A selective intramolecular 5-exo-dig or 6-endo-dig cyclization en route to 2-furanone or 2-pyrone containing tricyclic scaffolds

Article abstract of DOI:10.1021/jo201952p

Ringfused bicyclic 2-pyridones exhibit interesting biological properties against pili assembly in uropathogenic Escherichia coli (Pinkner, J. S. et al. Proc. Natl. Acad. Sci. U. S. A.2006, 103, 17897 - 17902; Aberg, V. et al. Org. Biomol. Chem.2007, 5, 18

Full text of DOI:10.1021/jo201952p

Article
pubs.acs.org/joc
A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en
Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds
Christoffer Bengtsson and Fredrik Almqvist*
Department of Chemistry, Umea University, SE-90187 Umea, Sweden
̊
̊
S
* Supporting Information
ABSTRACT: Ringfused bicyclic 2-pyridones exhibit interesting biological properties against pili assembly in uropathogenic
Escherichia coli (Pinkner, J. S. et al. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 17897−17902; Åberg, V. et al. Org. Biomol. Chem.
2007, 5, 1827−1834) as well as curli formation (Cegelski, L. et al. Nat. Chem. Biol. 2009, 5, 913−919). In the search for new
ring-fused central fragments, highly selective synthetic routes to the 2-furanone or 2-pyrone containing tricyclic scaffolds 1 and 2
have been developed.
interfering with the chaperone usher pathway.7 Interestingly, by
INTRODUCTION
■
varying the substitution pattern on these central fragments,
compounds with amyloid inhibiting properties could also be
synthesized. From this collection, compounds named curlicides
were identified that inhibit the formation of bacterial fibers,
curli, which are functional amyloid structures.8
Since there is a tremendous need for new central fragments
in drug discovery,9 we have, in parallel with the development of
antibacterial compounds, taken a more general approach to
synthesize different rigidified tricyclic peptidomimetic scaffolds
based on the 2-pyridone core10,11 (e.g., 7 and 8, Figure 2).
2-Pyridones are commonly found in biologically active natural
products1 (e.g., champtothecin), and they have also attracted
researchers for the design and synthesis of peptide backbone
mimetics.2 We have earlier described the synthesis of highly
substituted bicyclic dihydro thiazolo ring-fused 2-pyridones 3−
6 shown in Figure 1.3−6 These compounds, as their
Figure 2. Previously developed tricyclic peptidomimetic scaffolds 7
and 8, together with the new 2-furanone (1) and 2-pyrone (2)
containing tricyclic scaffolds described in this article. The peptide
backbone connectivity is highlighted in red.
Figure 1. Several methods to selectively introduce substituents onto
dihydro thiazolo ring-fused 2-pyridones.
corresponding carboxylic acids, were originally designed to
inhibit the formation of pili in uropathogenic Escherichia coli by
Received: September 21, 2011
Published: October 18, 2011
© 2011 American Chemical Society
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Figure 3. Reterosynthetic strategy to the 2-pyrone or 2-furanone containing tricyclic scaffolds.
Scheme 1. Synthesis of the Acetylene Functionalized Ring-Fused Bicyclic 2-Pyridone and Attempted Cyclization
Scheme 2. Synthesis of the TMSE Protected Key Intermediates
2-Pyrones and 2-furanones are interesting compounds with
widespread biological characteristics and are common in many
natural products, for instance Terreulactone A12 and (−)-Te-
trodecamycin.13 In all ring-fused 2-pyridone derived peptidomi-
metics previously developed in the group, the C-terminal
carboxylic ester was positioned in the ring system as a
substituent with freedom to rotate (see Figure 1). However,
introducing a ring-fused 2-pyrone or 2-furanone to the central
fragment would result in a more rigidified scaffold but still with a
peptide backbone connectivity. Herein, we present the develop-
ment of methods to regioselectively synthesize either 2-furanone
or 2-pyrone fused tricyclic scaffolds (1 and 2, Figure 2). These
are two new central fragments, which can be substituted with a
variety of substituents, thus having great potential in the future
design and synthesis of peptidomimetic compounds.
RESULTS AND DISCUSSION
■
It is known from the literature that 2-pyrones and 2-furanones
can be synthesized via a cyclization of a carboxylic acid ester
onto an alkyne.14 In some cases the selectivity between 5-exo-
dig and 6-endo-dig cyclization is poor, and for the reaction to
proceed well, high concentrations of acid and/or high
temperatures are demanded.15 Previously published results
show that Pd-catalyzed cross couplings such as the Suzuki−
Miyaura6 and Heck3 couplings are possible in the 2-position of
the ring-fused bicyclic 2-pyridones (Figure 3). On the basis of
these results, we envisioned a retrosynthetic strategy starting
with an oxidation/bromination reaction, followed by a
Sonogashira coupling, and finally an acid induced cyclization
onto the acetylene (Figure 3).
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a
Table 1. Catalyst Screen to Obtain Selectivity in the Cyclization Reaction
entry
catalyst (5 mol %)
ligand (5 mol %)
reaction time (h)
ratio 12:13
conversion (isolated yield) (%)
b
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd-IPr-NHC
Pd-SIPr-NHC
PdCl2
2
20:80
100
c
b
2
DPPF
2
5:95
100
3
DPPP
1
>99% of 13
90:10
100 (88)
100 (88)
4
2.5
2.5
2.5
2.5
2
b
5
95:5
100
b
6
50:50
80
7
Pd(PPh3)2Cl2
Pd(PPh3)4
complex mixture
complex mixture
8
d
b
9
Pd2(dba)3*CHCl3
PPh3AuCl/AgSbF6
AuCl3
1.5
3
20:80
5:95
100
b
10
11
100
b
3
50:50
100
a
b
c
The reactions were performed in a 10 mg/mL concentration. No byproducts detected by HPLC. DPPF = 1,1′-Bis(diphenylphosphino)ferrocene.
dba = dibenzylideneacetone.
d
a
Table 2. Lewis Acid Screen
entry
Lewis acid (10 eq)
ratio 12:13
reaction time (h)
comment
1
2
3
4
5
6
7
8
ZrCl4
TiCl4
SnCl4
TiCl3
InCl3
18
18
18
18
18
18
3
complex mixture
only ester deprotection
complex mixture
only ester deprotection
70% starting material
no reaction
80:20
SbF3
BF3*Et2O
SnCl2
100% of 12
100% conversion
no reaction
18
a
The reactions were performed in a 10 mg/mL concentration.
Synthesis of the acetylene functionalized bicyclic 2-pyridone
was straightforward and started from the known methylester
916 (Scheme 1). The oxidation/bromination reaction pre-
viously reported6 followed by the Pd(PPh3)2Cl2/CuI catalyzed
Sonogashira coupling with trimethylsilylacetylene (TMSA)
gave 11 in 73% yield. However, the following cyclization to
give compounds 12 and 13 did not proceed as expected. Even
when using TFA as solvent for 18 h at room temperature, only
starting material remained.
We anticipated that the corresponding carboxylic acid would
ring-close under milder conditions, hence changing the methyl
ester to a more acid labile ester that could withstand the
conditions used in the synthetic sequence; our choice was the
trimethylsilylethyl ester (TMSE).
