7.48 (d, J = 7.4, 2H), 7.40ꢀ7.35 (m, 2H),
7.34ꢀ7.30 (m, 1H), 5.24 (s, 2H), 2.14 (d, J = 6.6, 2H), 1.83ꢀ1.75
(m, 1H), 0.93 (d, J = 6.7, 6H); 13C NMR (125 MHz, CDCl3) δ 175.8,
158.6, 151.1, 135.3, 132.7, 132.6, 128.9, 128.6, 127.6, 115.5, 108.6, 97.5,
82.8, 71.4, 28.4, 27.8, 22.2; HRMS (EI) m/z calculated for C20H19NO4Na
[NaM+] 360.1206, found 360.1207.
General Method for the Synthesis of Weinreb Amides
(13ꢀ15). To a flame-dried round-bottomed flask containing a mag-
netic stirbar and under an atmosphere of argon was sequentially added
1 mmol benzoic acid, 2 mL CH2Cl2, 2 mmol oxalyl chloride, and 2 drops
(∼100 μL) of N,N-dimethylformamide. This mixture was stirred at
ambient temperature for 1 h, upon which it was concentrated. The
resulting material was placed under an atmosphere of argon, and to
this was sequentially added 10 mL CH2Cl2, 3 mmol triethylamine, and
1.5 mmol N-methoxy-N-methylammonium chloride. The reaction was
allowed to stir at room temperature for 2.5 h, at which time it was
quenched with a saturated aqueous NaHCO3 solution. This was extracted
twice with diethyl ether. The combined organic layers were washed with
aqueous saturated sodium chloride solution and then dried over magne-
sium sulfate. Filtration and concentration afforded pure products.
General Method for the Synthesis of Nitroenaminones
(19ꢀ27). To a pressure vessel containing a stirbar was added 1 mmol of
the aminobenzamide, followed by 1 mmol of the ynone in 1 mL of
methanol. The vessel was sealed and then stirred at 120 °C for 3 h. After
cooling, the solution was directly purified using flash column chroma-
tography (2:1 ethyl acetate/hexane).
1
N,2-Dimethoxy-N-methyl-4-nitrobenzamide (13) (87%). H NMR
(500 MHz, d6-DMSO) δ 7.87 (d, J = 8.2, 1H), 7.85 (s, 1H), 7.55 (d, J =
8.2, 1H), 3.93 (s, 3H), 3.44 (s, 3H), 3.32 (s, 3H), 3.27 (s, 3H).; 13C
NMR (125 MHz, d6-DMSO) δ 166.2, 155.9, 148.8, 132.1, 127.9, 115.5,
106.3, 61.1, 56.4, 31.7; HRMS (ESI) m/z calculated for C10H12N2O5Na
[NaM+] 263.0638, found 263.0640.
(Z)-2-Methoxy-4-((1-(2-methoxy-4-nitrophenyl)-5-methyl-1-oxohex-
2-en-3-yl)amino)benzamide (19) (13%). 1H NMR (500 MHz, CDCl3)
δ 13.14 (s, 1H), 8.20 (d, J = 8.4, 1H), 7.86 (dd, J = 2.0, 8.4, 1H), 7.79 (d,
J = 2.0, 1H), 7.73 (d, J= 8.4, 1H),7.61(s, 1H), 6.90(d, J=8.4, 1H), 6.75(s,
1H), 5.81 (s, 1H), 3.97 (s, 3H), 3.97 (s, 3H), 2.38 (d, J = 7.2, 2H),
1.88ꢀ1.78 (m, 1H), 0.91 (d, J = 6.6, 6H);13C NMR (125 MHz, CDCl3) δ
187.8, 166.4, 165.3, 158.7, 157.6, 149.7, 143.4, 136.6, 133.9, 130.6, 118.3,
117.1, 116.0, 107.7, 106.8, 100.4, 56.54, 56.47, 41.7, 27.7, 22.6; HRMS (EI)
m/z calculated for C22H25N3O6Na [NaM+] 450.1636, found 450.1635.
