Trimethylsilyl trifluoromethanesulfonate-promoted cyclocondensation of β-ketoenamides and subsequent nonaflation to pyrid-2-yl and pyrid-4-yl nonaflates as flexible precursors for polysubstituted pyridines

Article abstract of DOI:10.1055/s-0033-1338548

The intramolecular condensation of β-ketoenamides to 2- and/or 4-pyridone derivatives using either KOt-Bu or trimethylsilyl trifluoromethanesulfonate/Hu?nig's base was investigated. Subsequent nonaflation of the cyclization products allowed a facile purification and further functionalization through Suzuki-Miyaura couplings leading to new highly substituted pyridine derivatives. The dependence of the regioselectivity of cyclocondensation on the structure of the β-ketoenamides is discussed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338548

3288▌
PAPER
paper
Trimethylsilyl Trifluoromethanesulfonate-Promoted Cyclocondensation of
β-Ketoenamides and Subsequent Nonaflation to Pyrid-2-yl and Pyrid-4-yl
Nonaflates as Flexible Precursors for Polysubstituted Pyridines
Synthesis of Pyrid-4-yl and Pyrid-2-yl Nonaflates
Paul Hommes, Sarah Berlin, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received: 07.08.2013; Accepted after revision: 16.09.2013
Dedicated to Professor Ernst Schaumann on the occasion of his 70th birthday
TMSOTf/base-promoted condensation. Furthermore, we
Abstract: The intramolecular condensation of β-ketoenamides to
wanted to explore the reactivity of β-ketoenamides 7 bear-
2- and/or 4-pyridone derivatives using either KOt-Bu or trimethyl-
ing two enolizable methylene groups. We envisioned that
upon treatment with TMSOTf these compounds may cy-
silyl trifluoromethanesulfonate/Hünig’s base was investigated.
Subsequent nonaflation of the cyclization products allowed a facile
purification and further functionalization through Suzuki–Miyaura clize via intermediate 8 to give pyrid-4-ones 9 (path a) as
couplings leading to new highly substituted pyridine derivatives.
The dependence of the regioselectivity of cyclocondensation on the
well as via 10 to give pyrid-2-ones 11 (path b).
structure of the β-ketoenamides is discussed.
O
R1
R1
Key words: enamides, pyridines, cyclocondensation, nonaflates,
cross couplings
R4
O
R4
R1
NH
O
HN
R2
N
TMSOTf/R3N
R2
R2
OH
refs. 4, 5 and 7
R3
R4
R3
R3
With its ubiquitous structural motif in biologically active
compounds and functional materials pyridines belong
without doubt to the most important heterocycles.1 Since
the early days of organic chemistry this has been motivat-
ing chemists to search for efficient methods to synthesize
functionalized pyridine derivatives.2,3 In recent years our
group developed a remarkably flexible approach for the
preparation of highly functionalized pyrid-4-ones 2 by a
trimethylsilyl trifluoromethanesulfonate (TMSOTf)/base-
promoted intramolecular condensation of β-ketoenamides
1 (Scheme 1). A mechanistic proposal for the TMSOTf-
promoted cyclocondensation has previously been present-
ed suggesting an aldol-type step of an enolate or its equiv-
alent with the amide carbonyl group.4 Suitable cyclization
precursors can be synthesized by a three-component reac-
tion of lithiated alkoxyallenes, nitriles, and carboxylic ac-
ids,5 or by N-acylation of β-ketoenamines. Suitable
enamines are easily accessible via amination of 1,3-dike-
tones,6 or by trapping the Blaise intermediate with acetic
acid anhydride.7,8 Conversion of 4-hydroxypyridines 3
(the tautomers of 2) into the corresponding nonafluorobu-
tanesulfonates (nonaflates)9 allows for versatile subse-
quent transformations through Pd-catalyzed cross-
coupling reactions.10,11
1
2
3
R1
R1 = (het)aryl, alkenyl,
RF, CHR2
R4
R5
1) NfF or Nf2O
2) R5X, [Pd]
N
R2
R3
4
Scheme 1 Synthesis of highly functionalized pyridine derivatives
