Synthesis and antimicrobial activity of 4-hydroxy-4-(pyridyl)alk-3-en-2-ones

Article abstract of DOI:10.1016/j.bmc.2009.05.023

4-Hydroxy-4-(pyridyl)alk-3-en-2-ones were prepared by base-mediated condensation of ketones with pyridinecarboxylates. Several derivatives show weak antimicrobial activity against Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1016/j.bmc.2009.05.023

Bioorganic & Medicinal Chemistry 17 (2009) 4323–4326
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and antimicrobial activity of 4-hydroxy-4-(pyridyl)alk-3-en-2-ones
b
a,c,
Abdolmajid Riahi a, Martina Wurster b, Michael Lalk b, , Ulrike Lindequist , Peter Langer
*
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Institut für Pharmazie, Ernst-Moritz-Arndt-Universität Greifswald, F.-L.-Jahn-Str. 17, 17487 Greifswald, Germany
c Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 February 2009
Revised 5 May 2009
Accepted 11 May 2009
Available online 15 May 2009
4-Hydroxy-4-(pyridyl)alk-3-en-2-ones were prepared by base-mediated condensation of ketones with
pyridinecarboxylates. Several derivatives show weak antimicrobial activity against Gram-positive and
Gram-negative bacteria.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Antimicrobial activity
Diketones
N-Heterocycles
Pyridine
1. Introduction
idyl)alk-3-en-2-ones and their antimicrobial activity against
Gram-positive and Gram-negative bacteria.
Serious infections by resistant and multiresistant microbes are
dramatically increased during the recent years1,2 and represent
the second leading cause of death.3 Multiresistant strains of Staph-
ylococcus aureus, such as MRSA (Methicillin resistant S. aureus), are
often responsible for severe and life-threatening infections in pa-
tients during their stay in hospitals or in immunosuppressed per-
sons. Therefore, the development of new antimicrobial agents
represents an important task in medicinal chemistry. Its success
crucially relies on the search for new chemical entities (NCEs).
Unfortunately, pharmaceutical companies are more and more leav-
ing this area, due to economic reasons.4 Genomics, combinatorial
synthesis, and high throughput screening (HTS) are used to iden-
tify new lead structures. However, success is limited as chemical
companies have been unable to identify new and valid antimicro-
bial agents by random screening of compound libraries.4 In fact no
innovative antibiotics have been launched on the market for sev-
eral decades. It was not before 2000 and 2003 that the first new
NCEs, the oxazolidinone linezolid and the lipopeptide daptomycin,
appeared on the market, respectively.5,6 Recently, we have re-
ported that 2-vinylchroman-4-ones show a remarkable activity
against several humanpathogenic bacteria, including multiresis-
tant strains.7 Herein, we report the synthesis of 4-hydroxy-4-(pyr-
2. Results and discussion
2.1. Chemistry
We have earlier reported the synthesis of 4-hydroxy-4-(pyri-
dyl)alk-3-en-2-ones by LDA-mediated condensation reactions.8
We have found that better results (with respect to the purity of
the compounds and in some cases regarding the yield) are obtained
when sodium hydride (NaH)9 is used as the base. The NaH-medi-
ated condensation of ketones 1a-f with ethyl pyridine-2-carboxyl-
ate (2a) afforded the 4-hydroxy-4-(pyrid-2-yl)alk-3-en-2-ones 3a–
f (Scheme 1, Table 1). Products 3a–e exclusively exist in their enol
O
OH
O
N
R1
R1
O
N
3a-e
1a-e
i
+
EtO
O
O
O
2a
R1
N
R1
1f
* Corresponding authors. Fax: +49 3834 864885 (M.L.); Tel.: +49 381 4986410;
fax: +49 381 4986412 (P.L.).
3f
E-mail addresses: lalk@uni-greifswald.de (M. Lalk), peter.langer@uni-rostock.de
(P. Langer).