(Z)-2-Isopropoxy-4-((1-(2-methoxy-4-nitrophenyl)-5-methyl-1-oxohex-
2-en-3-yl)amino)benzamide (20) (28%). 1H NMR (500 MHz, CD2Cl2)
δ 13.07 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4, 2.1 Hz, 1H),
7.81 (d, J = 2.1 Hz, 1H), 7.76ꢀ7.75 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H),
6.89 (dd, J = 8.4, 1.9 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 5.87 (s, 1H), 5.78
(s, 1H), 4.75 (septet, J = 6.1 Hz, 1H), 3.98 (s, 3H), 2.40 (d, J = 7.3 Hz,
2H), 1.89ꢀ1.78 (m, 1H), 1.45 (d, J = 6.1 Hz, 6H), 0.91 (d, J = 6.6 Hz,
6H); 13C NMR (125 MHz, CD2Cl2) δ 187.5, 166.3, 165.4, 157.8, 157.3,
149.8, 143.3, 136.9, 133.7, 130.8, 119.6, 117.5, 115.9, 110.5, 107.0, 100.3,
72.8, 56.6, 41.7, 27.9, 22.4, 22.2; HRMS (EI) m/z calculated for
C24H29N3O6Na [NaM+] 478.1949, found 478.1950.
2-Isopropoxy-N-methoxy-N-methyl-4-nitrobenzamide (14) (97%).
1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 1.9, 8.2, 1H), 7.73 (d, J =
1.9, 1H), 7.37 (d, J = 8.2, 1H), 4.66 (m, 1H), 3.43 (s, 3H), 3.34 (s, 3H),
1.35 (d, J = 5.9, 6H); 13C NMR (125 MHz, CDCl3) δ 167.9, 155.2,
149.4, 133.2, 128.1, 115.5, 108.3, 77.5, 72.2, 61.6, 32.5, 22.0; HRMS (EI)
m/z calculated for C12H16N2O5Na [NaM+] 291.0951, found 291.0952.
2-(Benzyloxy)-N-methoxy-N-methyl-4-nitrobenzamide (15) (90%).
1H NMR (500 MHz, d6-DMSO) δ 7.94 (s, 1H), 7.89 (d, J = 8.2, 1H),
7.60 (d, J = 8.2, 1H), 7.42 (m, 4H), 7.34 (t, J = 7.0, 1H), 5.33 (s, 2H),
3.45 (s, 3H), 3.33 (s, 3H); 13C NMR (125 MHz, d6-DMSO) δ 166.3,
154.9, 148.6, 136.1, 132.5, 128.5, 128.0, 127.2, 115.8, 107.6, 70.1, 61.3,
31.8; HRMS (EI) m/z Ccalculated for C16H16N2O5Na [NaM+]
339.0951, found 339.0952.
General Method for the Synthesis of Ynones (16ꢀ18). To a
flame-dried round-bottomed flask under an atmosphere of argon and
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ARTICLE
(Z)-2-(Benzyloxy)-4-((1-(2-methoxy-4-nitrophenyl)-5-methyl-1-ox-
1
(Z)-2-(Benzyloxy)-4-((1-(2-(benzyloxy)-4-nitrophenyl)-5-methyl-1-
oxohex-2-en-3-yl)amino)benzamide (27) (42%). 1H NMR (500 MHz,
CD2Cl2) δ 13.15 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.91ꢀ7.84 (m, 3H),
7.58 (s, 1H), 7.54ꢀ7.35 (m, 10H), 6.90 (dd, J = 8.4, 1.8 Hz, 1H), 6.85 (d,
J = 1.8 Hz, 1H), 6.01 (s, 1H), 5.80 (s, 1H), 5.24 (s, 2H), 5.22 (s, 2H),
2.22 (d, J = 7.4 Hz, 2H), 1.64ꢀ1.55 (m, 1H), 0.73 (d, J = 6.6 Hz, 6H);
13C NMR (125 MHz, CD2Cl2) δ 186.8, 166.0, 165.5, 158.0, 156.9,
149.8, 143.5, 136.7, 136.0, 135.8, 133.7, 131.3, 129.3, 129.08, 129.05,
128.8, 128.3, 128.1, 119.0, 117.8, 116.1, 109.7, 108.2, 100.5, 71.8, 71.7,
41.5, 27.9, 22.3; HRMS (EI) m/z calculated for C34H33N3O6Na
[NaM+] 602.2262, found 602.2260.
