Regioselective halogenations and subsequent Suzuki-Miyaura coupling onto bicyclic 2-pyridones

Article abstract of DOI:10.1021/jo902458g

(Chemical Equation Presented) A selective synthesis of 6-bromo-8-iodo dihydro thiazolo ring-fused 2-pyridones is described. These halogenated 2-pyridones are selectively arylated by sequential Suzuki - Miyaura couplings. This approach can advantageously be used to synthesize focused libraries of substituted ring-fused 2-pyridones, a class of compounds with novel antibacterial properties.

Full text of DOI:10.1021/jo902458g

pubs.acs.org/joc
inhibitors for functional amyloids, curli, in uropathogenic
Regioselective Halogenations and Subsequent
Suzuki-Miyaura Coupling onto Bicyclic 2-Pyridones
Escherichia coli. These compounds have been named curli-
cides (e.g., FN075, Figure 1).6 In that study, it was also
concluded that the R1-substituent (e.g., 3-CF3Ph, Figure 1)
Christoffer Bengtsson and Fredrik Almqvist*
˚
Department of Chemistry, Umea University, SE-901 80
˚
Umea, Sweden
fredrik.almqvist@chem.umu.se
Received November 17, 2009
FIGURE 1. Examples of biologically active bicyclic 2-pyridones.
was of great importance for discriminating between com-
pounds with selective curlicide or pilicide properties. The
desired framework can be synthesized via an acyl ketene
imine cyclocondensation (Scheme 1).7 Starting from com-
mercially available nitriles to construct the imine part and by
preparing various acyl Meldrum’s acid derivatives, the two
substituents R1 and R2 can be directly introduced in the
2-pyridone forming reaction. Although this method has
proven to be robust and reliable in library synthesis8,9 it
suffers from the fact that the substituents must already be
introduced in the synthesis of the building-blocks and later
fine-tuning of structure activity relationships can therefore
be ineffective and time-consuming. In both the pilicide and
the curlicide projects the R1-substituent has proven to be of
great importance for biological activity. Therefore, in order
to synthesize focused libraries of pilicides and curlicides
more effectively, a strategy that allows for a later introduc-
tion of substituents would be highly desirable.
Halogenations of ring-fused 2-pyridones are known to
proceed well with high yields.10 However, selective halogena-
tions where two active positions in the 2-pyridone ring are
available are scarcely reported. Inspired by such a report on
selective halogenation of a related bicyclic 2-pyridone frame-
work,11 we saw a possibility of synthesizing pyridones 3a and
3b in larger amounts. These 2-pyridones could then be
halogenated and subsequently substituted with a variety of
substituents with transition metal-mediated cross couplings.
A selective synthesis of 6-bromo-8-iodo dihydro thiazolo
ring-fused 2-pyridones is described. These halogenated
2-pyridones are selectively arylated by sequential Suzuki-
Miyaura couplings. This approach can advantageously be
used to synthesize focused libraries of substituted ring-
fused 2-pyridones, a class of compounds with novel anti-
bacterial properties.
2-Pyridones are heterocycles, which can be found in a
variety of natural products and biologically active molecules
(Figure 1) such as militarinone AþD,1 leporin A,2 tenellin,2
cytisine,3 camptothecin, and ricinine. These products possess
different biological properties such as neurotrophic activity,
antifeedant, and nicotine agonist properties.
Substituted bicyclic 2-pyridones are known to act as
inhibitors of pilus assembly in uropathogenic Escherichia
coli (so-called pilicides).4 In addition, it has been seen that by
fine-tuning the substitution pattern onto these latter bicyclic
2-pyridones, an inhibitory effect on Aβ-peptide aggregation
involved in Alzheimer’s disease is evident.5 A very recent
study reveals that these amyloid inhibitors also act as
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17897–17902. (b) Aberg, V.; Almqvist, F. Org. Biomol. Chem. 2007, 5,
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972 J. Org. Chem. 2010, 75, 972–975
Published on Web 12/21/2009
DOI: 10.1021/jo902458g
r
2009 American Chemical Society

Bengtsson and Almqvist
JOCNote
SCHEME 1. Cyclocondensation between a Δ2-Thiazoline and
an Acyl Ketene Source
SCHEME 2. Selective Halogenations of the 2-Pyridones
TABLE 1. Selective Iodination Followed by Suzuki-Miyaura Coupling
in the 6-Position
TABLE 2. Regioselective Suzuki-Miyaura Couplings
entry
R
X
yield (%)
product
1
2
3
4
5
6
Me
CH2-1-naphthyl
Me
CH2-1-naphthyl
Me
CH2-1-naphthyl
Br
Br
I
82
85
75
73
83
86
4a
4b
5a
5b
6a
6b
I
Hence the bicyclic 2-pyridones 3a and 3b were synthesized.
