Predicting hydration propensities of biologically relevant α-ketoamides

Article abstract of DOI:10.1016/j.bmcl.2015.08.010

Quantum chemical calculations coupled to experiments were used to predict covalent hydration propensities of biologically relevant α-ketoamides. Experimentally determined hydration equilibrium constants for related ketones and aldehydes were compared to c

Full text of DOI:10.1016/j.bmcl.2015.08.010

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4153–4157
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Predicting hydration propensities of biologically relevant
a-ketoamides
Henry B. Wedler a, Teresa A. Palazzo a, Ryan P. Pemberton a, Christian S. Hamann b, Mark J. Kurth a,
Dean J. Tantillo a,
⇑
a Department of Chemistry, University of California, Davis, 1 Shields Avenue, Davis, CA 95616, USA
b Department of Chemistry & Biochemistry, Albright College, Reading, PA 19604, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Quantum chemical calculations coupled to experiments were used to predict covalent hydration propen-
Received 28 May 2015
Revised 1 August 2015
Accepted 6 August 2015
Available online 12 August 2015
sities of biologically relevant a-ketoamides. Experimentally determined hydration equilibrium constants
for related ketones and aldehydes were compared to computationally determined values to develop a
method for predicting hydration equilibrium constants. This method was used on six newly synthesized
a
-ketoamides to experimentally verify computational predictions. A correlation between calculation and
experiment was observed and applied to models of several pertinent APIs. Our results indicate that the
keto form is favored for practically all -ketoamides in biological environs.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
a
a-Ketoamide
Hydration propensity
Density functional theory
Predictive methods
Theory versus experiment
The
a
-ketoamide (oxo-amide, AKA) functional group is present
volumes. Boceprevir, for example, can covalently bind to its target
via nucleophilic attack of a serine residue onto the keto carbon
(Fig. 2).2 The ease of this reaction and the stability of the resulting
enzyme-inhibitor complex will be modulated by the inherent ten-
dency of the AKA to be hydrated, among other factors.10,11 Indeed,
the hemiketal enzyme-inhibitor covalent complex is stabilized rel-
ative to the non-covalent keto form via the His57 hydrogen bond
contact.
In the study described herein, quantum chemical calculations
paired with experiment were used to evaluate covalent hydration
propensities (lnKhyd; Scheme 1) for a wide range of AKAs. From
these studies, a facile method to predict whether a given AKA will
be predominantly hydrated in water was developed. To the best of
our knowledge, there is no experimental hydration propensity data
available for AKAs. Thus, to calibrate the computational approach
used herein,12 hydration energies and associated equilibrium con-
stants were calculated for eight ketones and aldehydes whose
hydration equilibrium constants were previously measured
(Scheme 1, Eq. 2; Table 1).13–15 The hydration equilibrium con-
stants for these eight compounds were experimentally re-deter-
mined, all with the same NMR method (vide infra) for
consistency. Correlation of these experimentally determined val-
ues to our computed hydration propensities verified the validity
of our computational method. Using this method, a simple correla-
tion equation describing the relationship of experimental and
in a variety of pharmaceutically relevant molecules. For example,
drug molecules with AKA functionality have been engineered to
act as substrate analogs for secretory phospholipase A21 and
NS3.4 serine protease.2,3 Tacrolimus (FK-506; Fig. 1) is used to treat
eczema4 and as an immunosuppressant to lower the risk of organ
transplant rejection.5 Varespladib (Fig. 1) is an anti inflammatory
agent.1 The didemnidines A and B6 and leptoclinidamines A–C7
are alkaloids that also possess an AKA attached to an indole.
Boceprevir2 and telaprevir3 (Fig. 1) are protease inhibitors used
to treat hepatitis C. While the AKA subunit is conserved in all of
these compounds, its pendant groups vary widely. Although the
AKA functional group is used regularly in developing bioactive
compounds, it is often unclear whether the keto carbon will be free
or covalently bound. In biologically relevant environments, these
species can be bound either by water (to form a geminal diol;
Scheme 1, Eq. 1)8 or by a nucleophilic protein residue (to form a
hemiketal).9 The pharmacophore of a drug molecule will be dis-
tinctly different depending on the preferred form—keto or
hydrate/hemiketal—of the AKA subunit. These subunits will dis-
play different hydrogen-bonding patterns and will occupy different
Abbreviations: AKA,
experimental; pred., predicted; iHB, intramolecular hydrogen bond.
a-ketoamide; eq., equilibrium; hyd, hydration; exp.,
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2015.08.010
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

4154
H. B. Wedler et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4153–4157
Figure 2. Boceprevir-protease co-crystal structure (PDB ID 3LOX) showing the
covalent linkage between the AKA moiety and a nucleophilic serine residue.