ohex-2-en-3-yl)amino)benzamide (21) (31%). H NMR (500 MHz,
CD2Cl2) δ 13.08 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.86 (dd, J = 8.4, 2.1
Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H),
7.50ꢀ7.37 (m, 5H), 6.94 (dd, J = 8.4, 1.7 Hz, 1H), 6.88 (d, J = 1.8 Hz,
1H), 5.87 (s, 1H), 5.70 (s, 1H), 5.23 (s, 2H), 3.97 (s, 3H), 2.34 (d, J = 7.3
Hz, 2H), 1.79 (m, 1H), 0.88 (d, J = 6.6 Hz, 6H); 13C NMR (125 MHz,
CD2Cl2) δ 187.6, 166.0, 165.3, 158.0, 157.8, 149.8, 143.5, 136.8, 135.8,
133.8, 130.8, 129.3, 129.1, 128.1, 118.9, 117.7, 115.9, 109.6, 107.0, 100.5,
71.8, 56.6, 41.7, 27.9, 22.4; HRMS (EI) m/z calculated for C28H29N3O6-
Na [NaM+] 526.1949, found 526.1942.
(Z)-4-((1-(2-Isopropoxy-4-nitrophenyl)-5-methyl-1-oxohex-2-en-3-
yl)amino)-2-methoxybenzamide (22) (46%). 1H NMR (500 MHz,
CDCl3) δ 13.14 (s, 1H), 8.20 (d, J = 8.4, 1H), 7.85ꢀ7.74 (m, 3H), 7.61
(s, 1H), 6.90 (d, J = 8.4, 1H), 6.74 (s, 1H), 5.97 (s, 1H), 5.81 (s, 1H),
4.78ꢀ4.68 (m, 1H), 3.97 (s, 3H), 2.38 (d, J = 7.2, 2H), 1.90ꢀ1.78
(m, 1H), 1.41 (d, J = 6.0, 6H), 0.91 (d, J = 6.6, 6H); 13C NMR (125
MHz, CDCl3) δ 187.7, 166.4, 164.6, 158.7, 155.9, 149.6, 143.6, 137.3,
133.9, 131.3, 118.2, 117.0, 115.6, 109.0, 107.6, 100.9, 77.5, 77.2, 77.0,
72.0, 56.5, 41.8, 27.7, 22.7, 22.1; HRMS (EI) m/z calculated for
C24H29N3O6Na [NaM+] 478.1949, found 478.1925.
(Z)-2-Isopropoxy-4-((1-(2-isopropoxy-4-nitrophenyl)-5-methyl-1-
oxohex-2-en-3-yl)amino)benzamide (23) (56%). 1H NMR (500 MHz,
CD2Cl2) δ 13.09 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.82ꢀ7.75 (m, 3H),
6.89 (dd, J = 8.4, 1.8 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 5.99 (s, 1H), 5.79
(s, 1H), 4.77 (septet, J = 6.0 Hz, 2H), 2.39 (d, J = 7.3 Hz, 2H), 1.85 (m,
1H), 1.45 (d, J = 6.1 Hz, 6H), 1.43 (d, J = 6.0 Hz, 6H), 0.91 (d, J = 6.6 Hz,
6H); 13C NMR (125 MHz, CD2Cl2) δ 187.6, 166.4, 165.0, 157.3, 156.1,
149.8, 143.5, 137.6, 133.7, 131.3, 119.5, 117.4, 115.5, 110.5, 109.1, 100.6,
72.8, 72.3, 41.8, 27.9, 22.5, 22.22, 22.00; HRMS (EI) m/z calculated for
C26H33N3O6Na [NaM+] 506.2262, found 506.2239.
General Method for the Synthesis of Aminoenaminones
(28ꢀ36). To a round-bottomed flask containing a magnetic stirbar and 1
mmol of the nitroenaminone was sequentially added 40 mg of K2CO3, 40
mg of PtO2, and 40 mL of methanol. The flask was sealed and flushed with
hydrogen three times using a balloon filled with hydrogen and a vacuum.
The mixture was then stirred vigorously under an atmosphere of hydrogen
for 45 min. After filtration through Celite and concentration, the crude
product mixture was taken up in a small amount of methanol and purified
via reverse-phase HPLC, and product was obtained in quantitative yield.