The methyl-substituted analogue 3 was synthesized via a
cyclocondensation between a commercially available acyl
ketene source 2 and the Δ2-thiazoline 17 in 79% yield
(Scheme 1). The CH2-1-naphthyl analogue 3b was prepared
according to a previously published procedure.7
b
aUsing Pd-NHC instead of Pd(OAc)2 did not increase the yield.
120 °C was used instead of 110 °C.
The subsequent bromination of these 2-pyridones, by
using HBr (aq 47%) and isoamyl nitrite in dichloromethane,
was expected to selectively occur in position 8. This was
based upon what had been reported for analogues, where the
sulfur in the fused five-membered ring was exchanged for
a methylene group.11 However, to our surprise we only
observed bromination in position 6 with the more electron-
rich dihydro thiazolo fused system (Table 1). Still, the yields
were good and the selectivity was excellent in both cases and
initial Suzuki-Miyaura couplings were therefore applied on
these 6-bromo analogues. Under ligand free conditions
(Pd(OAc)2, phenyl boronic acid, and microwave assisted
heating) the coupling reactions with the 6-bromo pyridones
4 did not perform well and only approximately 20% conver-
sion of the starting material was observed.
With this result in mind the 6-bromo-8-iodo analogues 7
were prepared in order to solve the previous selectivity
problem. In addition, it was possible to synthesize com-
pounds 7a and 7b in gram scale by selective bromination of
the 6-position, as previously described, followed by iodina-
tion of the 8-position with NIS in acetonitrile (Scheme 2).
Regioselective Suzuki-Miyaura couplings of bromo- and
iodo-substituted monocyclic 2-pyridones are reported in
the literature.12 However, no examples are reported for
these types of couplings with bromo- and iodo-substituted
ring-fused 2-pyridones. In addition, dihydrothiazolo fused
2-pyridones are known to be problematic in Suzuki-
Miyaura couplings.13 Still, with our previous results in hand
(Table 1), we were hoping to see a regioselective coupling
in the 8-position under ligand free conditions by using the
6-bromo-8-iodo analogues 7.
This problem could be solved by preparing the 6-iodo
analogues 5 instead, via the same strategy (changing HBr for
HI (aq 57%) in the halogenation procedure). This time the
following ligand free Suzuki-Miyaura coupling resulted in a
83% and 86% yield of the coupling products, respectively
(Table 1).
(12) Conreaux, D.; Bossharth, E.; Monteiro, N.; Desbordes, P.; Vors,
J.-P.; Balme, G. Org. Lett. 2007, 9, 271–274.
(13) (a) Seger, H.; Geyer, A. Synthesis 2006, 3224–3230. (b) Sellstedt, M.;
Almqvist, F. Org. Lett. 2008, 10, 4005–4007.
J. Org. Chem. Vol. 75, No. 3, 2010 973

Bengtsson and Almqvist
SCHEME 3. Second Suzuki-Miyaura Coupling
JOCNote
TABLE 3. Catalytic Transfer Hydrogenation of the 6-Bromopyridones
Experimental Section
General Procedure for the Preparation of 6-Bromo Bicyclic
2-Pyridones 4a,b. The dihydro thiazolo ring-fused 2-pyridone
3a or 3b (4.33 mmol) and 47% HBr (aq) (4.33 mmol) in DCM
(25 mL) were cooled to -40 °C with an acetone/CO2 (s) bath
and isoamylnitrite (8.66 mmol) was added, then the reaction
was stirred for 6 h (-40 to 5 °C). The reaction mixture was
diluted with DCM and washed with saturated NaHCO3 (aq)
and 10% Na2S2O5 (aq). The organic phase was dried (Na2SO4),
filtered, and concentrated. The crude product was purified with
column chromatography on silica gel (heptane:EtOAc) to give
products 4a,b.