Scheme 1. Synthesis of 3a–f. Reagents and conditions: (i) NaH (4.0 equiv), 2a
(1.0 equiv), 1a–f (2.0 equiv), Et2O, reflux, 2 h.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.023

4324
A. Riahi et al. / Bioorg. Med. Chem. 17 (2009) 4323–4326
Table 1
Table 2
Synthesis of 3a–f
Synthesis of 4a–e
1,3
R1
% (3)a
1,4
R1
% (4)a
a
b
c
d
e
f
Me
Et
nPr
nBu
Ph
65
55
66
50
61
55
a
b
c
d
e
Me
Et
nPr
nBu
Ph
53
67
70
62
65
Et
a
Yields of isolated products.
a
Yields of isolated products.
Table 3
Minimal inhibitory concentrations of selected compounds 3 and 4 (values given in lg/
tautomeric form. Product 3f exclusively resides in the keto form
which is often the case for 2-substituted 1,3-diketones. The syn-
thesis of 3a–c and 3e has been previously reported.8
mL)a
Compound
S. aureus
B. subtilis
E. coli
ATCC 6538
ATCC 11229
ATCC 6051
The condensation of ketones 1a–e with ethyl pyridine-3-car-
boxylate (2b) afforded the 4-hydroxy-4-(pyrid-3-yl)alk-3-en-2-
ones 4a–e (Scheme 2, Table 2). Products 4a–e exclusively exist in
their enol tautomeric form. The synthesis of 4a,8 4b,10 4d,11 and
4e11 has been previously reported. However, NMR and MS data
of 4b, 4d, and 4e have not yet been reported.
3a
3b
3c
3d
3e
3f
4a
4b
46.90
23.57
191.57
96.52
47.36
758.16
392.30
380.36
192.82
95.52
95.13
3.19
190.03
211.08
97.25
48.14
24.49
786.04
397.18
373.64
200.40
95.37
378.52
195.40
97.84
47.67
24.09
390.73
401.66
379.40
94.11
95.38
95.80
6.99
2.2. Biological activity
4c
4d
4e
The biological activity of compounds 3 and 4 was evaluated (Ta-
ble 3). Especially the growth of the Gram-positive bacteria S. aureus
and Bacillus subtilis and the Gram-negative Escherichia coli was
inhibited. The results of these studies are summarized in Table 3.
The antimicrobial activity of the 4-hydroxy-4-(pyridyl)alk-3-en-
2-ones is much lower compared to the standard antibiotic Ampicil-
lin, and shows an interesting influence of the substitution pattern.
The presence of the pyridine moiety is mandatory for the phar-
macological activity. The antibacterial activities strongly depend
on the substitution pattern of the pyridine moiety. The pyrid-2-yl
derivatives 3d, 3e and 4d, 4e are the most active compounds in this
study. Interestingly, only derivatives which exist in their enol tau-
tomeric form exhibit weak antimicrobial activity. In contrast, 3f
(which exclusively resides in the keto form) shows no antibacterial
activity against Gram-positive bacteria. Compound 3f only shows a
very weak activity against Gram-negative E. coli. This suggests that
the formation of the enol tautomeric form is essential for the anti-
biotic activity of the pyridyl compounds. Considering the influence
of substituent R1 it was found that more bulky residues lead to a
stronger growth inhibition. This is especially the case for B. subtilis.
In S. aureus this tendency is also observable but to a lower extent.
Beside this observation the highest antibacterial activity was found
for the phenyl derivatives 4e and 3e. The latter showed the highest
activity against all tested bacteria. The n-butyl-substituted deriva-
tives 4d and 3d also show a growth inhibition. Thorarensen and
coworkers reported the antibacterial activity of enolic compounds
with possible influence on the cell wall or protein synthesis.12
Investigation towards the mechanism of action will concentrate
on the role of the substitution pattern of the 1,3-diketo moiety.
Furthermore the investigation of possible alterations of the metab-
olism under influence of the pyridyl-derivatives in the tested bac-
teria is interesting and will be topic of future work.
94.64
12.48
Ampicillin
a
Minimal inhibitory concentrations were determined by a dilution assay (results
are averages of 3 independent experiments).
3. Conclusions
A
variety of novel 4-hydroxy-4-(pyrid-2-yl)alk-3-en-2-ones
were prepared by base-mediated condensation of ketones with
pyridinecarboxylates. Some derivatives show weak antimicrobial
activity against Gram-positive bacteria. Further investigations to-
wards the understanding of the mode of action are in progress.