(Z)-4-((1-(4-Amino-2-methoxyphenyl)-5-methyl-1-oxohex-2-en-3-
yl)amino)-2-methoxybenzamide (28). 1H NMR (500 MHz, CD2Cl2)
δ 13.14 (s, 1H), 8.09 (d, J = 8.4, 1H), 7.60 (d, J = 8.3, 1H), 7.59ꢀ7.54
(m, 1H), 6.86 (d, J = 8.5, 1H), 6.75 (s, 1H), 6.29 (d, J = 8.4, 1H), 6.23 (s,
1H), 6.11 (s, 1H), 5.73ꢀ5.64 (m, 1H), 4.05 (s, 2H), 3.97 (s, 3H), 3.84
(s, 3H), 2.42 (d, J = 7.2, 2H), 1.89ꢀ1.78 (m, 1H), 0.92 (d, J = 6.6, 6H);
13C NMR (125 MHz, CD2Cl2) δ 188.9, 166.3, 161.6, 160.1, 159.0,
151.3, 144.9, 133.5, 132.6, 120.6, 117.0, 116.1, 107.2, 106.9, 101.6, 97.8,
56.5, 55.8, 42.2, 27.6, 22.5; HRMS (EI) m/z calculated for C22H27N3O4-
Na [NaM+] 420.1894, found 420.1893.
(Z)-4-((1-(4-Amino-2-methoxyphenyl)-5-methyl-1-oxohex-2-en-3-
yl)amino)-2-isopropoxybenzamide (29). 1H NMR (500 MHz,
CD2Cl2) δ 13.09 (s, 1H), 8.10 (d, J = 8.5, 1H), 7.76 (bs, 1H), 7.60
(d, J = 8.3, 1H), 6.83 (d, J = 8.5, 1H), 6.75 (s, 1H), 6.29 (d, J = 8.4, 1H),
6.23 (s, 1H), 6.09 (s, 1H), 5.67 (bs, 1H), 4.80ꢀ4.69 (m, 1H), 4.04 (s,
2H), 3.84 (s, 3H), 2.40 (d, J = 7.3, 2H), 1.87ꢀ 1.78 (m, 1H), 1.44 (d, J =
6.1, 6H), 0.91 (d, J = 6.6, 6H); 13C NMR (125 MHz, CD2Cl2) δ 188.8,
166.6, 161.8, 160.1, 157.3, 151.3, 144.7, 133.6, 132.6, 120.6, 118.2, 116.4,
109.4, 107.1, 101.3, 97.8, 72.6, 55.8, 42.2, 27.6, 22.5, 22.3; HRMS (EI)
m/z calculated for C24H31N3O4Na [NaM+] 448.2207, found 448.2208.
(Z)-4-((1-(4-Amino-2-methoxyphenyl)-5-methyl-1-oxohex-2-en-3-
yl)amino)-2-(benzyloxy)benzamide (30). 1H NMR (500 MHz, CD2Cl2)
δ 13.12 (s, 1H), 8.12 (d, J = 8.5, 1H), 7.61 (d, J = 8.4, 1H), 7.57 (bs, 1H),
7.47 (d, J= 7.2, 2H), 7.43 (t, J= 7.2, 2H), 7.40 (d, J= 7.1, 1H), 6.88 (dd, J=
2.0, 8.5, 1H), 6.83 (d, J = 2.0, 1H), 6.29 (dd, J = 2.1, 8.4, 1H), 6.22 (d, J =
2.0, 1H), 6.10 (s, 1H), 5.63 (bs, 1H), 5.21 (s, 2H), 3.84 (s, 3H), 2.36 (d,
J = 7.2, 2H), 1.87ꢀ1.72 (m, 1H), 0.89 (d, J = 6.6, 6H); 13C NMR (125
MHz, CD2Cl2) δ 188.9, 166.3, 161.7, 160.1, 158.1, 151.4, 144.8, 136.0,
133.6, 132.6, 129.3, 129.0, 128.2, 120.6, 117.5, 116.5, 108.3, 107.1, 101.5,
97.8, 71.8, 55.8, 42.1, 27.6, 22.5; HRMS (EI) m/z calculated for
C28H31N3O4Na [NaM+] 496.2207, found 496.2206.