(3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester (4b). Com-
pound 4b (1.5 g, 81%) was isolated as a pale yellow foam: [R]D -107
(c 0.5, CHCl3). IR λ 1750, 1643, 1575, 1487, 1212. 1H NMR (400
MHz, CDCl3) δ 7.86-7.91 (m, 1H), 7.77-7.84 (m, 2H), 7.48-7.53
(m, 2H), 7.42-7.47 (m, 1H), 7.31-7.35 (m, 1H), 5.64 (s, 1H), 5.57
(dd, J = 8.5, 2.6 Hz,1H), 4.30-4.51 (m, 2H), 3.81 (s, 3H), 3.66 (dd,
J = 11.8, 8.5 Hz, 1H), 3.47 (dd, J = 11.8, 2.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ 168.1, 158.1, 153.4, 145.7, 134.0, 133.2, 132.2,
128.9, 128.2, 128.0, 126.7, 126.1, 125.7, 124.0, 111.4, 101.8, 63.9,
53.6, 40.2, 32.3. HRMS (ESþ) calcd [M þ Hþ] for C20H16BrNO3S
430.0113, obsd 430.0110.
Indeed, in the case of phenylboronic acid and 4-car-
boxyphenylboronic acid, this was possible and the 8-coupled
2-pyridones 8a-d were obtained in acceptable yields (Table 2).
When p-methoxy-substituted phenyl boronic acid or the
indol analogues were used, the reaction was not feasible
under ligand free conditions. However, these boronic acids
could be introduced to the 2-pyridone scaffold without
affecting the regioselectivity, by exchanging Pd(OAc)2 with
the commercially available Pd-source PEPPSI-iPr (Pd-
NHC), which was used in 5 mol % (the addition of more
Pd-NHC catalyst in these cases did not increase the yields).
In all the couplings, small amounts of the deiodinated
product 4 were observed as a byproduct, but no double
coupled products were seen.
General Procedure for the Preparation of 6-Bromo-8-iodo
Bicyclic 2-Pyridones 7a,b. To the 6-bromo bicyclic 2-pyridone
4a or 4b (3.25 mmol) in MeCN (35 mL) was added NIS (3.58
mmol) and the reaction was refluxed for 3.5 h. The solvent
was evaporated and the crude material was diluted with EtOAc
(150 mL) and washed with saturated NaHCO3 (aq) and 10%
Na2S2O5 (aq). The organic phase was dried (Na2SO4), filtered,
and concentrated, and the crude material was purified with
column chromatography on silca gel (heptane:EtOAc) to give
compounds 7a,b.
The yields decreased by approximately 20% when the
more sterically hindered CH2-1-naphthyl-substituted 2-pyri-
dones were reacted, as compared to the methyl substitution
(Table 2). Adding more than 1 equiv of the boronic acid only
yielded the dicoupled product as a byproduct.
The 6-bromo pyridones 8b, 8d, 8f, and 8h were easily
dehalogenated by catalytic transfer hydrogenation (ammo-
nium formate and Pd/C) to give 9a-d in excellent yields
(Table 3).
(3R)-6-Bromo-8-iodo-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester (4b).
Compound 4b (1.65 g, 91%) was isolated as a pale yellow foam:
[R]D -127 (c 0.5, CHCl3). IR λ 1750, 1628, 1553, 1466. 1H NMR
(400 MHz, CDCl3) δ8.10 (d, J =8.5Hz, 1H), 7.91 (d, J =7.9Hz,
1H), 7.78 (d, J = 8.2 Hz, 1H), 7.59-7.65 (m, 1H), 7.52-7.58 (m,
1H), 7.33-7.38 (m, 1H), 6.86-6.91 (m, 1H), 5.98 (dd, J = 8.8,
2.5 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 3H), 3.86 (dd, J = 11.8, 8.8 Hz,
1H), 3.59 (dd, J = 11.8, 2.5 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 168.1, 157.5, 153.5, 151.9, 134.0, 131.9, 130.8, 129.1,
127.6, 126.5, 126.0, 125.8, 123.9,123.0, 112.8, 67.1, 66.3, 53.8,
44.6, 31.5. HRMS (ESþ) calcd [M þ Hþ] for C20H15BrINO3S
555.9087, obsd 555.9081.