4. Experimental
4.1. General comments
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spectro-
metric data (MS) were obtained by electron ionization (EI, 70 eV),
chemical ionization (CI, H2O) or electrospray ionization (ESI). For
preparative scale chromatography, silica gel (60–200 mesh) was
used. Melting points are uncorrected.
4.2. Antibiotic susceptibility tests
Bacterial strains were obtained from the ATCC. The minimum
inhibitory concentration (MIC) was determined by microdilution
according to the recommendations of the Clinical and Laboratory
Standards Institute (CLSI).13 The MIC was determined in 96 well
microtiter plates in a final volume of 200 ll without agitation.
The initial inoculum was 2 ꢀ 105 bacterial cells per well. The plates
were incubated for 24 h at 37 °C.
O
O
OH
O
4.3. General procedure for the synthesis of 1,3-dicarbonyl
compounds 3a–f and 4a–e
i
EtO
+
R1
R1
1a-e
N
N
2b
4a-e
To a stirred suspension of NaH (4.0 equiv) in anhydrous diethyl
ether (1.0 mL/2.5 mmol of 1) at 0 °C was added 2a or 2b (1.0 equiv)
and ketone 1a–f (2.0 equiv) at 20 °C. The mixture was refluxed for
Scheme 2. Synthesis of 4a–e. Reagents and conditions: (i) NaH (4.0 equiv), 2b
(1.0 equiv), 1a–e (2.0 equiv), Et2O, reflux, 2 h.

A. Riahi et al. / Bioorg. Med. Chem. 17 (2009) 4323–4326
4325
2 h, cooled and a diluted aqueous solution of NH4Cl was added. The
4.7. 1-Hydroxy-1-(pyrid-2-yl)hept-1-en-3-one (3d)
organic and the aqueous layer were separated and the latter was
extracted with diethylether (3 ꢀ 20 mL). The combined organic
layers were washed with brine, dried (Na2SO4), filtered and the sol-
vent of the filtrate was removed in vacuo. The residue was purified
by chromatography (silica gel, heptanes/EtOAc = 30:1?20:1) to
give products 3 or 4. Compounds 1a–f and 2a–b are commercially
available. The synthesis of 3a–c and 3e has been previously re-
ported.8 The synthesis of 4a,8 4b,10 4d,11 and 4e11 has been previ-
ously reported. However, NMR and MS data of 4b, 4d, and 4e have
not yet been reported.
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL),
2-hexanone (5.9 mL, 48.0 mmol) and 2a (3.3 mL, 24.0 mmol),
3d was isolated as a light yellow oil (2.46 g, 50%). 1H NMR
(250 MHz, CDCl3): d 0.86 (t, 3J = 7.3 Hz, 3H, (CH2)3CH3), 1.25–
1.40 (m, 2H, CH2CH2CH2CH3), 1.56–1.67 (m, 2H, CH2CH2CH2CH3),
2.40 (t, 3J = 7.5 Hz, 2H, CH2CH2CH2CH3), 6.75 (s, 1H, CH), 7.30–
7.36 (m, 1H, CHpy), 7.72ꢁ7.79 (m, 1H, CHpy), 8.99–8.02 (m, 1H,
CHpy), 8.57–8.60 (m, 1H, CHpy), 15.66 (s(br), 1H, OH). 13C NMR
(75 MHz, CDCl3): d 14.1 (CH3), 22.5, 28.0, 39.17 (CH2), 96.8
(CH), 122.1, 126.2, 137.1, 149.3 (CHpy), 152.3 (Cpy), 180.8
~
4.4. 4-Hydroxy-4-(pyrid-2-yl)but-3-en-2-one (3a)
(COH), 198.5 (CO). IR (neat cmꢁ1):
m
¼ 2956 (w), 2871 (w),
1720 (w), 1720 (m), 1578 (m), 1563 (m), 1461 (m), 1430 (m),
1378 (w), 1281 (m), 1146 (w), 1087 (m), 1043 (w), 991 (w),
825 (w), 785 (s), 742 (m), 692 (w), 618 (m). GC–MS (EI,
70 eV): m/z (%) = 205 ([M+], 7), 163 (30), 149 (12), 148 (100),
135 (13), 122 (11), 121 (35), 120 (18), 106 (78), 93 (27), 79
(37), 78 (100), 52 (12), 51 (16), 41 (12). HRMS (EI): Calcd for
C12H15O2N: 205.11029; found: 205.110456.