via TMSOTf-promoted cyclocondensation of β-ketoenamides 1
(Nf = nonafluorobutanesulfonyl)
O
O
R6
R6
R4
NH
O
HN
R2
base
R2
R4
ref. 13
R3
R3
5
6
R6
This work:
OTMS
R6
R4
O
TMSOTf, R3N
path a
N
OTMS
HN
R2
R4
R2
O
R6
8
9
NH
O
R2
It is known that β-ketoenamides of type 5 bearing fairly
acidic protons in α-position to the amide carbonyl moiety
[R6 = (het)aryl or electron-withdrawing substituents] cy-
clize under basic conditions to provide pyrid-2-one deriv-
atives 6 (Scheme 2).12,13 We were therefore interested, if
this kind of transformation would also be possible via a
7
R4
OTMS
N
O
R6
R6
R4
OTMS
R4
HN
R2
path b
TMSOTf, R3N
R2
10
11
Scheme 2 Cyclocondensation of β-ketoenamides to pyrid-2-ones 11
and/or pyrid-4-ones 9
SYNTHESIS 2013, 45, 3288–3294
Advanced online publication: 10.10.2013
0
0
3
9
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7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0033-1338548; Art ID: SS-2013-T0555-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrid-4-yl and Pyrid-2-yl Nonaflates
3289
An analogous regiounselective reactivity is well known
from the Camps cyclization14 – the base-promoted cyclo-
condensation of o-(amido)acetophenones. The use of sub-
strates with two α-acidic carbonyl moieties in the Camps
cyclization employing alkali hydroxides or alkoxides as
base usually provides mixtures of 2- and 4-quinolones as
products. In contrast, as recently reported, treatment of
such o-(acetamido)acetophenone derivatives with TMS-
OTf in presence of triethylamine exclusively provides 4-
quinolones.15
Table 1 Cyclocondensation of β-Ketoenamides 14a–d to Pyrid-2-
ones 15a–d
O
O
R2
R1
R2
TMSOTf (A)
HN
R1
NH
O
or
R1
R1
KOt-Bu (B)
14
15
Entry
R1
R2
Methoda
Yield (%)
1
2
3
4
5
6
7
14a
14b
Ph
Ph
Ph
Ph
Me
Et
Ph
Ph
Me
Me
Ph
Ph
H
A
B
A
B
B
B
B
15a
15b
79
87
93
In order to explore the reactivity of β-ketoenamides of
type 5 and 7, we prepared a series of cyclization precur-
sors as depicted in Scheme 3: amination of simple 1,3-di-
ketones 12a–c to enamines 13a–c followed by acylation
with acyl chlorides or the corresponding anhydrides pro-
vided the β-ketoenamides 14a–h in moderate to good
yields (see Supporting Information for details).
b
–
14c
14d
14e
15c
15d
15e
62c
81d
e
O
Me
–
R2CH2COCl
R2
NH3
O
O
NH2
O
a Method A: TMSOTf (5.0 equiv), DIPEA (4.0 equiv), DCE, sealed
tube, 90 °C, 3 d; Method B: KOt-Bu (1.5 equiv), THF, 0 °C to r.t., 20
h.
NH
O
or
R1
R1
R1
R1
R1
R1
(R2CH2CO)2O
R1
R1
b No conversion.
Ph 12a
Ph 13a
38–85%
14a–h
=
=
2 = H, Me, Ph,
Bn, OMe
c Enamine 13b detected in traces.
Me
Me
R
12b
13b
Et
12c
Et
13c
d Enamine 13c isolated in 11% yield.
e Enamine 13b isolated in 90% yield.
Scheme 3 Preparation of β-ketoenamides 14a–h
directly convert the crude product mixture into the corre-
sponding nonaflates whose dramatically decreased polar-
ity allows a facile chromatographic purification. As
anticipated, enamides 14c–h can cyclize via two different
pathways. After subsequent nonaflation of the unpurified
intermediates the pyrid-4-yl nonaflates 16 and in some
cases small amounts of the pyrid-2-yl nonaflates 17 were
obtained.19 Except for pyrid-4-yl nonaflate 16g (76%, Ta-
ble 2, entry 5), the yields were only moderate, neverthe-
less the experiments clearly reveal that upon treatment
with TMSOTf there is a strong preference of the β-keto-
enamides 14c–h to cyclize via intermediates of type 8 to
deliver pyrid-4-ones. Unless being enforced in precursors
such as 14a,b (R1 ≠ CH2R, Table 1), the TMSOTf-pro-
moted cyclocondensation via intermediates of type 10 ap-
parently plays only a minor role. This competing
cyclization to pyrid-2-ones was only observed for en-
amides 14c, 14d, and 14h bearing substituents R2 that fa-
cilitate enolization20 of the amide methylene moiety
(R2 = Ph or OMe).