Table 1
Literature, newly measured, and predicted (Eq. 5) lnKhyd values for select ketones and
aldehydes13,16,30,32–40
Structure
lnKhyd,lit.
ꢀ10.6
lnKhyd,exp.
ꢀ6.97
lnKhyd,pred.
ꢀ4.9
O
1
2
O
O
ꢀ8.8
ꢀ4.87
ꢀ5.0
H
Figure 1. Four pharmaceuticals containing AKA groups (highlighted in red).
ꢀ0.486
ꢀ0.162
ꢀ1.31
ꢀ2.6
H
O
3
4
ꢀ0.163
0.7
Cl
Cl
Cl
O
0.0582
0.262
ꢀ2.0
Cl
O
5
6
7
1.06
2.3
ꢀ0.371
ꢀ0.693
ꢀ1.6
H
O
4.0
Scheme 1. Representative hydration equilibria.
H
O
F
F
computed results was developed for the rapid prediction of hydra-
tion propensities of AKAs. Bartberger et al., as well as Gómez-Bom-
barelli and coworkers previously reported computational versus
literature experimental correlation data for a broad range of car-
bonyl compounds and their hydrates.16,17 Our approach has the
advantage of employing a systematic conformational search to
identify the lowest energy conformers of both keto and hydrate
forms and of using a set of experimental values all determined
with the same technique. Our approach for determination of
hydration propensities is based on thermodynamic methods,
although kinetic methodology can also be applied.18–20
10.3
8.52
5.9
H
F
8
electronic energies (E). The sum of the energies of water and the
keto form was subtracted from the energy of the geminal diol form,
yielding a
DErxn (Eq. 3). Correlations based on DGrxn were found to
be less reliable.29 Reaction energies were then converted to calcu-
lated equilibrium constants (Eq. 4) in which R is the ideal gas con-
stant and T is the temperature in Kelvin (298 K was used here;
results in Table 2).
Spartan1021 was used to perform conformational searches on all
structures using the Merck Molecular Force Field (MMFF94),22 and
using the default torsional settings. All conformers were then opti-
mized as minima using Gaussian09,23 with the B3LYP/6-31+G(d,p)
level of theory,24–27 in water employing the SMD polarizable con-
tinuum model.12,15,16,28
D
Erxn ¼ Ehydrate ꢀ ðEketo þ Ewater
Þ
ð3Þ
ln Khyd;calcd ¼ ꢀ rxn=RT
Hydration equilibrium data for aldehydes and ketones provided
a starting point from which a correlation between experiment and
theory was developed. Intending to measure hydration equilibrium
D
E
ð4Þ
The lowest-energy conformers were used to calculate hydration
propensities using zero-point energy (unscaled) corrected

H. B. Wedler et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4153–4157
4155
The Hine method uses NMR population analysis of 13C satellite
peaks of the major species in solution relative to the minor species
to determine Khyd for equilibria with relatively small Keq. values
(for additional experimental details see Supporting information).
A reasonable correlation was observed between our experimen-
tally determined data and calculated equilibrium constants
(R2 = 0.9, Fig. 3). The absolute values of our experimentally deter-
mined hydration propensities are similar but not identical to those
found in the literature; note, however, that our values were all
measured using a single method. In the case of acetone, an exper-
imental versus literature difference of a factor of approximately 40
is observed. While this is a substantial difference, it is likely due to
differences in the specific manner in which NMR spectra were
obtained (temperature, instrument, etc.); the value reported herein
is reproducible and obtained with the same method as were the
other values we report. The correlation equation derived from
our calculated and measured values is:
Table 2
Computationally determined
AKAs
DErxn, and calculated and correlated lnKhyd,pred. of select
Structure
D
E reaction
lnKhyd,calcd.
lnKhyd,pred.