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Scheme 3. Selective Cyclizations of the mCF3Ph Substituted Bicyclic 2-Pyridone
Scheme 4. Tentative Mechanism of the Pd(OAc)2/DPPP Catalyzed Selective 5-exo-dig Cyclization
The TMSE esters (15 and 16) were synthesized via the
corresponding acid chlorides to give the racemic TMSE esters
15 and 16 in excellent yields (Scheme 2). The following
oxidation/bromination with excess NaH and BrCCl3 in MeCN,
previously developed,6 was slightly modified by changing
MeOH for 2-(trimethylsilyl)ethanol (TMSE−OH) because of
problems with transesterification. The reaction was yielding
surprisingly well, considering that TMSE esters have been
reported labile toward NaH in some cases.17 The bromides 17
and 18 were exposed to a Pd(PPh3)2Cl2/CuI catalyzed
Sonogashira coupling with TMSA followed by deprotection
of the TMS group with K2CO3 in MeOH/THF 4:1 to yield the
TMSE protected key intermediates 19 and 20 in 61 and 62%
yield, respectively (Scheme 2).
To our delight, this time the following ring closure worked,
and the 6-endo-dig (12) and 5-exo-dig (13) products were
obtained in a 1:1 ratio. Since the first conditions (20% TFA in
DCM at room temperature) did not give any selectivety, a
screen with different catalysts and conditions was performed
(Table 1). Although most of the conditions tested resulted in a
preference for the 5-exo-dig (13) product with almost complete
selectivity with Pd(OAc)2 and 1,3-bis(diphenylphosphino)-
propane (DPPP) (Table 1, entry 3). Catalysts based upon N-
heterocyclic carbenes (NHC) gave rewarding selectivity in
favor of the 6-endo-dig product 12 (Table 1, entries 4 and 5).
In an attempt to further increase the selectivity between 5-
exo-dig and 6-endo-dig cyclization in the Pd-NHC catalyzed
reactions, a set of Lewis acid additives were screened, and here
BF3*Et2O was by far the most effective Lewis acid (Table 2,
entry 7). Indeed, complete selectivity for the 6-endo-dig product
12 was obtained. As a control, the reaction was also performed
without Pd-catalyst, and under these conditions, fast depro-
tection of the TMSE ester was observed but no cyclization.
Even when the BF3*Et2O amount was increased to 20%, only
TMSE ester deprotection was observed.
Changing the cPr substituent on the 2-pyridone scaffold (19)
for the more electron withdrawing mCF3Ph substituent (20)
had a surprisingly large impact on the cyclization rate, even
though it is located far away from the reaction center. Under
noncatalyzed conditions, the reaction only reached 20%
conversion after 18 h reaction at room temperature with
DCM/TFA 80:20 as solvent. However, the catalyzed reactions
were efficient and carried out with excellent regioselectivity
between the 5-exo-dig (21) and 6-endo-dig (22) in 1 and 3 h,
respectively (Scheme 3).
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Table 3. Synthesis of the Internal Acetylenes
compound
R
yield (%)
23a
23b
23c
23d
23e
23f
nPr
cPr
Ph
86
84
95
89
86
95
pMeOPh
mCF3Ph
3-thienyl
Table 4. Cyclization of the Internal Acetylenes
entry
compound
R
catalyst (5 mol %)
ligand (5 mol %)
solvent
time (h)
conversion (isolated yield) (%)
100 (99)
1
24a
24a
24a
24b
24b
24b
24c
24c
24c
24d
24d
24d
24e
24e
24e
24f
nPr
nPr
nPr
cPr
cPr
cPr
Ph
I
28
1
a
2
Pd(OAc)2
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
II
III
I
100
a
3
Pd-IPr-NHC
2
100
4
1
100 (99)
a
5
Pd(OAc)2
II
III
I
1
100
a
6
Pd-IPr-NHC
4
100
7
18
1
100 (98)
a
8
Ph
Pd(OAc)2
II
III
I
100
a
9
Ph
Pd-IPr-NHC
18
1
100
10
11
12
13
14
15
16
17
18
pMeOPh
pMeOPh
pMeOPh
mCF3Ph
mCF3Ph
mCF3Ph
3-thienyl
3-thienyl
3-thienyl
100 (99)
a
Pd(OAc)2
II
III
I
1
100
a
Pd-IPr-NHC
2.5
100
96
2
90 (88)
a
Pd(OAc)2
II
III
I
100
a
Pd-IPr-NHC
2
100
20
1
100 (99)
a
24f
Pd(OAc)2
II
III
100
a
24f
Pd-IPr-NHC
1.5
100
a
No byproducts detected by HPLC.
The mechanism of the selective Pd-IPr-NHC catalyzed 6-
endo-dig cyclization in DCM/BF3*Et2O 95:5 is still not known.
The selective Pd(OAc)2/DPPP catalyzed 5-exo-dig cyclization
is believed to proceed via the Pd(II) catalytic cycle shown in
Scheme 4.18 The Pd(OAc)2/DPPP catalyzed reaction was also
performed with 5% TFA in DCM as solvent, but these
conditions gave less selectivity, with about 5% of the 6-endo-dig
product 22 formed.
The great results obtained with the terminal acetylenes,
regarding regioselectivity and yields in the ring-forming
reaction, encouraged further studies but with substituted
acetylenes. Hence, a set of different internal acetylenes was
synthesized in high yields from the bromo intermediate 17
(Table 3).
Next, the internal acetylenes 23a−f were exposed to the ring
closing procedure under the optimized conditions (Table 4).
Surprisingly, the reactions only gave the 6-endo-dig products
24a−f regardless of which conditions were used; without
catalyst the reaction rates were much slower (Table 4, entries 1,
7, 10, 13, and 16). The faster ring-closure of the cPr substituted
acetylene under noncatalyzed conditions (Table 4, entry 4) is
attributed to the cation stabilizing properties of the “sp2-like”
hybridization of the cPr carbons.19
CONCLUSIONS
■
In conclusion, we have shown that the 2-furanone or the 2-
pyrone containing tricyclic scaffolds (12, 13, 21, 22) can be
synthesized with excellent selectivity in good yields from the
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solid material was suspended in DCM (30 mL), and oxalylchloride
(2.81 mmol, 0.25 mL), together with DMF (5 drops), was added; the
reaction was stirred at rt for 10 min. 2-(Trimethylsilyl)ethanol (7.65
mmol, 1.1 mL) was added, and the reaction was stirred at rt for
additional 20 min. The reaction mixture was diluted with DCM and
washed with saturated NaHCO3 (aq); the organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified
by column chromatography on silica gel (heptane/EtOAc 90:10 →
60:40) to give the desired compound (1.15 g, 94%) as a colorless
TMSE protected terminal acetylenes 19 and 20 under Pd-
catalysis. In the latter case, it was discovered that exchanging
TFA for BF3*Et2O as an acidic additive gave complete 6-endo-
dig selectivity in the Pd-NHC catalyzed reaction. The
substituted 2-pyrone tricyclic scaffolds 24a−f were synthesized
in quantitative yields from the corresponding internal
acetylenes 23a−f. This was proven to work excellently for
alkyl, cycloalkyl, aryl, and heteroaryl substituted acetylenes.
Hence, two new rigid tricyclic central fragments, which both
have a peptide backbone connectivity, onto which it is easy to
introduce substituents and fuctional groups, have been
constructed. These central fragments are interesting in the
synthesis of future peptidomimetics.