Next, the cyclizations of β-ketoenamides 14a–h were in-
vestigated (Tables 1 and 2). We first conducted the intra-
molecular condensation of the dibenzoylmethane (12a)-
derived enamides 14a and 14b using TMSOTf and diiso-
propylethylamine (DIPEA; Hünig’s base) (Table 1, en-
tries 1 and 3). Due to the lack of a methyl ketone moiety
as in 7 these substrates cannot cyclize to pyrid-4-ones. We
were pleased to find that they were converted into the ex-
pected pyrid-2-ones 15a and 15b in good yields upon
treatment with TMSOTf. For the cyclization of compound
14a the traditional conditions using KOt-Bu16 allowed a
shorter reaction time and provided a slightly higher yield
(entry 2). For compound 14b, however, the TMSOTf-pro-
moted condensation proved to be the superior method
since the KOt-Bu protocol failed in this case (entry 4). Us-
ing the latter protocol the acetylacetone (12b)- and hep-
tan-3,5-dione (12c)-derived enamides 14c and 14d
smoothly cyclized to the pyrid-2-ones 15c16 and 15d (en-
tries 5 and 6). In both cases a competing deacylation lead-
ing to the formation of the corresponding enamines 13b
and 13c was observed. For enamide 14e the KOt-Bu pro-
tocol resulted in complete deacylation to 13b, the expect-
ed pyrid-2-one 15e was not detected, indicating that this
method – as also concluded by Fisyuk et al. for related
compounds17 – requires substituents that are able to stabi-
lize a negative charge next to R2.
Pyrid-2-ones 15c and 15d obtained by the KOt-Bu-pro-
moted cyclization could also successfully be nonaflated.
The corresponding pyrid-2-yl nonaflates 17c and 17d
were obtained in good yields (Scheme 4).
As already mentioned in the introduction, the nonafloxy
group allows a large number of subsequent transforma-
tions. Exemplarily, we subjected the pyridyl nonaflates
16c and 17d to Suzuki–Miyaura reactions10,21 (Scheme 5).
The excellent yields of the cross-coupled products 18 and
The TMSOTf/DIPEA promoted intramolecular conden-
sations of β-ketoenamides 14c–h are summarized in Table
2. In these cases isolation and purification of the cycliza-
tion products was rather difficult.18 Therefore, we chose to
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3288–3294

3290
P. Hommes et al.
PAPER
enamides to pyrid-2-ones via the TMSOTf-promoted in-
tramolecular condensation and that the presented method
adds a new version to established protocols. β-Ketoen-
amides bearing two enolizable methylene groups showed
a strong preference to cyclize to pyrid-4-one derivatives.
Although the yields are often only moderate the simplicity
and versatility of this approach should be useful. The cy-
clization products could successfully be transformed to
the corresponding nonaflates that could be used as compo-
nents of Pd-catalyzed couplings to highly substituted pyr-
idine derivatives.
Table 2 TMSOTf-Promoted Cyclocondensation of β-Ketoenamides
14c–h and Subsequent Nonaflationa
R2
O
ONf
R2
R2
R3
a
NH
O
N
N
+
R3
R3
R3
R3
ONf
R3
14
16
17
Entry
R2
R3
Yield
(%)b
Yield
(%)b
1
2
3
4
5
6
14c
14d
14e
14f
Ph
Ph
H
H
16c
16d
16e
16f
15–20 17c
3–9
6
Me
H
30
33
52
76
12
17d
17e
17f
Reactions were generally performed under argon in flame-dried
flasks or sealed tubes; liquid components were added by syringe.
Products were purified by flash column chromatography on silica
gel (230–400 mesh, Merck and Macherey & Nagel). Unless stated
otherwise, yields refer to analytically pure samples. 1H NMR
[CHCl3 (δ = 7.26), TMS (δ = 0.00) as internal standard], 13C NMR
[CDCl3 (δ = 77.0) as internal standard], and 19F NMR spectra were
recorded with Bruker AC 500, Jeol ECX 400, or Jeol Eclipse 500
instruments in CDCl3 solutions. Integrals are in accordance with as-
signments; coupling constants are given in Hz. All 13C NMR spectra
are proton-decoupled. For detailed peak assignments 2D spectra
were measured (COSY, HMQC, HMBC). 13C NMR signals of Nf
group [CF3(CF2)3] are not given since unambiguous assignment was
not possible due to strong splitting by coupling with the 19F nuclei.
IR spectra were recorded on a Jasco FT/IR-4100 spectrometer.