StartingwithNaH (2.30 g, 96.0 mmol), diethylether (18 mL), ace-
tone (3.5 mL, 48.0 mmol) and 2a (3.3 mL, 24.0 mmol), 3a was iso-
lated as a yellowish solid, mp = 48–50 °C (2.055 g, 65%). 1H NMR
(250 MHz, CDCl3): d 2.23 (s, 3H, CH3), 6.82 (s, 1H, CH), 7.38–7.43
(m, 1H, CHpy), 7.80–7.86 (m, 1H, CHpy), 8.06–8.09 (m, 1H, CHpy),
8.65–8.66 (m, 1H, CHpy), 15.69 (s(br), 1H, OH). 13C NMR (75 MHz,
CDCl3): d 26.1 (CH3), 97.2 (CH), 122.1, 126.2, 137.0, 149.0 (CHpy),
~
152.1 (Cpy), 180.7 (COH), 195.0 (CO). IR (KBr, cmꢁ1):
m
¼ 3117 (w),
4.8. 3-Hydroxy-1-phenyl-3-(pyrid-2-yl)prop-2-en-1-one (3e)
3066 (w), 2957 (w), 2870 (w), 1605 (m), 1579 (m), 1463 (m), 1416
(m), 1353 (m), 1284 (m), 1245 (m), 1183 (m), 1158 (m), 1079 (m),
1043 (w) 990 (m), 907 (m), 848 (m), 784 (s), 746 (m), 620 (m), 584
(w), 545 (m). GC–MS (EI, 70 eV): m/z (%) = 163 (M+, 46), 148 (84),
134 (8), 121 (28), 106 (64), 96 (14), 85 (15), 79 (75), 78 (100), 52
(25), 51 (31), 50 (10), 43 (35), 39 (10). HRMS (EI): Calcd for
C9H9O2N: 163.06278; found: 163.063192.
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL),
acetophenone (5.6 mL, 48.0 mmol) and 2a (3.3 mL, 24.0 mmol),
3e was isolated as a light yellow solid mp = 81–83 °C (3.30 g,
61%). 1H NMR (250 MHz, CDCl3): d 7.44–7.55 (m, 4H, CHAr), 7.59
(s, 1H, CH), 7.82–7.89 (m, 1H, CHAr), 8.05–8.09 (m, 2H, CHAr),
8.14–8.18 (m, 1H, CHAr), 8.69–8.72 (m, 1H, CHAr), 16.59 (s(br), 1H,
OH). 13C NMR (75 MHz, CDCl3): d 93.6 (CH), 122.1, 126.2 (CHAr),
127.3 (2 ꢀ CHAr), 128.5 (2 ꢀ CHAr), 132.7 (CHAr), 135.4 (CPh),
137.1, 149.3 (CHAr), 152.6 (Cpy), 183.6 (COH), 186.3 (CO). IR (neat
~
4.5. 1-Hydroxy-1-(pyrid-2-yl)pent-1-en-3-one (3b)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL),
cmꢁ1):
m
¼ 3120 (w), 3055 (w), 2959 (w), 2872 (w), 1681 (w),
2-butanone (4.37 mL, 48.0 mmol) and 2a (3.3 mL, 24.0 mmol),
1598 (m), 1455 (m), 1417 (m), 1278 (m), 1250 (m), 1212 (m),
1178 (m), 1145 (m), 1086 (m), 1041 (w) 992 (m), 908 (m), 831
(w), 770 (s), 749 (m), 686 (m), 608 (m). GC–MS (EI, 70 eV): m/z
(%) = 225 (M+, 53), 208 (10), 198 (9), 197 (20), 196 (49), 180 (29),
168 (15), 147 (37), 120 (11), 105 (100), 98 (16), 96 (23), 92 (19),
89 (10), 84 (43), 79 (41), 78 (51), 77 (46), 75 (11), 72 (23), 69
(62), 65 (17). HRMS (EI): Calcd for C14H11O2N: 225.07843; found:
225.078442.