1
foam: H NMR (400 MHz, CDCl3) δ 7.92−7.87 (m, 1H), 7.85−7.78
(m, 2H), 7.52−7.40 (m, 3H), 7.32−7.29 (m, 1H), 5.78 (s, 1H), 5.55
(dd, J = 2.2, 8.6 Hz, 1H), 4.54−4.35 (m, 2H), 4.35−4.24 (m, 2H),
3.67 (dd, J = 8.6, 11.7 Hz, 1H), 3.51 (dd, J = 2.2, 11.7 Hz, 1H), 1.71−
1.62 (m, 1H), 1.08−0.88 m, 4H), 0.80−0.71 (m, 2H), 0.05 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 168.4, 161.4, 156.7, 147.1, 134.1,
134.0, 132.0, 128.9, 127.7, 127.6, 126.3, 125.8, 125.6, 123.9, 115.5,
113.6, 65.0, 63.0, 36.3, 31.8, 17.3, 11.3, 7.8, 7.5, −1.5 (3C); IR λ 1734,
1653, 1577, 1483, 1425; [α]D = 0 (c0.5, CHCl3); HRMS (ES) calcd
[M + Na] for C27H31NNaO3SSi 500.1692, obsd 500.1694.
EXPERIMENTAL SECTION
■
General Methods. Unless stated otherwise, all reagents and
solvents were used as received from commercial suppliers. DMF was
distilled under a vacuum and stored over 3 Å molecular sieves. MeCN
and MeOH were dried with 3 Å molecular sieves for at least 20 h
before use. CuI was purified by refluxing with DCM for 20 h in a
Soxhlet apparatus and stored under dark and dry conditions. All HPLC
was performed on a C18 reversed-phase column with H2O/MeCN
mixtures as eluent. Microwave heated reactions were performed in a
microwave reactor; temperatures were monitored with an IR-probe.
TLC was performed on silica gel detected with UV light. Column
chromatography was employed on normal phase silica gel (eluents
given in brackets). Optical rotation was measured with a polarimeter at
20 °C and 589 nm. IR was recorded on a spectrometer equipped with
(3RS)-2-(Trimethylsilyl)ethyl 7-(Naphthalen-1-ylmethyl)-5-
oxo-8-(3-(trifluoromethyl)phenyl)-3,5-dihydro-2H-thiazolo-
[3,2-a]pyridine-3-carboxylate (16). Compound 14 (2.02 mmol, 1
g) was dissolved in THF (20 mL), and 1 M LiOH (4.0 mmol, 4 mL)
was added; the reaction was stirred at rt for 15 min. The reaction
mixture was quenched with acidic water (pH ∼ 1, set with 1 M HCl)
and extracted with EtOAc; the organic phase was dried (Na2SO4),
filtered, and concentrated. The solid material was suspended in DCM
(30 mL), and oxalylchloride (2.22 mmol, 0.19 mL), together with
DMF (5 drops), was added; the reaction was stirred at rt for 10 min.
2-(Trimethylsilyl)ethanol (6.1 mmol, 0.87 mL) was added, and the
reaction was stirred at rt for additional 15 min. The reaction mixture
was diluted with DCM and washed with saturated NaHCO3 (aq);
the organic phase was dried (Na2SO4), filtered, and concentrated. The
crude material was purified by column chromatography on silica gel
(heptane/EtOAc 90:10 → 60:40) to give the desired compound (1.06
g, 90%) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 7.83−7.80
(m, 1H), 7.75−7.71 (m, 1H), 7.61−7.53 (m, 3H), 7.51−7.32 (m, 5H),
7.21−7.16 (m, 1H), 5.99−5.92 (m, 1H), 5.60 (dd, J = 2.3, 8.6 Hz,
1H), 4.39−4.24 (m, 2H), 4.04−3.87 (m, 2H), 3.72−3.63 (m, 1H),
3.51−3.43 (m, 1H), 1.08−1.00 (m, 2H), 0.05 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 168.0, 161.3, 153.9, 147.3, 137.2, 133.9, 133.6 (d, J =
41 Hz, 1C), 133.4, 131.7, 131.4 (splitted q, J = 32 Hz, 1C), 129.6,
128.9, 127.9, 127.8, 127.0 (splitted d, J = 31 Hz, 1C), 126.2, 125.7,
125.4, 125.2, 123.9 (q, J = 270 Hz, 1C), 123.5, 115.8, 114.6, 65.3, 63.9,
36.9, 31.9, 17.4, −1.4 (3C); IR λ 1740, 1653, 1579, 1482, 1436, 1331;
[α]D = 0 (c0.5, CHCl3); HRMS (ES) calcd [M + Na] for
C31H30F3NNaO3SSi 604.1566, obsd 604.1566.
2-(Trimethylsilyl)ethyl 2-Bromo-8-cyclopropyl-7-(naphtha-
len-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyridine-3-carboxy-
late (17). Compound 15 (2.76 mmol, 1.32 g) was dissolved in dry
MeCN (30 mL, dried over 3 Å MS), NaH (8.3 mmol, 200 mg),
BrCCl3 (8.3 mmol, 0.82 mL), and 2-(trimethylsilyl)ethanol (5.52
mmol, 0.79 mL); the reaction was stirred at rt for 8 h. MeCN was
evaporated, and the crude material was quenched with saturated
NaHCO3 (aq) and extracted with EtOAc. The organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified
by column chromatography on silica gel (heptane/EtOAc 95:5 →
85:15) to give the desired compound (1.1 g, 72%) as a yellow foam:
1H NMR (400 MHz, CDCl3) δ 7.89−7.84 (m, 1H), 7.81−7.75 (m,
1
an ATR device. H and 13C NMR spectra were recorded on a 400 or
500 MHz spectrometer at 298 K and calibrated using the residual peak
of solvent as internal standard [CDCl3 (CHCl3 δH 7.26 ppm, CDCl3
δC 77.16 ppm), DMSO-d6 (DMSO-d5 δH 2.49 ppm, DMSO-d6 δC
39.5 ppm), DCM-d2 (DCM-d1 δH 5.32 ppm, DCM-d2 δC 53.84
ppm)]. HRMS was performed using a mass spectrometer with
electrospray ionization (ES+); sodiumformate was used as calibration
chemical.
Methyl 8-Cyclopropyl-2-ethynyl-7-(naphthalen-1-ylmethyl)-
5-oxo-5H-thiazolo[3,2-a]pyridine-3-carboxylate (11). Com-
pound 10 (1.73 mmol, 0.81 g), CuI (0.17 mmol, 32 mg),
Pd(PPh3)3Cl2 (0.09 mmol, 63 mg), and TEA (3.46 mmol, 0.48 mL)
were dissolved in dry DMF (15 mL). Ethynyltrimethylsilane (5.19
mmol, 0.73 mL) dissolved in dry DMF (0.5 mL) was added, and the
reaction 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; the organic phase was dried (Na2SO4), filtered,
and concentrated. The crude product was dissolved in MeOH/THF
4:1 (15 mL), and K2CO3 (1.73 mmol, 239 mg) was added; the
reaction was stirred at rt for 15 min. The reaction mixture was diluted
with saturated NaHCO3 and extracted with EtOAc; the organic phase
was dried (Na2SO4), filtered, and concentrated. The crude reaction
mixture was purified by column chromatography on silica gel
(heptane/EtOAc 90:10 → 70:30) to give the desired compound
1
(0.52 g, 73%) as a yellow foam: H NMR (400 MHz, DMSO-d6) δ
8.00−7.92 (m, 1H), 7.92−7.83 (m, 2H), 7.57−7.43 (m, 3H), 7.39−
7.31 (m, 1H), 5.56 (s, 1H), 5.15 (s, 1H), 4.55 (s, 2H), 3.82 (s, 3H),
1.89−1.79 (m, 1H), 1.02−0.94 (m, 2H), 0.77−0.70 (m, 2H); 13C
NMR (100 MHz, DMSO-d6) δ 159.5, 157.1, 155.1, 144.9, 134.3,
133.8, 133.4, 131.4, 128.6, 127.5, 127.4, 126.3, 125.8, 125.6, 123.9,
112.0, 110.1, 108.9, 92.9, 70.5, 53.2, 35.4, 10.6, 7.4 (2C); IR λ 1739,
1655, 1567, 1468, 1430; HRMS (ES) calcd [M + Na] for
C25H19NNaO3S 436.0984, obsd 436.0972.