(kcal/mol)
9 (NO2)
10 (CN)
11 (CF3)
12 (H)
13 (CH3)
14 (NH2)
4.56
ꢀ1.32
5.65
3.70
4.40
7.50
ꢀ7.70
2.23
ꢀ9.54
ꢀ6.22
ꢀ7.49
ꢀ12.7
ꢀ4.43
ꢀ3.92
ꢀ5.84
ꢀ5.30
ꢀ5.51
ꢀ6.36
O
3.88
3.75
2.85
1.60
0.76
ꢀ0.48
ꢀ6.55
ꢀ6.33
ꢀ4.81
ꢀ2.71
ꢀ1.28
ꢀ0.81
ꢀ5.35
ꢀ5.32
ꢀ5.07
ꢀ4.72
ꢀ4.49
ꢀ4.15
N
H
NH2
O
15
16
17
18
19
20
O
NH2
O
O
ln Khyd;pred: ¼ ðln Khyd;calcd: ꢀ 0:85Þ=1:56
ð5Þ
O
NH2
N
Since experimental hydration data for AKAs were not available,
several were targeted for synthesis. After being deemed syntheti-
cally accessible, compounds 9–14 (Scheme 2) were analyzed com-
putationally using the same approach described above for ketones
and aldehydes.
Syntheses of 9–13 were carried out successfully (with yields
similar to those reported) using the method described by Du and
Ji.41,47 Reduction of 9 to 14 was carried out using Fe0 powder and
acetic acid.42 Hydration equilibria for these AKAs were determined
using NMR population analysis via the Hine method.30 A reason-
able correlation was observed (Fig. 4, R2 = 0.79).
O
O
O
O
O
O
N
OH
NH2
NH2
O
The lower R2 value for the AKA series than for the aldehyde/
ketone series is likely due to the smaller range of experimental
lnKhyd values sampled (due to lack of synthetic accessibility). Our
findings are consistent with hydration propensity being directly
related to the electronic and steric properties of substituents in
proximity to the AKA moiety.43,44 Compound 14 (X = NH2) was
not included in the correlation because it displays a hydration
propensity so low as to be difficult to measure, leading to signifi-
cant experimental error.
During the course of our analysis it was observed that the
hydrate forms of 9–14 have a defined conformational preference
that has a direct impact on their calculated energies. The lowest
energy structures consistently contained an intramolecular hydro-
gen bond (iHB) between one of the hydroxyl groups of the geminal
diol and the carbonyl oxygen of the amide. In contrast, other
geometries among the set of energetically relevant conformations
containing this iHB (e.g., chair flips of a piperidinyl moiety) had
O
ꢀ0.73
1.22
ꢀ4.08
O
N
H
21
22
23
24
25
O
O
H
N
NH2
ꢀ1.85
ꢀ2.12
ꢀ3.32
ꢀ5.58
3.12
3.58
5.61
9.42
ꢀ3.77
ꢀ3.70
ꢀ3.36
ꢀ2.74
O
O
O
H
N
NH2
O
F
NH2
O
O
O
F
F
N
F
OH
O
Exp/Lit vs Calc
20
O
N
ꢀ6.79
11.46
ꢀ2.41
O
y = 1.56x + 0.85
R² = 0.90
15
10
5
26
27
28
O
NH2
ꢀ8.44
ꢀ9.27
14.25
15.65
ꢀ1.95
ꢀ1.72
F
F
O
O
0
F
NH2
-15
-10
-5
0
5
10
lnK (Exp/Lit)
y = 1.17x + 0.21
R² = 0.87
15
-5
F
O
-10
-15
constants for several AKAs (vide infra) using the method described
by Hine,30 we first tested the method using commercially available
aldehydes and ketones (Table 1).31
Figure 3. Correlation between aldehydes and ketones 1–8: lnKhyd,lit. versus
lnKhyd,calcd (green) and Khyd,exp. versus lnKhyd,calcd (black). Computed equilibrium
constants were obtained with SMD(water)-B3LYP/6-31+G(d,p).

4156
H. B. Wedler et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4153–4157
to minimize computational demands (Table 2; see also Supporting
information). When Eq. 6 is applied to these model compounds, we
predict that all four drugs will exist essentially exclusively in their
keto form in water or highly aqueous tissues. Of course, the inher-
ent reactivity of a molecule is only the beginning of the story.46
Within the active site of an enzyme the hydration propensities of
these species may differ greatly, but the strength of binding of an
AKA drug to its target will depend on the preferred hydration state
in solution.