3b was isolated as
a
yellowish oil (2.10 g, 55%). 1H NMR
(250 MHz, CDCl3): d 1.21 (t, 3J = 7.4 Hz, 3H, CH2CH3), 2.50 (q,
3J = 7.7, 2H, CH2CH3), 6.82 (s, 1H, CH), 7.37ꢁ7.42 (m, 1H, CHpy),
7.79ꢁ7.86 (m, 1H, CHpy), 8.05–8.08 (m, 1H, CHpy), 8.64ꢁ8.66
(m, 1H, CHpy), 15.69 (s(br), 1H, OH). 13C NMR (75 MHz, CDCl3):
d 9.4 (CH2CH3), 32.4 (CH2CH3), 96.2 (CH), 122.0, 126.1, 137.2,
149.5 (CHpy), 152.3 (Cpy), 180.4 (COH), 199.6 (CO). IR (neat, cm
~
ꢁ1):
m
¼ 2976 (w), 2879 (w), 1601 (m), 1577 (s), 1577 (s),
1460 (m), 1413 (m), 1312 (m), 1241 (m), 1044 (m), 993 (m),
829 (m), 781 (s), 742 (s), 689 (m), 543 (w). GC–MS (EI, 70 eV):
m/z (%) = 177 ([M+], 12), 162 (4), 148 (100), 106 (68), 79 (25),
78 (77), 52 (10), 51 (15). HRMS (EI): Calcd for C10H11O2N:
177.07843; found: 177.078306.
4.9. 2-Methyl-1-(pyrid-2-yl)pentane-1,3-dione (3f)
Starting with NaH (2.30 g, 96 mmol), diethyl ether (18 mL), 3-
pentanone (5.1 mL, 48.0 mmol) and 2a (3.3 mL, 24.0 mmol), 3f
was isolated as a light red oil (2.52 g, 55%). 1H NMR (250 MHz,
CDCl3): d 1.08 (t, 3J = 7.4 Hz, 3H, CH2CH3), 1.39 (d, 3J = 7.6 Hz, 3H,
CH3), 2.70 (q, 3J = 7.0, 2H, CH2CH3), 4.86 (q, 3J = 7.1, 1H, CHCH3),
7.42ꢁ7.47 (m, 1H, CHpy), 7.79ꢁ7.86 (m, 1H, CHpy), 8.03–8.07 (m,
1H, CHpy), 8.60ꢁ8.63 (m, 1H, CHpy). 13C NMR (75 MHz, CDCl3): d
7.8, 12.7 (CH3), 35.3 (CH2), 54.1 (CH), 122.4, 127.3, 137.1, 148.7
~
4.6. 1-Hydroxy-1-(pyrid-2-yl)hex-1-en-3-one (3c)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL), 2-
pentanone (5.1 mL, 48.0 mmol) and 2a (3.26 mL, 24.0 mmol), 3c
was isolated as a yellowish oil (3.04 g, 66%). 1H NMR (250 MHz,
CDCl3): d 0.98 (t, 3J = 7.4 Hz, 3H, CH2CH2CH3), 1.66–1.80 (m, 2H,
CH2CH2CH3), 2.44 (t, 3J = 7.2 Hz, 2H, CH2CH2CH3), 6.81 (s, 1H, CH),
7.36–7.42 (m, 1H, CHpy), 7.78ꢁ7.85 (m, 1H, CHpy), 8.05–8.09 (m,
1H, CHpy), 8.63–8.66 (m, 1H, CHpy), 15.77 (s(br), 1H, OH). 13C NMR
(75 MHz, CDCl3): d 13.9 (CH2CH2CH3), 19.3 (CH2CH2CH3), 41.6
(CH2CH2CH3), 97.0 (CH), 122.3, 126.4, 137.3, 149.5 (CHpy), 152.7
~
(CHpy), 152.3 (Cpy), 198.5, 208.9 (CO). IR (neat cmꢁ1):
m
¼ 2978
(w), 2877 (w), 1716 (s), 1697 (s), 1584 (m), 1569 (w), 1455 (m),
1410 (w), 1324 (m), 1286 (w), 1223 (m), 1113 (w), 1038 (w), 995
(m), 950 (m), 790 (w), 781 (w), 742 (m), 667 (w), 618 (m). GC–
MS (EI, 70 eV): m/z (%) = 191 ([M+], 1), 163 (10), 162 (93), 135
(91), 134 (30), 107 (27), 106 (69), 80 (11), 79 (67), 78 (100), 57
(25), 52 (15), 51(24), 29 (19). HRMS (EI): Calcd for C11H13O2N:
191.09408; found: 191.093912.