(3RS)-2-(Trimethylsilyl)ethyl 8-Cyclopropyl-7-(naphthalen-1-
ylmethyl)-5-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyridine-3-car-
boxylate (15). Compound 9 (2.55 mmol, 1 g) was dissolved in THF
(20 mL), and 1 M LiOH (5.1 mmol, 5.1 mL) was added; the reaction
was stirred at rt for 20 min. The reaction mixture was quenched with
acidic water (pH ∼ 1, set with 1 M HCl) and extracted with EtOAc;
the organic phase was dried (Na2SO4), filtered, and concentrated. The
2H), 7.50−7.43 (m, 2H), 7.43−7.36 (m, 1H), 7.24−7.19 (m, 1H),
5.89 (s, 1H), 4.50 (s, 2H), 4.52−4.44 (m, 2H), 1.81−1.71 (m, 1H),
1.20−1.12 (m, 2H), 1.07−1.00 (m, 2H), 0.78−0.71 (m, 2H), 0.04 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 159.8, 158.1, 153.9, 146.8,
134.1, 134.0, 132.0, 131.2, 129.0, 127.9, 127.5, 126.4, 125.9, 125.6,
123.7, 112.2, 112.1, 103.1, 65.7, 36.4, 17.3, 11.0, 7.9 (2C), −1.4 (3C);
IR λ 1723, 1654, 1567, 1469; HRMS (ES) calcd [M + Na] for C27H28
BrNNaO3SSi 576.0640, obsd 576.0635.
2-(Trimethylsilyl)ethyl 2-Bromo-7-(naphthalen-1-ylmethyl)-
5-oxo-8-(3-(trifluoromethyl)phenyl)-5H-thiazolo[3,2-a]-
pyridine-3-carboxylate (18). Compound 16 (1.01 mmol, 0.59 g)
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was dissolved in dry MeCN (15 mL), NaH (3.03 mmol, 73 mg),
BrCCl3 (3.03 mmol, 0.3 mL) and 2-(trimethylsilyl)ethanol (2.02
mmol, 0.29 mL); the reaction was stirred at rt for 10 h. MeCN was
evaporated, and the crude material was quenched with saturated
NaHCO3 (aq) and extracted with EtOAc. The organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified
by column chromatography on silica gel (heptane/EtOAc 95:5 →
85:15) to give the desired compound (0.55 g, 83%) as a yellow foam:
1H NMR (400 MHz, CDCl3) δ 7.83−7.78 (m, 1H), 7.74−7.70 (m,
1H), 7.65−7.61 (m, 1H), 7.58−7.50 (m, 3H), 7.47−7.30 (m, 4H),
7.16−7.11 (m, 1H), 6.10 (s, 1H), 4.57−4.47 (m, 2H), 4.06 (s, 2H),
1.25−1.15 (m, 2H), 0.07 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
159.4, 158.0, 151.3, 147.1, 136.1, 133.9, 133.4, 133.3, 132.1 (q, J = 33
Hz, 1C), 131.5, 131.3, 130.3, 128.9, 128.0, 127.8, 126.7 (q, J = 3 Hz,
1C), 126.3, 125.9 (q, J = 3 Hz, 1C), 125.8, 125.4, 123.7 (q, J = 271 Hz,
1C), 123.4, 113.3, 112.3, 102.9, 65.9, 36.8, 17.3, −1.4 (3C); IR λ 1734,
1661, 1570, 1467, 1436; HRMS (ES) calcd [M + Na] for C31H27
BrF3NNaO3SSi 680.0514, obsd 680.0528.
6-Cyclopropyl-7-(naphthalen-1-ylmethyl)-1H,9H-pyrano-
[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione (12). Com-
pound 19 (0.04 mmol, 20 mg) and Pd-NHC (0.002 mmol, 1.4 mg)
were dissolved in DCM/BF3*Et2O 95:5 (2 mL), and the reaction was
stirred at rt for 3 h. The reaction mixture was diluted with DCM and
washed with saturated NaHCO3 (aq); the organic phase was dried
(Na2SO4) filtered and concentrated. The crude material was purified
by HPLC and freeze-dried to give the desired compound (14 mg,
88%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.90−7.85 (m,
1H), 7.82−7.76 (m, 2H), 7.56 (d, J = 8 Hz, 1H), 7.51−7.43 (m, 2H),
7.43−7.37 (m, 1H), 7.27−7.22 (m, 1H), 6.57 (d, J = 8 Hz, 1H), 6.04
(s, 1H), 4.51 (s, 2H), 1.82−1.73 (m, 1H), 1.10−1.03 (m, 2H), 0.80−
0.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.2, 153.2, 150.3,
149.4, 143.6, 142.5, 134.1, 134.0, 132.0, 129.0, 127.9, 127.6, 126.4,
125.9, 125.6, 123.7, 122.8, 115.8, 112.7, 100.7, 36.2, 11.2, 8.2 (2C); IR
λ 1735, 1655, 1602, 1477; HRMS (ES) calcd [M + Na] for
C24H17NNaO3S 422.0827, obsd 422.0818.