(Z)-4-((1-(4-Amino-2-isopropoxyphenyl)-5-methyl-1-oxohex-2-en-
3-yl)amino)-2-methoxybenzamide (31). 1H NMR (500 MHz, CD2Cl2)
δ13.16 (s, 1H), 8.09 (d, J=8.5,1H),7.64(d,J= 8.4, 1H), 7.58 (bs, 1H), 6.86
(dd, J = 1.9, 8.5, 1H), 6.75 (d, J = 1.9, 1H), 6.28 (dd, J = 2.3, 8.2, 1H), 6.27 (s,
1H), 6.21 (d, J = 2.0, 1H), 5.74 (s, 1H), 4.59 (septet, J = 6.0, 1H), 4.02 (s,
2H), 3.97 (s, 3H), 2.42 (d, J = 7.2, 2H), 1.91ꢀ1.79 (m, 1H), 1.62 (s, 1H),
1.38 (d, J = 6.0, 6H), 0.92 (d, J = 6.6, 6H).;13C NMR (125 MHz, CD2Cl2) δ
188.9, 166.4, 161.3, 159.0, 158.4, 151.2, 145.0, 133.5, 132.9, 121.4, 117.0,
116.0, 107.4, 106.9, 101.9, 100.1, 71.1, 56.5, 42.4, 27.5, 22.6, 22.3; HRMS (EI)
m/z calculated for C24H31N3O4Na [NaM+] 448.2207, found 448.2208.
(Z)-4-((1-(4-Amino-2-isopropoxyphenyl)-5-methyl-1-oxohex-2-en-
3-yl)amino)-2-isopropoxybenzamide (32). 1H NMR (500 MHz,
CD2Cl2) δ 13.12 (s, 1H), 8.10 (d, J = 8.5, 1H), 7.77 (bs, 1H), 7.64 (d,
(Z)-2-(Benzyloxy)-4-((1-(2-isopropoxy-4-nitrophenyl)-5-methyl-1-
oxohex-2-en-3-yl)amino)benzamide (24) (54%). 1H NMR (500 MHz,
CD2Cl2) δ 13.10 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.82ꢀ7.78 (m, 2H),
7.60 (s, 1H), 7.50ꢀ7.36 (m, 5H), 7.33 (s, 1H), 6.93 (dd, J = 8.4, 1.8 Hz,
1H), 6.88 (d, J = 1.8 Hz, 1H), 5.99 (s, 1H), 5.85 (s, 1H), 5.23 (s, 2H),
4.77 (septet, J = 6.1 Hz, 1H), 2.33 (d, J = 7.3 Hz, 2H), 1.86ꢀ1.76 (m,
1H), 1.43 (d, J = 6.1 Hz, 6H), 0.88 (d, J = 6.6 Hz, 6H).; 13C NMR (125
MHz, CD2Cl2) δ 187.7, 166.1, 164.9, 158.0, 156.1, 149.8, 143.6, 137.5,
135.8, 133.7, 131.3, 129.3, 129.1, 128.1, 118.9, 117.6, 115.5, 109.5, 109.1,
100.8, 72.3, 71.8, 41.8, 27.8, 22.5, 22.0; HRMS (EI) m/z calculated for
C30H33N3O6Na [NaM+] 554.2262, found 554.2236.
(Z)-4-((1-(2-(Benzyloxy)-4-nitrophenyl)-5-methyl-1-oxohex-2-en-
1
3-yl)amino)-2-methoxybenzamide (25) (13%). H NMR (500 MHz,
CD2Cl2) δ 13.17 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.92ꢀ7.86 (m, 2H),
7.58 (s, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.45ꢀ7.34 (m, 3H), 6.89 (dd, J =
8.4, 1.8 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.01 (s, 1H), 5.24 (s, 1H), 3.97
(s, 3H), 2.30 (d, J = 7.3 Hz, 2H), 1.71ꢀ1.58 (m, 1H), 0.77 (d, J = 6.6 Hz,
6H); 13C NMR (125 MHz, CD2Cl2) δ 186.9, 166.1, 165.5, 158.9, 156.9,
149.8, 143.6, 136.7, 136.0, 133.6, 131.3, 129.1, 128.8, 128.4, 118.5, 117.4,
116.1, 108.2, 108.2, 100.6, 71.7, 56.6, 41.6, 27.8, 22.3; HRMS (EI) m/z
calculated for C28H29N3O6Na [NaM+] 526.1949, found 526.1949.