(Cpy), 180.6 (COH), 198.3 (CO). IR (neat cmꢁ1):
m
¼ 2962 (w),
2873 (w), 1720 (w), 1601 (m), 1577 (s), 1577 (s), 1458 (m), 1430
(m), 1333 (m), 1283 (m), 1086 (m), 993 (m), 827 (w), 785 (s),
742 (s), 690 (m), 618 (m). GC–MS (EI, 70 eV): m/z (%) = 191 ([M+],
9), 163 (13), 148 (100), 121 (17), 106 (78), 93 (15), 79 (30), 78
(87), 52 (11), 51 (16), 43 (13). HRMS (EI): Calcd for C11H13O2N:
191.09408; found: 191.093919.
4.10. 4-Hydroxy-4-(pyrid-3-yl)but-3-en-2-one (4a)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL),
acetone (3.5 mL, 48.0 mmol) and 2b (3.3 mL, 24.0 mmol), 4a was
isolated as a light orange solid, mp = 50–52 °C (2.07 g, 53%). 1H

4326
A. Riahi et al. / Bioorg. Med. Chem. 17 (2009) 4323–4326
NMR (250 MHz, CDCl3): d 2.17 (s, 3H, CH3), 6.13 (s, 1H, CH), 7.32–
7.37 (m, 1H, CHpy), 8.08–8.12 (m, 1H, CHpy), 8.66–6.68 (m, 1H,
CHpy), 9.01 (s, 1H, CHpy), 15.92 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3): d 26.0 (CH3), 97.2 (CH), 123.7, 128.5, 148.4, 152.7, (CHAr),
~
13.8 (CH3), 22.3, 27.7, 39.1 (CH2), 96.5 (CH), 123.4 (CHpy), 130.8
(Cpy), 134.3, 148.5, 152.6 (CHpy), 181.1 (COH), 197.7 (CO). IR (neat
cmꢁ1):
m
¼ 3041 (w), 2957 (w), 2871 (w), 1586 (s), 1464 (m), 1410
~
(m), 1378 (w), 1270 (m), 1128 (w), 1093 (m), 1021 (m), 946 (w),
853 (w), 770 (s), 699 (s), 620 (w), 565 (w). GC–MS (EI, 70 eV): m/
z (%) = 205 ([M+], 5), 176 (12), 163 (65), 162 (28), 149 (10), 148
(100), 121 (13), 106 (67), 78 (33), 69 (15), 51 (14), 41 (8). HRMS
(EI): Calcd for C12H15O2N: 205.11029; found: 205.110456.
134.5 (Cpy), 181.2 (COH), 194.6 (CO). IR (neat, cmꢁ1):
m
¼ 2952
(w), 2919 (w), 1926 (w), 1584 (s), 1411 (m), 1371 (s), 1204 (m),
1077 (s), 824 (m), 872 (s), 695 (s), 543 (w). GC–MS (EI, 70 eV):
m/z (%) = 163 ([M+], 67), 162 (100), 148 (97), 106 (66), 104 (9),
85 (25), 79 (26), 78 (53), 69 (18), 65 (10), 51 (29), 50 (13), 43
(33), 39 (11). HRMS (EI): Calcd for C9H9O2N: 163.06278; found:
163.062897.
4.14. 3-Hydroxy-1-phenyl-3-(pyrid-3-yl)prop-2-en-1-one (4e)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL),
acetophenone (5.6 mL, 48.0 mmol) and 2b (3.3 mL, 24.0 mmol),
4e was isolated as a light yellow solid, mp = 118–120 °C (3.50 g,
65%). 1H NMR (250 MHz, CDCl3): d 6.86 (s, 1H, CH), 7.41–7.62 (m,
4H, CHAr), 7.98–8.01 (m, 2H, CHAr), 8.25–8.28 (m, 1H, CHAr),
8.76–8.78 (m, 1H, CHAr), 9.19 (s, 1H, CHAr), 16.50 (s(br), 1H, OH).