5-Cyclopropyl-3-methylidene-6-(naphthalen-1-ylmethyl)-
8H-furo[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,8(3H)-dione
(13). Compound 19 (0.04 mmol, 20 mg), Pd(OAc)2 (0.002 mmol,
0.4 mg), and DPPP (0.002 mmol, 0.8 mg) were dissolved in DCM/
TFA 85:15 (2 mL), and the reaction was stirred at rt for 1 h. The
reaction mixture was diluted with DCM and washed with saturated
NaHCO3 (aq); the organic phase was dried (Na2SO4) filtered and
concentrated. The crude material was purified by HPLC and freeze-
dried to give the desired compound (14 mg, 88%) as a yellow solid:
1H NMR (400 MHz, CDCl3) δ 7.91−7.85 (m, 1H), 7.83−7.74 (m,
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-2-ethynyl-7-(naphtha-
len-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]pyridine-3-carboxy-
late (19). Compound 17 (1.8 mmol, 1 g), CuI (0.18 mmol, 34 mg),
Pd(PPh3)3Cl2 (0.09 mmol, 63 mg) and TEA (3.6 mmol, 0.5 mL) were
dissolved in dry DMF (15 mL). Ethynyltrimethylsilane (5.4 mmol,
0.76 mL) dissolved in dry DMF (1 mL) was added, and the reaction
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; the organic phase was dried (Na2SO4), filtered, and
concentrated. The crude product was dissolved in MeOH/THF 4:1
(15 mL), and K2CO3 (1.8 mmol, 0.25 g) was added; the reaction was
stirred at rt for 10 min. The reaction mixture was diluted with
saturated NaHCO3 and extracted with EtOAc; the organic phase was
dried (Na2SO4), filtered, and concentrated. The crude reaction
mixture was purified by column chromatography on silica gel
(heptane/EtOAc 95:5 → 85:15) to give the desired compound
2H), 7.52−7.38 (m, 3H), 7.27−7.21 (m, 1H), 6.01 (s, 1H), 5.34 (d,
J = 3.4 Hz, 1H), 5.03 (d, J = 3.4 Hz, 1H), 4.52 (s, 2H), 1.82−1.72 (m,
1H), 1.14−1.05 (m, 2H), 0.84−0.76 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 158.6, 154.7, 153.3, 149.8, 145.8, 141.1, 134.2, 133.7, 133.3,
131.9, 129.1, 128.1, 127.6, 126.5, 126.0, 125.7, 123.7, 115.4, 114.0,
96.8, 36.5, 11.8, 8.2 (2C); IR λ 1782, 1664, 1569, 1464, 1134; HRMS
(ES) calcd [M + Na] for C24H17NNaO3S 422.0827, obsd 422.0815.
3-Methylidene-6-(naphthalen-1-ylmethyl)-5-[3-
(trifluoromethyl)phenyl]-8H-furo[3′,4′:4,5][1,3]thiazolo[3,2-a]-
pyridine-1,8(3H)-dione (21). Compound 20 (0.07 mmol, 40 mg),
Pd(OAc)2 (0.004 mmol, 0.8 mg), and DPPP (0.004 mmol, 1.6 mg)
were dissolved in DCM/TFA 85:15 (4 mL), and the reaction was
stirred at rt for 1 h. The reaction mixture was diluted with DCM and
washed with saturated NaHCO3 (aq); the organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified
by HPLC and freeze-dried to give the desired compound (30 mg,
1
(0.55 g, 61%) as a yellow foam: H NMR (400 MHz, DMSO-d6) δ
7.98−7.92 (m, 1H), 7.90−7.83 (m, 2H), 7.54−7,43 (m, 3H), 7.36−
7.31 (m, 1H), 5.53 (s, 1H), 5.11 (s, 1H), 4.54 (s, 2H), 4.36−4.28 (m,
2H), 1.88−1.79 (m, 2H), 1.04−0.93 (m, 4H), 0.76−0.69 (m, 2H),
−0.02 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 159.0, 157.1, 155.1,
144.9, 134.3 (splitted, 2C), 133.5, 131.5, 128.6, 127.6, 127.4, 126.4,
125.8, 125.7, 123.9, 112.0, 110.1, 108.5, 92.8, 70.6, 64.7, 35.5, 16.6,
10.6, 7.4 (2C), −1.6 (3C); IR λ 1732, 1654, 1568, 1466, 1247; HRMS
(ES) calcd [M + Na] for C29H29 NNaO3SSi 522.1535, obsd 522.1530.
2-(Trimethylsilyl)ethyl 2-Ethynyl-7-(naphthalen-1-ylmethyl)-
5-oxo-8-(3-(trifluoromethyl)phenyl)-5H-thiazolo[3,2-a]-
pyridine-3-carboxylate (20). Compound 18 (0.8 mmol, 525 mg),
CuI (0.08 mmol, 15 mg), Pd(PPh3)3Cl2 (0.04 mmol, 28 mg), and
TEA (1.6 mmol, 0.22 mL) were dissolved in dry DMF (10 mL).
Ethynyltrimethylsilane (2.4 mmol, 0.34 mL) dissolved in dry DMF
(1 mL) was added, and the reaction 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; the organic phase was dried
(Na2SO4), filtered, and concentrated. The crude product was dissolved
in MeOH/THF 4:1 (10 mL), and K2CO3 (0.8 mmol, 0.11 g) was
added; the reaction was stirred at rt for 10 min. The reaction mixture
was diluted with saturated NaHCO3 and extracted with EtOAc; the
organic phase was dried (Na2SO4), filtered, and concentrated. The
crude reaction mixture was purified by column chromatography on
silica gel (heptane/EtOAc 95:5 → 85:15) to give the desired
compound (0.3 g, 62%) as a yellow foam: 1H NMR (400 MHz,
DMSO-d6) δ 7.91−7.85 (m, 1H), 7.82−7.63 (m, 6H), 7.49−7.34 (m,
3H), 7.26−7.20 (m, 1H), 5.89 (s, 1H), 5.11 (s, 1H), 4.42−4.32 (m,
2H), 4.14 (s, 2H), 1.09−1.01 (m, 2H), 0.02 (s, 9H); 13C NMR (100
MHz, DMSO-d6) δ 158.8, 157.1, 152.1, 145.5, 136.0, 134.4, 134.1,
133.8, 133.3, 131.1, 130.6, 130.1 (q, J = 31 Hz, 1C), 128.5, 127.5,
127.4, 126.6 (q, J = 3 Hz, 1C), 126.2, 125.7, 125.6 (q, J = 3 Hz, 1C),
125.4, 123.8 (q, J = 272 Hz, 1C), 123.6, 113.1, 110.5, 108.3, 93.1, 70.2,
64.9, 35.8, 16.6, −1.6 (3C); IR λ 1734, 1662, 1570, 1471, 1329; HRMS
(ES) calcd [M + Na] for C33H28F3NNaO3SSi 626.1409, obsd
626.1412.
1
85%) as a yellow solid: H NMR (400 MHz, DMSO-d6) δ 7.92−7.87
(m, 1H), 7.83−7.68 (m, 6H), 7.50−7.37 (m, 3H), 7.25−7.20 (m, 1H),
5.96 (s, 1H), 5.64 (d, J = 4 Hz, 1H), 5.43 (d, J = 4 Hz, 1H), 4.15 (s,
2H); 13C NMR (125 MHz, DMSO-d6) δ 157.2, 152.8, 151.6, 151.3,
144.7, 140.7, 135.6, 134.3, 133.7, 133.2, 132.3, 131.1, 130.6, 130.1 (q,
J = 30 Hz, 1C), 128.4, 127.4, 127.3, 126.6 (splitted 1C), 126.1, 125.6
(2C), 125.3, 123.7 (q, J = 271 Hz, 1C), 123.5, 114.2, 113.0, 98.8, 35.7;
IR λ 1798, 1680, 1583, 1479, 1332; HRMS (ES) calcd [M + Na] for
C28H16F3NNaO3S 526.0701, obsd 526.0698.