A method for predicting hydration propensities (lnKhyd) of AKAs
using straightforward quantum chemical techniques was devel-
oped and validated via NMR population analysis. As AKA subunits
are found in a variety of drugs and drug candidates, the method
described herein is relevant to the design of new medicinal com-
pounds and the interpretation of their mode of action. We predict
that the keto forms of these species predominate in aqueous solu-
O
O
CuI
O2 (balloon)
N
O
Piperidine
Toluene
X
X
9-13
X=NO2 (92%), CN (94%),
CF3 (74%), H (32%),
CH3 (25%)
X=NO2 (9), CN (10),
CF3 (11), H (12),
CH3 (13)
O
O
Fe0
AcOH, 50oC
96%
N
N
O
O
H2N
14
O2N
9
tion, even in the case of AKAs with electron deficient a-carbonyls.
This prediction is directly relevant to drug–receptor binding. For
example, delivery of the keto form of boceprevir to its target is a
requirement for nucleophilic attack by the active-site serine
(Fig. 2). Corresponding hydrates would require dehydration either
before or during nucleophilic attack. Controlling hydration propen-
sity by design also may address other ADME considerations, and
foreknowledge of hydration propensity may also aid in the inter-
pretation of results from the various in vitro and in vivo pre-clini-
cal assays required during drug development.
Scheme 2. Synthesis of AKAs 9–14.
little effect on the calculated energies. It was also observed that the
lowest energy conformers of hydrated b-fluorinated compounds
had an additional weak hydrogen bond between fluorine and the
other hydroxyl group of the geminal diol. Tayyari and coworkers
also have shown that conformational searching of related hydrated
carbonyl compounds is essential in predicting low energy confor-
mations that capitalize on this iHB.45 Thus, if computational
resources are limited, users employing the method described
herein may reasonably begin by using only a structure containing
these iHBs.
Our results indicate that the SMD(water)-B3LYP/6-31+G(d,p)
level of theory is a reasonable method for rapidly predicting hydra-
tion propensities of AKAs. Bartberger et al. also used this method
for other carbonyl compounds.16 Equilibrium constants computed
at this level of theory (Khyd,calcd) can be converted to predicted val-
ues (Khyd,pred.) using the following correlation equation (Eq. 6,
derived from data in Fig. 4):
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2015.08.
010.
References and notes
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ln Khyd;pred: ¼ ðln Khyd;calcd ꢀ 1:07Þ=2:69
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ð6Þ
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AKA exp vs calc
0
-6
-5.5
-5
-4.5
-4
-3.5
-3
-5
-10
-15
p-NO2
p-CF3
p-H
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p-CH3
p-NH2
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R² = 0.79
-20
-25
lnK (exp)
Figure 4. Correlation between lnKhyd,calcd and lnKhyd,exp. for AKAs 9–14. Computed
equilibrium constants were obtained with SMD(water)-B3LYP/6-31+G(d,p).

H. B. Wedler et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4153–4157
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mixture was stirred @ 50 °C for 1.5 h. TLC in 40% ethyl acetate in hexanes
indicated complete consumption of starting material. Crude mixture was
neutralized with saturated sodium bicarbonate (aq), extracted with ethyl
acetate, and washed with brine. The combined organic fractions were dried
over sodium sulfate, filtered, and concentrated in vacuo to afford the desired
product as a dark beige solid (43 mg, 96%).
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9 (1-(4-Nitrophenyl)-2-(piperidin-1-yl)ethane-1,2-dione)
Prepared by general synthetic procedure 1a (1.51 mmol of the requisite
acetophenone derivative used as purchased) to produce 365 mg of a light beige
solid (92%, mp 97.2–97.6 °C). IR (neat) mmax 2940, 2852, 1683, 1634, 1524 and
1349 cmꢀ1 1H NMR (600 MHz, Acetone-d6) 8.45 (ddd, J = 9.04, 4.23, 1.82 Hz,
.
2H), 8.22 (ddd, J = 8.82, 4.23, 2.00 Hz, 2H), 3.76 (dd, J = 10.23, 4.53 Hz, 2H), 3.39
(dd, J = 11.66, 6.02 Hz, 2H), 1.78 (m, 4H), 1.61 (m, 2H) 13C NMR (150 MHz,
Acetone-d6) 220.1, 193.7, 167.1, 160.0, 153.7, 146.8, 76.1, 71.3, 55.4, 54.6, 53.4.
HRMS calculated for [C13H14N2O4]+ 263.1032 [M+H]+; found 263.1027.