13C NMR (75 MHz, CDCl3): d 93.65 (CH), 123.5 (CHAr), 127.3
(2 ꢀ CHAr), 128.8 (2 ꢀ CHAr), 131.2 (CPh), 132.8, 133.4 (CHAr),
135.1 (Cpy), 148.4, 152.9 (CHAr), 183.5 (COH), 186.4 (CO). IR (neat
~
4.11. 1-Hydroxy-1-(pyrid-3-yl)pent-1-en-3-one (4b)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL), 2-
butanone (4.4 mL, 48.0 mmol) and 2b (3.3 mL, 24.0 mmol), 4b was
isolated as a yellowish oil (2.86 g, 67%). 1H NMR (250 MHz, CDCl3):
d 1.21 (t, 3J = 7.4 Hz, 3H, CH2CH3), 2.48 (q, 3J = 8.5, 2H, CH2CH3), 6.17
(s, 1H, CH), 7.38ꢁ7.41 (m, 1H, CHpy), 8.13ꢁ8.18 (m, 1H, CHpy),
8.71–8.73 (m, 1H, CHpy), 9.06 (s, 1H, CHpy), 15.94 (s(br), 1H, OH).
13C NMR (75 MHz, CDCl3): d 9.6 (CH2CH3), 32.5 (CH2CH3), 95.9
(CH), 123.4 (CHpy), 130.7 (Cpy), 134.4, 148.2, 152.6 (CHpy), 180.5
~
cmꢁ1):
m
¼ 3108 (w), 3056 (w), 2917 (w), 1587 (m), 1519 (m),
1463 (m), 1404 (m), 1279 (m), 1240 (m), 1188 (m), 1154 (m),
1115 (m), 1063 (m), 1036 (w) 963 (m), 841 (w), 804 (m), 769 (s),
717 (m), 683 (s), 607 (m). GC–MS (EI, 70 eV): m/z (%) = 225 ([M+],
83), 224 (100), 196 (24), 148 (23), 147 (24), 106 (25), 105 (40),
79 (19), 78 (30), 77 (46), 69 (40), 51 (29). HRMS (EI): Calcd for
C14H11O2N: 225.07843; found: 225.078866.
(COH), 198.6 (CO). IR (neat cmꢁ1):
m
¼ 2975 (w), 2879 (w), 1720
(w), 1587 (s), 1461 (m), 1412 (m), 1320 (m), 1268 (m), 1153 (w),
1087 (w), 1022 (m), 993 (w), 907 (w), 804 (w), 710 (m), 620 (w),
543 (w). GC–MS (EI, 70 eV): m/z (%) = 177 ([M+], 37), 176 (11),
149 (14), 148 (100), 106 (43), 78 (27), 69 (12), 51 (14). HRMS
(EI): Calcd for C10H11O2N: 177.07843; found: 177.078509.
Acknowledgements
4.12. 1-Hydroxy-1-(pyrid-3-yl)hex-1-en-3-one (4c)
Financial support by the State of Mecklenburg-Vorpommern
(UG 07068) and the Deutsche Forschungsgemeinschaft (SFB/
TRR34 and La1289/2-1) is gratefully acknowledged.
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL), 2-
pentanone (5.1 mL, 48.0 mmol) and 2b (3.3 mL, 24.0 mmol), 4c
was isolated as
a
light yellow oil (3.20 g, 70%). 1H NMR
(250 MHz, CDCl3): d 0.93 (t, 3J = 7.4 Hz, 3 H, CH2CH2CH3), 1.58–
1.73 (m, 2H, CH2CH2CH3), 2.36 (t, 3J = 7.2 Hz, 2H, CH2CH2CH3),
6.10 (s, 1H, CH), 7.30–7.35 (m, 1H, CHpy), 8.07ꢁ8.12 (m, 1H, CHpy),
References and notes
1. Rachakonda, S.; Cartee, L. Curr. Med. Chem. 2004, 11, 775.
2. Walsh, C. Antibiotics, Actions, Origins, Resistance; ASM: Washington, DC, 2003.
3. (a) World health organisation (WHO) Geneva, World Health Report-2002,
2002.; (b) Nathan, C. Nature 2004, 431, 899.
4. Review: von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Häbich, D.
Angew. Chem., Int. Ed. 2006, 45, 5072.