7-(Naphthalen-1-ylmethyl)-6-[3-(trifluoromethyl)phenyl]-
1H,9H-pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione
(22). Compound 20 (0.07 mmol, 40 mg) and Pd-NHC (0.004 mmol,
2.7 mg) were dissolved in DCM/BF3*Et2O 95:5 (4 mL), and the
reaction was stirred at rt for 3 h. The reaction mixture was diluted with
DCM and washed with saturated NaHCO3 (aq); the organic phase
was dried (Na2SO4), filtered, and concentrated. The crude material
was purified by HPLC and freeze-dried to give the desired compound
(32 mg, 91%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.85−
7.78 (m, 1H), 7.76−7.70 (m, 1H), 7.67−7.61 (m, 1H), 7.60−7.49 (m,
3H), 7.57 (d, J = 4 Hz, 1H), 7.48−7.29 (m, 4H), 7.15−7.09 (m, 1H),
6.46 (d, J = 4 Hz, 1H), 6.28 (s, 1H), 4.08 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 158.9, 150.7, 150.6, 149.2, 143.8, 142.2, 136.3, 134.0,
133.5, 133.3, 132.2 (q, J = 33 Hz, 1C), 131.6, 130.4, 129.0, 128.1,
127.9, 126.9 (splitted 1C), 126.4, 126.0 (splitted 1C), 125.8, 125.4,
123.7 (q, J = 272 Hz, 1C), 123.4, 122.9, 115.9, 114.2, 100.5, 36.9; IR λ
1748, 1660, 1603, 1482, 1328; HRMS (ES) calcd [M + Na] for
C28H16F3NNaO3S 526.0701, obsd 526.0705.
9823
dx.doi.org/10.1021/jo201952p|J. Org. Chem. 2011, 76, 9817−9825

The Journal of Organic Chemistry
Article
Typical Procedure for Synthesis of Internal Acetylenes
23. 2-(Trimethylsilyl)ethyl 8-Cyclopropyl-7-(naphthalen-1-yl-
methyl)-5-oxo-2-(pent-1-ynyl)-5H-thiazolo[3,2-a]pyridine-3-
carboxylate (23a). Compound 17 (0.47 mmol, 0.26 g), CuI (0.047
mmol, 9 mg), Pd(PPh3)3Cl2 (0.023 mmol, 16 mg), and TEA (0.94
mmol, 0.13 mL) were dissolved in dry DMF (4.5 mL). 1-Pentyne
(1.41 mmol, 0.14 mL) dissolved in dry DMF (0.5 mL) was added, and
the reaction 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; the organic phase was dried (Na2SO4), filtered,
and concentrated. The crude reaction mixture was purified by column
chromatography on silica gel (heptane/EtOAc 95:5 → 85:15) to give
1.84−1.72 (m, 1H), 1.23−1.14 (m, 2H), 1.10−1.01 (m, 2H), 0.82−
0.74 (m, 2H), 0.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.0,
158.5, 154.5, 145.6, 134.9, 134.7, 134.0 (2C), 132.0, 131.3 (q,
J = 33 Hz, 1C), 129.2, 129.0, 128.6 (splitted, 1C), 127.8, 127.5, 126.4,
126.3 (splitted, 1C), 125.9, 125.6, 123.7, 123.5 (q, J = 271 Hz, 1C),
122.4, 112.1 (2C), 109.5, 98.1, 78.1, 65.6, 36.4, 17.4, 11.0, 8.0 (2C),
−1.5 (3C); IR λ 1732, 1662, 1570, 1472, 1329; HRMS (ES) calcd
[M + Na] for C36H32F3NNaO3SSi 666.1722, obsd 666.1719.
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-7-(naphthalen-1-yl-
methyl)-5-oxo-2-(thiophen-3-ylethynyl)-5H-thiazolo[3,2-a]-
pyridine-3-carboxylate (23f). Following the procedure for 23a, the
1
title compound (150 mg, 95%) was isolated as a yellow foam: H
1
the desired compound (0.22 g, 86%) as a yellow foam: H NMR (400
NMR (400 MHz, CDCl3) δ 7.84−7.79 (m, 1H), 7.79−7.70 (m, 2H),
7.57−7.53 (m, 1H), 7.45−7.39 (m, 2H), 7.39−7.33 (m, 1H), 7.29−
7.24 (m, 1H), 7.21−7.17 (m, 1H), 7.14−7.10 (m, 1H), 5.86 (s, 1H),
4.51−4.44 (m, 2H), 4.46 (s, 2H), 1.75−1.66 (m, 1H), 1.18−1.10 (m,
2H), 1.01−0.93 (m, 2H), 0.73−0.66 (m, 2H), 0.00 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 160.1, 158.3, 154.1, 145.6, 134.0, 133.9, 133.6,
131.9, 130.9, 129.6, 128.8, 127.7, 127.4, 126.3, 126.0, 125.7, 125.5,
123.7, 120.4, 111.9 (2C), 110.3, 95.4, 76.2, 65.3, 36.2, 17.3, 10.9, 7.9
(2C), −1.5 (3C); IR λ 1724, 1654, 1560, 1466; HRMS (ES) calcd
[M + Na] for C33H31NNaO3S2Si 604.1412, obsd 604.1412.
MHz, CDCl3) δ 7.88−7.83 (m, 1H), 7.82−7.74 (m, 2H), 7.50−7.42
(m, 2H), 7.42−7.36 (m, 1H), 7.24−7.19 (m, 1H) 5.87 (s, 1H), 4.50
(s, 2H), 4.49−4.42 (m, 2H), 2.43 (t, J = 8 Hz, 2H) 1.79−1.70 (m,
1H), 1.63 (m, 2H), 1.18−1.11 (m, 2H), 1.04−0.97 (m, 2H) 1.03 (t,
J = 4 Hz, 3H), 0.76−0.71 (m, 2H), 0.04 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 160.4, 158.4, 154.0, 145.7, 134.2, 134.0, 133.2, 132.0,
128.9, 127.7, 127.5, 126.3, 125.8, 125.6, 123.8, 111.8 (2C), 111.1,
102.7, 68.4, 65.2, 36.3, 21.9, 21.7, 17.3, 13.5, 11.0, 8.0 (2C), −1.4
(3C); IR λ 1734, 1662, 1474; HRMS (ES) calcd [M + Na] for
C32H35NNaO3SSi 564.2005, obsd 564.2016.
6-Cyclopropyl-7-(naphthalen-1-ylmethyl)-3-propyl-1H,9H-
pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione
(24a). Compound 23a (0.18 mmol, 100 mg) was dissolved in DCM/TFA
80:20 (4 mL), and the reaction was stirred at rt for 28 h. The reaction
mixture was diluted with DCM and washed with saturated NaHCO3
(aq); the organic phase was dried (Na2SO4), filtered, and concentrated
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-2-(cyclopropylethyn-
yl)-7-(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]-
pyridine-3-carboxylate (23b). Following the procedure for 23a,
1
the title compound (82 mg, 84%) was isolated as a yellow foam: H
NMR (400 MHz, CDCl3) δ 7.89−7.83 (m 1H), 7.82−7.74 (m, 2H),
7.50−7.42 (m, 2H), 7.39 (t, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H),
5.86 (s, 1H), 4.50 (s, 2H), 4.50−4.42 (m, 2H), 1.78−1.68 (m, 1H),
1.52−1.44 (m, 1H), 1.18−1.10 (m, 2H), 1.04−0.97 (m, 2H), 0.97−
0.90 (m, 2H), 0.89−0.82 (m, 2H), 0.77−0.70 (m, 2H), 0.05 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 160.4, 158.4, 154.0, 145.7, 134.2,
134.0, 133.3, 132.0, 128.9, 127.7, 127.5, 126.3, 125.8, 125.6, 123.8,
111.9 (2C), 111.2, 105.9, 65.2, 63.2, 36.4, 17.3, 11.0, 9.4 (2C), 8.0
(2C), 0.7, −1.4 (3C); IR λ 1732, 1659, 1569, 1473; HRMS (ES) calcd
[M + Na] for C32H33NNaO3SSi 562.1848, obsd 562.1849.