However, if further substitution in position 6 is desired this
can be accompished by using Pd-NHC as a palladium
source. The 6-indole derivative 10 was synthesized in a
72% yield by allowing 8a to be coupled in a second Suzu-
ki-Miyaura coupling, in the pressence of 5 mol % of Pd-
NHC and KF in dry methanol at 120 °C for 10 min, under
microwave irradiation (Scheme 3). Ligand free Pd(OAc)2
only gave a 20% conversion of the starting material by using
the same conditions.
In conclusion, we have shown that dihydro thiazolofused
2-pyridones can be halogenated with complete regioselec-
tivity in position 6. This halogenation selectivity, which is
opposite to what has been described earlier for ring-fused
2-pyridones, can be used with advantage to synthesize
6-bromo-8-iodo-substituted bicyclic 2-pyridones in gram
scale. Methods to selectively couple these dihalogenated
2-pyridones have been developed. These new methodologies
now allow for a faster and more efficient exploration of the
effect that the substitution patterns have on these scaffolds in
various biological systems.
General Procedure for the Preparation of 6-Bromo-8-aryl
Bicyclic 2-Pyridones 8a-h. A mixture of 6-bromo-8-iodo-bicyclic
2-pyridone 7a or 7b (0.1 mmol), boronic acid (0.1 mmol), KF (0.2
mmol), and Pd(OAc)2 (0.01 mmol) or PEPPSI-iPr (0.005 mmol)
˚
in dry MeOH (1.3 mL, dried over 3 A MS) was heated in the
microwave oven at 110 °C for 10 min. The reaction mixture
was diluted with saturated NaHCO3 (aq) and extracted with
EtOAc (30 mL). The organic phase was dried (Na2SO4), filtered,
and concentrated, and the crude material was purified with
974 J. Org. Chem. Vol. 75, No. 3, 2010

Bengtsson and Almqvist
JOCNote
column chromatography on silca gel (heptane:EtOAc) to give
compounds 8a-h.
114.9, 64.5, 56.0, 53.6, 37.2, 32.1. HRMS (ESþ) calcd [M þ Hþ]
for C27H23NO4S 458.1426, obsd 458.1424.
(3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-di-
hydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester
(8b). Compound 8b (30 mg, 66%) was isolated as a colorless
foam: [R]D -102 (c 0.5, CHCl3). IR λ 1749, 1649, 1469, 1216. 1H
NMR (400 MHz, CDCl3) δ 7.80-7.85 (m, 1H), 7.69-7.74 (m,
2H), 7.32-7.48 (m, 3H), 7.14-7.20 (m, 2H), 7.02-7.12 (m, 3H),
6.94-7.00 (m, 1H), 5.77 (dd, J = 8.6, 2.6 Hz,1H), 4.25-4.38 (m,
2H), 3.89 (s, 3H), 3.72 (dd, J = 11.8, 8.6 Hz, 1H), 3.49 (dd, J =
11.8, 2.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 168.3, 157.8,
152.3, 146.3, 136.3, 133.7, 132.7, 131.7, 129.9, 129.3, 128.8,
128.8, 128.8, 128.6, 127.2, 126.1, 125.7, 125.6, 124.6, 122.9,
117.1, 114.7, 65.1, 53.7, 37.4, 31.9. HRMS (ESþ) calcd [M þ
Hþ] for C26H20BrNO3S 506.0426, obsd 506.0423
General Procedure for the Preparation of 6-Hydro-8-aryl
Bicyclic 2-Pyridones 9a-d. A mixture of 6-bromo-8-aryl bicyclic
2-pyridone 8b, 8d, 8f, or 8h (0.1 mmol), 10% Pd/C (20 mg), and
ammonium formate (1 mmol) in MeOH (3 mL) was heated to
reflux for 3 h. The reaction mixture was diluted with water and
extracted with EtOAc (30 mL). The organic phase was filtered
through celte, dried (Na2SO4), filtered, and concentrated. The
crude material was purified with column chromatography on
silca gel (heptane:EtOAc) to give compounds 9a-d.