5. Review: Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed. 2003, 42, 2010.
6. (a) Raja, A.; LaBonte, J.; Lebbos, J.; Kirkpatrick, P. Nat. Rev. Drug Disc. 2003, 2,
943; (b) Alder, J. D. Drugs Today 2005, 41, 81.
7. (a) Albrecht, U.; Lalk, M.; Langer, P. Bioorg. Med. Chem. 2005, 13, 1531; (b)
Langer, P. Chim. Oggi/Chem. Today 2008, 26, 9; (c) Nguyen, V. D.; Wolf, C.;
Mäder, U.; Lalk, M.; Langer, P.; Lindequist, U.; Hecker, M.; Antelmann, H.
Proteomics 2007, 7, 1391.
8.64–8.67 (m, 1H, CHpy), 9.0 (s, 1H, CHpy), 15.96 (s(br), 1H, OH). 13
C
NMR (75 MHz, CDCl3): d 13.8 (CH2CH2CH3), 19.3 (CH2CH2CH3), 41.0
(CH2CH2CH3), 96.2 (CH), 123.4 (CHpy), 130.8 (Cpy), 134.3, 148.5,
152.6 (CHpy), 181.4 (COH), 197.4 (CO). IR (neat cmꢁ1):
m
¼ 3041
~
(w), 2963 (w), 2873 (w), 1720 (w), 1587 (s), 1462 (m), 1410 (m),
1380 (w), 1339 (w), 1264 (m), 1193 (m), 1090 (w), 1021 (m),
906 (m), 825 (w), 773 (m), 700 (s), 649 (w), 563 (w). GC–MS (EI,
70 eV): m/z (%) = 191 ([M+], 26), 163 (15), 149 (12), 148 (100),
106 (38), 78 (25), 69 (12), 51 (11). HRMS (EI): Calcd for
C11H13O2N: 191.09408; found: 191.093962.
8. Yawer, M. A.; Riahi, A.; Adeel, M.; Hussain, I.; Fischer, C.; Langer, P. Synthesis
2008, 1276.
9. The use of sodium hydride has been previously reported in this context. See:
Satake, A.; Nakata, T. J. Am. Chem. Soc. 1998, 120, 10391.
10. Ref. 1 6395309; Journal; Giudice, Maria Rosaria Del; Mustazza, Carlo; Borioni,
Anna; Gatta, Franco; Tayebati, Khosrow; Amenta, Francesco; Tucci, Paolo;
Pieretti, Stefano; ARPMAS; Arch.Pharm.(Weinheim Ger.); EN; 336; 3; 2003; pp
143–154.
11. Ref. 1 1046238; Journal; Kuick; Adkins; JACSAT; J. Am. Chem. Soc. 1935, 57, 143,
145.
12. Thorarensen, A.; Zurenkob, G. E.; Sweeneyb, M. T.; Marottib, K. R.; Boyleb, T. P.
Bioorg. Med. Chem. Lett. 2001, 11, 2931.
4.13. 1-Hydroxy-1-(pyrid-3-yl)hept-1-en-3-one (4d)
Starting with NaH (2.30 g, 96.0 mmol), diethyl ether (18 mL), 2-
hexanone (5.9 mL, 48.0 mmol) and 2b (3.3 mL, 24.0 mmol), 4d was
isolated as a yellowish oil (3.05 g, 62%). 1H NMR (250 MHz, CDCl3):
d
0.94 (t, 3J = 7.2 Hz, 3H, (CH2)3CH3), 1.32–1.47 (m, 2H,
CH2CH2CH2CH3), 1.61–1.73 (m, 2H, CH2CH2CH2CH3), 2.45 (t,
3J = 7.3 Hz, 2H, CH2CH2CH2CH3), 6.17 (s, 1H, CH), 7.36–7.42 (m,
1H, CHpy), 8.13ꢁ8.18 (m, 1H, CHpy), 8.71–8.73 (m, 1H, CHpy), 9.06
(s, 1H, CHpy), 16.02 (s(br), 1H, OH). 13C NMR (75 MHz, CDCl3): d
13. Clinical and Laboratory Standards Institute. 2006. Methods for dilution
antimicrobial susceptibility tests for bacteria that grow aerobically.
Document M7-A7. CLSI, Wayne, Pa.