1
to give the desired product (79 mg, 99%) as a yellow foam: H NMR
(400 MHz, CDCl3) δ 7.89−7.83 (m, 1H), 7.83−7.73 (m, 2H), 7.50−
7.35 (m, 3 h), 7.23 (d, J = 8 Hz, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.49
(s, 2H), 2.53 (t, J = 8 Hz, 2H), 1.79−1.65 (m, 3H), 1.09−1.00 (m,
2H), 0.97 (t, J = 4 Hz, 3H), 0.78−0.70 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 165.3, 159.2, 152.9, 150.2, 144.1, 143.8, 134.0 (2C), 131.9,
129.0, 127.8, 127.5, 126.4, 125.8, 125.6, 123.7, 120.5, 115.7, 112.6,
97.1, 36.1, 35.6, 20.3, 13.5, 11.1, 8.2 (2C); IR λ 1734, 1654, 1616,
1578, 1474, 1420; HRMS (ES) calcd [M + Na] for C27H23NNaO3S
464.1296, obsd 464.1298.
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-7-(naphthalen-1-yl-
methyl)-5-oxo-2-(phenylethynyl)-5H-thiazolo[3,2-a]pyridine-
3-carboxylate (23c). Following the procedure for 23a, the title
3,6-Dicyclopropyl-7-(naphthalen-1-ylmethyl)-1H,9H-
pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione
(24b). Compound 23b (0.19 mmol, 100 mg) was dissolved in DCM/
TFA 80:20 (4 mL), and the reaction was stirred at rt for 1 h. The reaction
mixture was diluted with DCM and washed with saturated NaHCO3
(aq); the organic phase was dried (Na2SO4), filtered, and concentrated
1
compound (147 mg, 95%) was isolated as a yellow foam: H NMR
(400 MHz, CDCl3) δ 7.90−7.85 (m, 1H), 7.84−7.76 (m, 2H), 7.54−
7.45 (m, 4H), 7.44−7.34 (m, 4H), 7.24 (d, J = 4 Hz, 1H), 5.91 (s,
1H), 4.57−4.48 (m, 4H), 1.83−1.73 (m, 1H), 1.23−1.15 (m, 2H),
1.08−1.00 (m, 2H), 0.81−0.73 (m, 2H), 0.04 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 160.2, 158.5, 154.2, 145.7, 134.1, 134.0, 133.9, 132.0,
131.9 (2C), 129.8, 128.9, 128.6 (2C), 127.8, 127.5, 126.3, 125.8, 125.6,
123.7, 121.4, 112.0 (2C), 110.4, 100.1, 76.7, 65.4, 36.4, 17.4, 11.0, 8.0
(2C), −1.5 (3C); IR λ 1733, 1665, 1570, 1473; HRMS (ES) calcd
[M + Na] for C35H33NNaO3SSi 598.1848, obsd 598.1850.
1
to give the desired product (83 mg, 99%) as a yellow foam: H NMR
(400 MHz, CDCl3) δ 7.89−7.82 (m, 1H), 7.82−7.73 (m, 2H), 7.50−
7.35 (m, 3H), 7.23 (d, J = 8 Hz, 1H), 6.37 (s, 1H), 6.01 (s, 1H), 4.49
(s, 2H), 1.87−1.69 (m, 2H), 1.20−1.12 (m, 2H), 1.09−0.96 (m, 4H),
0.78−0.69 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.2, 159.2,
152.7, 149.6, 144.7, 143.6, 134.0 (2C), 131.9, 128.9, 127.8, 127.5,
126.3, 125.8, 125.6, 123.7, 119.5, 115.6, 112.6, 95.5, 36.1, 14.5, 11.1,
9.1 (2C), 8.2 (2C); IR λ 1734, 1654, 1607, 1474; HRMS (ES) calcd
[M + Na] for C27H21NNaO3S 462.1140, obsd 462.1135.
6-Cyclopropyl-7-(naphthalen-1-ylmethyl)-3-phenyl-1H,9H-
pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione
(24c). Compound 23c (0.25 mmol, 145 mg) was dissolved in DCM/
TFA 80:20 (6 mL), and the reaction was stirred at rt for 18 h. The reaction
mixture was diluted with DCM and washed with saturated NaHCO3
(aq); the organic phase was dried (Na2SO4), filtered, and concentrated
to give the desired product (117 mg, 98%) as a yellow solid: 1H
NMR (400 MHz, CDCl3) δ 7.92−7.84 (m, 3H), 7.84−7.76 (m, 2H),
7.52−7.38 (m, 6H), 7.28−7.23 (m, 1H), 6.95 (s, 1H), 6.06 (s, 1H),
4.52 (s, 2H), 1.83−1.74 (m, 1H), 1.12−1.04 (m, 2H), 0.83−0.76 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 159.9, 159.2, 153.1, 149.2, 144.1,
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-2-((4-methoxyphenyl)-
ethynyl)-7-(naphthalen-1-ylmethyl)-5-oxo-5H-thiazolo[3,2-a]-
pyridine-3-carboxylate (23d). Following the procedure for 23a,
1
the title compound (145 mg, 89%) was isolated as a yellow foam: H
NMR (400 MHz, DMSO-d6) δ 7.98−7.91 (m, 1H), 7.91−7.82 (m,
2H), 7.55−7.42 (m, 5H), 7.34 (d, J = 8 Hz, 1H), 7.03−6.95 (m, 2H),
5.54 (s, 1H), 4.53 (s, 2H), 4.41−4.32 (m, 2H), 3.79 (s, 3H), 1.88−
1.77 (m, 1H), 1.08−1.00 (m, 2H), 1.00−0.91 (m, 2H), 0.76−0.67 (m,
2H), −0.03 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 160.6, 159.2,
157.0, 154.6, 144.9, 134.3, 133.4, 133.3 (2C), 132.5, 131.4, 128.6,
127.5, 127.4, 126.3, 125.8, 125.6, 123.9, 114.6 (2C), 111.9, 111.7,
110.1, 109.8, 100.3, 75.1, 64.4, 55.4, 35.4, 16.8, 10.6, 7.4 (2C), −1.7
(3C); IR λ 1728, 1654, 1605, 1568, 1507, 1466; HRMS (ES) calcd
[M + Na] for C36H35NNaO4SSi 628.1954, obsd 628.1945.
2-(Trimethylsilyl)ethyl 8-Cyclopropyl-7-(naphthalen-1-yl-
methyl)-5-oxo-2-((3-(trifluoromethyl)phenyl)ethynyl)-5H-
thiazolo[3,2-a]pyridine-3-carboxylate (23e). Following the pro-
cedure for 23a, the title compound (145 mg, 86%) was isolated as a
yellow foam: H NMR (400 MHz, CDCl3) δ 7.91−7.84 (m, 1H),
7.84−7.75 (m, 3H), 7.70−7.63 (m, 2H), 7.54−7.45 (m, 3H), 7.44−
7.38 (m, 1H), 7.25 (d, J = 8 Hz, 1H), 5.91 (s, 1H), 4.57−4.49 (m, 4H),
143.8, 134.2, 134.1, 132.1, 131.5, 130.5, 129.3 (2C), 129.1, 128.0, 127.6,
126.5, 126.1 (2C), 125.9, 125.7, 123.8, 121.2, 116.0, 112.8, 95.2, 36.2,
11.2, 8.3 (2C); IR λ 1748, 1663, 1605, 1482; HRMS (ES) calcd [M +
Na] for C30H21NNaO3S 498.1140, obsd 498.1146.