10 (4-(2-Oxo-2-(piperidin-1-yl)acetyl)benzonitrile)
24. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
25. Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
Prepared by general synthetic procedure 1a (1.72 mmol of the requisite
acetophenone derivative used as purchased) to produce 394 mg of a beige solid
26. Lynch, B. J.; Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2003, 107, 1384.
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98, 11623.
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reactions (equilibria, rates, mechanisms) in solution, see: Plata, R. E.; Singleton,
D. A. J. Am. Chem. Soc. 2015, 137, 3811.
(94%, mp 78.9–79.1 °C). IR (neat) m .
max 2953, 2867, 2233, 1680 and 1635 cmꢀ1
1H NMR (600 MHz, Acetone-d6) 8.15 (ddd, J = 8.80, 3.25, 1.88 Hz, 2H), 8.01
(ddd, J = 8.45, 3.44, 1.92 Hz, 2H), 3.68 (dd, J = 11.54, 5.23 Hz, 2H), 3.35 (dd,
J = 10.47, 5.71 Hz, 2H), 1.71 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H) 13C NMR
(150 MHz, Acetone-d6) 190.6, 164.1, 136.4, 133.0, 129.8, 117.4, 46.5, 41.6 26.1,
25.2, 23.9 HRMS calculated for [C15H14N2O2]+ 243.1134 [M+H]+; found
243.1125.
30. Hine, J.; Redding, R. W. J. Org. Chem. 1970, 35, 2769.
11 (1-(Piperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethane-1,2-dione)
Prepared by general synthetic procedure 1a (1.33 mmol of the requisite
acetophenone derivative used as purchased) to produce 281 mg as a dark beige
solid (74%, mp 65.5–65.7 °C). IR (neat) mmax 2951, 2863, 1686, 1636 and
31. Schmidt and coworkers used NMR population analysis to determine Khyd for
pyridine carboxaldehyde. They relied on the use of additives to stabilize the
hydrate form of this aldehyde making it experimentally detectable. This
approach necessarily affects the equilibrium constant observed, thus was not
used in our study. See: Schmidt, A.-K. C.; Stark, C. B. W. Org. Lett. 2011, 13, 4164.
32. Guthrie, J. P. Can. J. Chem. 1975, 53, 898.
1286 cmꢀ1 1H NMR (600 MHz, Acetone-d6) 8.20 (d, J = 8.27 Hz, 2H), 8.00 (d,
.
J = 8.49 Hz, 2H), 3.77 (dd, J = 10.33, 6.29 Hz, 2H), 3.38 (dd, J = 11.86, 5.57 Hz,
2H), 1.79 (m, 4H), 1.61 (m, 2H) 13C NMR (150 MHz, Acetone-d6) 220.8, 194.0,
165.7, 164.3(q, J = 164.4 Hz), 159.5, 155.7, 154.1, 152.3, 146.8, 76.1, 71.2, 55.4,
54.6, 53.5 HRMS calculated for [C13H14F3NO2]+ 286.1055 [M+H]+; found
286.1056.
33. Guthrie, J. P. Can. J. Chem. 1978, 56, 962.
34. Note that the value reported by Guthrie (Ref. 33) for benzaldehyde is actually
for 4-chlorobenzaldehyde. To the best of our knowledge, there is no previously
reported value for the hydration propensity of parent benzaldehyde. Sander, E.
G.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 6154.
35. Gruen, L. C.; McTigue, P. T. J. Chem. Soc. 1963, 5217.
36. Kurz, J. L. J. Am. Chem. Soc. 1967, 89, 3524.
12 (1-Phenyl-2-(piperidin-1-yl)ethane-1,2-dione)
Prepared by general synthetic procedure 1a (2.49 mmol of the requisite
acetophenone used as purchased) to produce 173 mg as a beige solid (32%, mp
1011–101.6 °C). IR (neat) mmax 2941, 2861, 1669 and 1640 cmꢀ1 1H NMR
.
37. Sutton, H. C.; Downes, T. M. J. Chem. Soc., Chem. Commun. 1972, 1.
38. Wiberg, K. B.; Morgan, K. M.; Maltz, H. J. Am. Chem. Soc. 1994, 116, 11067.
39. Henaff, P. L. Bull. Soc. Chim. Fr. 1968, 1968.
40. Valenta, P. Collect. Czech., Chem. Commun. 1960, 25, 853.
41. Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460.