(Z)-4-((1-(2-(Benzyloxy)-4-nitrophenyl)-5-methyl-1-oxohex-2-
1
en-3-yl)amino)-2-isopropoxybenzamide (26) (31%). H NMR (500
MHz, CD2Cl2) δ 13.14 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.92ꢀ7.85 (m,
3H), 7.76 (s, 1H), 7.51 (d, J = 7.3 Hz, 2H), 7.46ꢀ7.35 (m, 3H), 6.86 (dd,
J = 8.4, 1.8 Hz, 1H), 6.78 (d, J = 1.8 Hz, 1H), 6.01 (s, 1H), 5.85 (s, 1H),
5.24 (s, 2H), 4.74 (septet, J = 6.1 Hz, 1H), 2.28 (d, J = 7.4 Hz, 2H),
1.68ꢀ1.59 (m, 1H), 1.44 (d, J = 6.1 Hz, 6H), 0.76 (d, J = 6.6 Hz, 6H);
13C NMR (125 MHz, CD2Cl2) δ 186.8, 166.4, 165.6, 157.2, 156.9,
149.7, 143.3, 136.7, 136.0, 133.7, 131.3, 129.1, 128.8, 128.3, 119.6, 117.5,
116.1, 110.6, 108.2, 100.4, 72.8, 71.7, 41.6, 27.9, 22.3, 22.2; HRMS
(EI) m/z calculated for C30H33N3O6Na [NaM+] 554.2262, found
554.2263.
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ARTICLE
J = 8.4, 1H), 6.84 (dd, J = 1.9, 8.5, 1H), 6.75 (d, J = 1.8, 1H), 6.28 (dd, J =
2.1, 8.4, 1H), 6.26 (s, 1H), 6.21 (d, J = 2.0, 1H), 5.77 (s, 1H), 4.75 (septet,
J = 6.1, 1H), 4.59 (septet, J = 6.0, 1H), 4.02 (bs, 2H), 2.40 (d, J = 7.3, 2H),
1.90ꢀ1.78 (m, 1H), 1.63 (s, 1H), 1.44 (d, J = 6.1, 6H), 1.38 (d, J = 6.0,
6H), 0.91 (d, J = 6.6, 6H); 13C NMR (125 MHz, CD2Cl2) δ 188.9, 166.6,
161.5, 158.4, 157.3, 151.2, 144.7, 133.5, 132.9, 121.5, 118.1, 116.4, 109.3,
107.4, 101.6, 100.1, 72.6, 71.1, 42.3, 27.6, 22.6, 22.32, 22.25; HRMS (EI)
m/z calculated for C26H35N3O4Na [NaM+] 476.2520, found 476.2519.
(Z)-4-((1-(4-Amino-2-isopropoxyphenyl)-5-methyl-1-oxohex-2-en-
3-yl)amino)-2-(benzyloxy)benzamide (33). 1H NMR (500 MHz,
CD2Cl2) δ 13.14 (s, 1H), 8.12 (d, J = 8.5, 1H), 7.64 (d, J = 8.4, 1H),
7.58 (bs, 1H), 7.49ꢀ7.37 (m, 5H), 6.88 (dd, J = 1.9, 8.5, 1H), 6.82 (d, J =
1.8, 1H), 6.29ꢀ6.26 (m, 2H), 6.21 (d, J = 2.0, 1H), 5.66 (bs, 1H), 5.21
(s, 2H), 4.59 (septet, J = 6.1, 1H), 4.01 (bs, 2H), 2.35 (d, J = 7.2, 2H),
1.87ꢀ1.76 (m, 1H), 1.38 (d, J = 6.0, 6H), 0.89 (d, J = 6.6, 6H); 13C NMR
(125 MHz, CD2Cl2) δ 188.9, 166.3, 161.4, 158.4, 158.1, 151.2, 144.9,
136.0, 133.6, 132.9, 129.3, 129.0, 128.2, 121.4, 117.4, 116.5, 108.3, 107.4,
101.9, 100.1, 71.8, 71.1, 42.3, 27.6, 22.6, 22.3; HRMS (EI) m/z
calculated for C30H35N3O4Na [NaM+] 524.2520, found 524.2522.