6-Cyclopropyl-3-(4-methoxyphenyl)-7-(naphthalen-1-yl-
methyl)-1H,9H-pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-
1,9-dione (24d). Compound 23d (0.24 mmol, 145 mg) was
1
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dx.doi.org/10.1021/jo201952p|J. Org. Chem. 2011, 76, 9817−9825

The Journal of Organic Chemistry
Article
dissolved in DCM/TFA 80:20 (6 mL), and the reaction was stirred at
rt for 1 h. The reaction mixture was diluted with DCM and washed
with saturated NaHCO3 (aq); the organic phase was dried (Na2SO4),
filtered, and concentrated to give the desired product (120 mg, 99%)
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1
as a yellow solid: H NMR (400 MHz, CD2Cl2 + 1% TFA) δ 7.99−
7.88 (m, 4H), 7.71−7.66 (m, 1H), 7.58 (s, 1H), 7.56−7.47 (m, 3H),
7.38−7.33 (m, 1H), 7.11−7.05 (m, 2H), 6.53 (s, 1H), 4.79 (s, 2H),
3.91 (s, 3H), 2.23−2.11 (m, 1H), 1.45−1.36 (m, 2H), 1.04−0.96 (m,
1H); 13C NMR (100 MHz, CD2Cl2 + 1% TFA) δ 164.8, 162.9, 161.0,
157.8, 157.0, 152.2, 148.6, 134.6, 132.3, 131.9, 129.5 (3C), 129.2,
128.8, 127.3, 126.6, 126.2, 125.5, 123.6, 120.5, 119.2, 115.7 (2C),
112.8, 97.3, 56.2, 37.0, 11.9, 9.0 (2C); IR λ 1738, 1657, 1606, 1571,
1505, 1472; HRMS (ES) calcd [M + Na] for C31H23NNaO4S
528.1245, obsd 528.1250.
(2) (a) Reiner, J. E.; Lim-Wilby, M. S.; Brunck, T. K.; Ha-Uong, T.;
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6-Cyclopropyl-7-(naphthalen-1-ylmethyl)-3-[3-
(trifluoromethyl)phenyl]-1H,9H-pyrano[3′,4′:4,5][1,3]thiazolo-
[3,2-a]pyridine-1,9-dione (24e). Compound 23e (0.23 mmol, 145
mg) was dissolved in DCM/TFA 80:20 (6 mL), and the reaction was
stirred at rt for 120 h. The reaction mixture was diluted with DCM and
washed with saturated NaHCO3 (aq); the organic phase was dried
(Na2SO4), filtered, and concentrated to give the desired product (110
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(7) (a) Pinkner, J. S.; Remaut, H.; Buelens, F.; Miller, E.; Åberg, V.;
Pemberton, N.; Hedenstrom, M.; Larsson, A.; Seed, P.; Waksman, G.;
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̈
1
mg, 88%) as a yellow foam: H NMR (400 MHz, CDCl3) δ 8.05 (s,
1H), 8.02−7.95 (m, 1H), 7.86−7.79 (m, 1H), 7.79−7.70 (m, 2H),
7.67 (d, J = 8 Hz 1H), 7.57−7.49 (m, 1H), 7.46−7.38 (m, 2H), 7.38−
7.32 (m, 1H), 7.21 (d, J = 8 Hz, 1H), 7.10 (s, 1H), 6.00 (s, 1H), 4.47
(s, 2H), 1.79−1.68 (m, 1H), 1.08−0.98 (m, 2H), 0.76−0.68 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 159.0, 157.5, 153.3, 148.7, 144.0,
143.8, 133.9, 133.8, 131.8, 131.6 (q, J = 32 Hz, 1C), 131.0, 129.8,
129.0, 128.9, 127.8, 127.6 (splitted, 1C), 127.5, 126.3, 125.8, 125.5,
123.6 (q, J = 270 Hz, 1C), 123.6, 122.6 (splitted, 1C), 121.4, 115.4,
112.8, 96.6, 36.0, 11.0, 8.1 (2C); IR λ 1742, 1660, 1474, 1323; HRMS
(ES) calcd [M + Na] for C31H20F3NNaO3S 566.1014, obsd 566.1023.
6-Cyclopropyl-7-(naphthalen-1-ylmethyl)-3-(thiophen-3-yl)-
1H,9H-pyrano[3′,4′:4,5][1,3]thiazolo[3,2-a]pyridine-1,9-dione
(24f). Compound 23f (0.18 mmol, 105 mg) was dissolved in DCM/
TFA 80:20 (4 mL), and the reaction was stirred at rt for 20 h. The
reaction mixture was diluted with DCM and washed with saturated
NaHCO3 (aq); the organic phase was dried (Na2SO4), filtered, and
concentrated to give the desired product (86 mg, 99%) as a yellow
̈
(8) Cegelski, L.; Pinkner, J. S.; Hammer, N. D.; Cusumano, C. K.;
Hung, C. S.; Chorell, E.; Åberg, V.; Walker, J. N.; Seed, P. C.;
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1
solid: H NMR (400 MHz, CDCl3) δ 7.88−7.82 (m, 1H), 7.82−7.76
(m, 1H), 7.76−7.67 (m, 2H), 7.43−7.34 (m, 2H), 7.34−7.24 (m, 3H),
7.20−7.13 (m, 1H), 6.68 (s, 1H), 5.95 (s, 1H), 4.41 (s, 2H), 1.72−
1.61 (m, 1H), 1.01−0.92 (m, 2H), 0.71−0.63 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 159.1, 155.9, 153.0, 149.1, 144.4, 143.7, 134.1,
134.0, 132.7, 132.0, 129.0, 127.9, 127.6 (splitted, 2C), 127.0, 126.4,
125.9, 125.6, 124.5, 123.8, 120.5, 115.7, 112.7, 95.0, 36.1, 11.1, 8.2
(2C); IR λ 1747, 1662, 1606, 1475; HRMS (ES) calcd [M + Na] for
C28H19NNaO3S2 504.0704, obsd 504.0698.
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ASSOCIATED CONTENT
■
(16) Emtenas, H.; Taflin, C.; Almqvist, F. Mol. Diversity 2003, 7,
̈
S
* Supporting Information
165−169.
1H NMR and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet http://pubs.
acs.org.
(17) Serrano-Wu, M. H.; Regueiro-Ren, A.; St. Laurent, D. R.;
Carroll, T. M.; Balasubramanian, B. N. Tetrahedron Lett. 2001, 42,
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AUTHOR INFORMATION
(19) De Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809−826.
■
Corresponding Author
*Tel.: +46907866925. Fax: +46907867655. E-mail: fredrik.
almqvist@chem.umu.se.
ACKNOWLEDGMENTS
■
We are thankful for financial support from the Swedish
Research Council (621-2010-4730), the Knut and Alice
Wallenberg Foundation, and the Kempe Foundation
(SJCKMS).
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dx.doi.org/10.1021/jo201952p|J. Org. Chem. 2011, 76, 9817−9825