(3R)-8-(4-Methoxyphenyl)-7-naphthalen-1-ylmethyl-5-oxo-2,3-
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl
Ester (9b). Compound 9b (39mg, 91%) was isolated as a colorless
foam: [R]D -94 (c 0.5, MeCN). IR λ 1751, 1653, 1485. 1H NMR
(400 MHz, d3-MeCN) δ 7.86-7.91 (m, 1H), 7.78-7.82 (m, 1H),
7.67-7.71 (m, 1H), 7.40-7.50 (m, 3H), 7.20-7.30 (m, 3H),
6.92-6.97 (m, 2H), 5.55-5.57 (m, 1H), 5.48 (dd, J = 9.0,
2.6 Hz, 1H), 4.01 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.73 (dd,
J = 12, 9.0 Hz, 1H), 3.41 (dd, J = 12, 2.6 Hz, 1H). 13C NMR(100
MHz, d3-MeCN) δ 169.9, 161.6, 160.6, 155.9, 149.2, 135.6, 134.8,
132.6, 132.4 (broad), 132.3 (broad), 129.6 (2C), 128.6, 128.3,
127.1, 126.8, 126.6, 124.8, 115.8, 115.3 (broad), 115.0 (broad),
(3R)-6-(1H-Indol-5-yl)-7-methyl-5-oxo-8-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester (10).
A mixture of (3R)-6-bromo-7-methyl-5-oxo-8-phenyl-2,3-di-
hydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl es-
ter (8a) (20 mg, 0.053 mmol), PEPPSI-iPr (1.8 mg, 0.0026
mmol), indole-5-boronic acid (13 mg, 0.08 mmol), and KF
˚
(6 mg, 0.11 mmol) in dry MeOH (1 mL, dried over 3 A MS) was
heated in the microwave oven at 120 °C for 10 min. The
reaction mixture was diluted with water and pH was set to
8 with saturated NaHCO3, the water phase was extracted with
EtOAc (50 mL). The organic phase was dried (Na2SO4),
filtered, and concentrated. The crude product was purified
with column chromatography on silica gel (heptane:EtOAc
20:80). The title compound was isolated as a colorless foam
(16 mg, 72% yield): [R]D -92 (c 0.5, CHCl3). IR λ 3233, 1750,
1627, 1491, 1215. 1H NMR (400 MHz, d6-DMSO) δ 11.07 (br s,
1H), 7.43-7.50 (m, 2H), 7.29-7.42 (m, 6H), 6.92 (dd, J = 8.3,
1.7 Hz, 1H), 6.39-6.43 (m, 1H), 5.6 (dd, J = 9.1, 2.8 Hz, 1H),
3.84 (dd, J = 12.0, 9.1, 1H), 3.74 (s,3H), 3.48 (dd, J = 12.0, 2.8,
1H), 1.75 (s, 1H). 13C NMR (100 MHz, d6-DMSO) δ 168.9,
159.9, 146.8, 144.3, 137.5, 134.9, 129.9 (2C), 128.8 (2C), 127.9,
127.4, 127.1, 126.4, 125.4, 123.6, 121.8, 115.1, 110.7, 101.1,
63.9, 52.8, 30.5, 19.4. HRMS (ESþ) calcd [M þ Hþ] for
C24H20N2O3S 417.1273, obsd 417.1271
Acknowledgment. We thank the Swedish Research Council,
Knut and the Alice Wallenberg Foundation and the JC Kempe
Foundation (SJCKMS) for financial support.
Supporting Information Available: Experimental proce-
dures and spectroscopic data, and copies of 1H and 13C NMR
for new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 975