(Z)-4-((1-(4-Amino-2-(benzyloxy)phenyl)-5-methyl-1-oxohex-2-en-
3-yl)amino)-2-methoxybenzamide (34). 1H NMR (500 MHz,
CD2Cl2) δ 13.17 (s, 3H), 8.07 (d, J = 8.5, 1H), 7.71 (d, J = 8.3, 1H),
7.57 (bs, 1H), 7.50 (d, J = 7.2, 2H), 7.41 (t, J = 7.3, 2H), 7.37 (d, J = 7.3,
1H), 6.82 (dd, J = 2.0, 8.5, 1H), 6.72 (d, J = 2.0, 1H), 6.33 (dd, J = 2.0, 8.3,
1H), 6.31 (d, J = 2.0, 1H), 6.23 (s, 1H), 5.65 (bs, 1H), 5.09 (s, 2H), 4.06
(bs, 2H), 3.95 (s, 3H), 2.25 (d, J = 7.3, 2H), 1.63ꢀ1.54 (m, 1H), 0.74 (d,
J = 6.6, 6H); 13C NMR (125 MHz, CD2Cl2) δ 188.2, 166.3, 161.9, 159.4,
158.9, 151.4, 144.9, 137.1, 133.5, 133.0, 128.9, 128.5, 128.4, 120.4, 117.0,
116.2, 107.6, 107.0, 101.6, 98.9, 71.0, 56.5, 42.0, 27.5, 22.3; HRMS (EI)
m/z calculated for C28H31N3O4Na [NaM+] 496.2207, found 496.2209.
(Z)-4-((1-(4-Amino-2-(benzyloxy)phenyl)-5-methyl-1-oxohex-2-en-
3-yl)amino)-2-isopropoxybenzamide (35). 1H NMR (500 MHz,
CD2Cl2) δ 13.13 (s, 1H), 8.08 (d, J = 8.5, 1H), 7.75 (bs, 1H), 7.71
(d, J = 8.3, 1H), 7.50 (d, J = 7.2, 1H), 7.41 (t, J = 7.3, 1H), 7.37 (d, J = 7.3,
1H), 6.80 (dd, J = 2.0, 8.5, 1H), 6.72 (d, J = 2.0, 1H), 6.33 (dd, J = 2.0,
8.3, 1H), 6.31 (d, J = 2.0, 1H), 6.22 (s, 1H), 5.65 (bs, 1H), 5.09 (s, 2H),
4.72 (septet, J = 6.0, 1H), 4.06 (bs, 2H), 2.23 (d, J = 7.4, 2H), 1.62ꢀ1.52
(m, 1H), 1.42 (d, J = 6.1, 6H), 0.73 (d, J = 6.6, 6H); 13C NMR (125
MHz, CD2Cl2) δ 188.2, 166.6, 162.1, 159.4, 157.3, 151.3, 144.6, 137.1,
133.5, 132.9, 128.9, 128.5, 128.4, 120.4, 118.2, 116.5, 109.5, 107.6, 101.3,
98.9, 72.6, 71.0, 41.9, 27.5, 22.3, 22.2; HRMS (EI) m/z calculated for
C30H34N3O4 [(M-H)ꢀ] 500.2555, found 500.2552.
VT-NMR Experiment. A 10 mM solution of 23 in d6-DMSO was
prepared and loaded into an NMR tube. The 1H NMR spectrum at 10 K
intervals (from 300 to 380 K) was acquired. The chemical shift of the
enaminone NH proton at each 10 K interval was recorded and plotted.
The slope of the plot of ppm vs T gave the temperature-dependent
coefficient (Δδ/ΔK) of the enaminone NH proton (ꢀ0.8 ppb/K).
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR Spectra for
S
b
Compounds 1ꢀ3 and 7ꢀ36. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Email: andrew.hamilton@chem.ox.ac.uk.
’ ACKNOWLEDGMENT
The National Science Foundation (CHE-0750357) and the
University of Oxford are thanked for their financial support of
this work. The authors thank the following people for their
contribution in the noted areas: Richard T. W. Scott (X-ray
crystalography); University of Oxford NMR and Mass Spectro-
metry Research Facilities personnel (NMR and HRMS); Ian
Jones, Dr. Andrew Jamieson, and Dr. Sam Thompson (helpful
discussions).
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Titration Experiment. Ten NMR tubes were each charged with 1 mL
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