(600 MHz, Acetone-d6) 7.83 (dd, J = 8.00, 1.18 Hz, 2H), 7.74 (ddd, J = 14.82,
7.18, 2.36 Hz, 1H), 7.60 (dd, J = 16.09, 8.00 Hz, 2H), 3.55 (dd, J = 12.15, 5.75 Hz,
2H), 3.16 (dd, J = 12.15, 5.75 Hz, 2H), 1.57 (m, 4H), 1.38 (m, 2H). 13C NMR
(150 MHz, Acetone-d6) 209.1, 192.1, 165.1, 134.6, 135.5, 129.2, 129.1, 46.5,
41.4, 26.0, 25.3, 24.1 HRMS calculated for [C13H16NO2]+ 218.1176 [M+H]+;
found 218.1667.
42. Shi, L.; Wu, T.-T.; Wang, Z.; Xue, J.-Y.; Xu, Y.-G. Eur. J. Med. Chem. 2014, 84, 698.
43. Bell, R. P. Adv. Phys. Org. Chem. 1966, 4, 1.
13 (1-(Piperidin-1-yl)-2-(p-tolyl)ethane-1,2-dione)
44. Orvis, J.; Hurst, M.; Fortenberry, R. Struct. Chem. 2014, 25, 1513.
45. Tayyari, S. F.; Holakoei, S.; Mahdizadeh, S. J. J. Mol. Struc. 2013, 1041, 190.
46. Natesan, S.; Balaz, S. Curr. Pharm. Des. 2013, 19, 4316.
Prepared by general synthetic procedure 1a (2.24 mmol of the requisite
acetophenone used as purchased) to produce 132 mg as a tan oil (25%). IR
(neat) mmax 2940, 2860, 1675 and 1643 cmꢀ1 1H NMR (600 MHz, Acetone-d6)
.
47. Synthetic procedure 1a for preparation of
a
-ketoamides (9–13): All chemicals
7.82 (d, J = 7.81 Hz, 2H), 7.40 (d, J = 8.69 Hz, 2H), 3.65 (dd, J = 10.93, 5.04 Hz,
2H), 3.28 (dd, J = 11.69, 5.51 Hz, 2H), 1.70 (m, 2H), 1.64 (m, 2H), 1.50 (m, 2H)
13C NMR (150 MHz, Acetone-d6) 209.1, 191.7, 165.2, 145.7, 131.1, 129.7, 129.3,
46.5, 41.4, 26.1, 25.3, 24.1, 20.9 HRMS calculated for [C14H18NO2]+ 232.1332[M
+H]+; found 232.1667.
were purchased from common chemical supply companies and used without
further purification. A flame fried round bottom flask with magnetic stir bar
was charged with substituted acetophenone (1 equiv) in anhydrous toluene
(0.4 M). To this was added piperidine (1.1 equiv), and CuI (0.1 equiv). The
solution was placed under a molecular oxygen atmosphere and heated to 65 °C
for 5 h (as monitored by thin layer chromatography [TLC]). The reaction
mixture was extracted with ethyl acetate, washed with water and brine, and
the organic layer dried over sodium sulfate. The crude mixture was filtered,
concentrated in vacuo and purified via column chromatography (30–50:70–50
14 (1-(4-Aminophenyl)-2-(piperidin-1-yl)ethane-1,2-dione)
Prepared by synthetic procedure 1b. IR (neat) mmax 3427, 3347, 2945, 2923,
1642 and 1588 cmꢀ1 1H NMR (600 MHz, DMSO-d6) 7.50 (d, J = 8.45 Hz, 2H),
.
6.59 (d, J = 7.09 Hz, 2H), 6.44 (BS, 2H), 3.52 (dd, J = 10.67, 6.53 Hz, 2H), 3.14 (dd,
J = 11.54, 6.75 Hz, 2H), 1.59 (m, 2H), 1.53 (m, 2H), 1.38 (m, 2H) 13C NMR
(150 MHz, DMSO-d6) 189.9, 166.3, 155.8, 132.2, 120.6, 113.4, 46.7, 41.4, 26.2,
25.5, 24.3 HRMS calculated for [C13H17N2O2]+ 233.1285[M+H]+; found
233.1667.
ethyl acetate/hexanes) to afford the desired
(25–94%).
Synthetic procedure 1b for reduction of 9–14: Compound 9 (51 mg, 0.194 mmol)
a-ketoamide as an off white solid