HRMS analyses were performed with Varian Ionspec QFT-7 (ESI-
FT ICRMS) and Agilent 6210 ESI-TOF instruments. The elemental
analyses were recorded with PerkinElmer CHN-Analyzer 2400,
Vario EL, or Vario EL III instruments. Melting points were mea-
sured with a Reichert apparatus and are uncorrected. CH2Cl2 and
THF were purified with a MB SPS-800 dry solvent system. Unless
stated otherwise all other solvents and reagents were purchased
from commercial suppliers and were used without further purifica-
tion. Compounds 13a,22 13b,23 13c,6 14e,24 and 15c16 were prepared
according to literature procedures.
–
Me
H
–
14g
14h
Bn
H
16g
16h
17g
17h
–
OMe
H
6
a Reaction conditions: 1. TMSOTf (5.0 equiv), DIPEA (4.0 equiv),
DCE, sealed tube, 90 °C, 3 d; 2. NaH (5.0–7.0 equiv), NfF (2.5–3.0
equiv), THF, r.t., overnight.
b Yields over two steps.
O
ONf
NaH, NfF
HN
N
THF
r.t., 1 d
R
R
R
R
R = Me
Et
15c
15d
17c 71%
17d 85%
Scheme 4 Nonaflation of pyrid-2-ones 15c and 15d
19 once again demonstrate that pyridyl nonaflates are ide-
al substrates for Pd-catalyzed reactions.
TMSOTf-Promoted Cyclization of β-Ketoenamides; General
Procedure 1 (Method A)
TMSOTf (5 equiv) was added dropwise to a stirred solution of the
β-ketoenamide (1 equiv) and DIPEA (4 equiv) in DCE (25
mL/mmol) under an atmosphere of argon. The mixture was stirred
at 90 °C in a sealed tube for 3 d (large scale reactions may be per-
formed using a Schlenk flask equipped with a reflux condenser).
After cooling to r.t., sat. aq NH4Cl solution was added and the layers
were separated. The aqueous layer was extracted with CH2Cl2 or
EtOAc (3 ×) and the combined organic layers were dried with
Na2SO4, filtered, and evaporated to dryness. The obtained crude
product was purified by flash column chromatography on silica gel.
In conclusion, we could demonstrate in this report that it
is indeed possible to cyclize suitably substituted β-keto-
PhB(OH)2, K2CO3
Pd(PPh3)4 (5 mol%)
N
N
DMF, 80 °C, 4 h
97%
ONf
KOt-Bu-Promoted Cyclization of β-Ketoenamides; General
Procedure 2 (Method B)
16c
18
Following a procedure by Fisyuk et al.,15 KOt-Bu (1.5 equiv) was
added to a stirred solution of the β-ketoenamide (1 equiv) in THF
(~10 mL/mmol) at 0 °C. The mixture was stirred overnight while
being allowed to warm up to r.t. The solvent was evaporated under
reduced pressure and the remaining residue was stirred for 5 min
with H2O (~5 mL/mmol). The precipitate was collected by filtration
and dried under reduced pressure to provide the product.
CN
ONf
4-(NC)C6H4B(OH)2, K2CO3
Pd(PPh3)4 (5 mol%)
N
N
DMF, 80 °C, 6 h
94%
In case of no or only little precipitation, CH2Cl2 was added and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 ×) and the combined organic layers were dried with
Na2SO4, filtered, and evaporated under reduced pressure. If re-
quired, the obtained product was purified by flash column chroma-
tography on silica gel.
17d
19
Scheme 5 Suzuki–Miyaura couplings of pyrid-4-yl and pyrid-2-yl
nonaflates 16c and 17d leading to highly substituted pyridine deriva-
tives
Synthesis 2013, 45, 3288–3294
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrid-4-yl and Pyrid-2-yl Nonaflates
3291
3,4,6-Triphenylpyridin-2(1H)-one (15a)
H, 5-H), 7.23–7.26, 7.29–7.32, 7.37–7.40 (3 m, 2 H, 1 H, 2 H,
C6H5), 12.15 (s br, 1 H, NH).
13C NMR (CDCl3, 126 MHz): δ = 12.6, 14.3 (2 q, CH3), 26.2, 26.7
(2 t, CH2), 105.4 (d, C-5), 126.9 (d, C6H5), 127.1 (s, C-3), 128.0,
130.2, 135.9 (2 d, s, C6H5), 148.8, 155.0 (2 s, C-4, C-6), 164.4 (s, C-
2).
Method A: According to general procedure 1, β-ketoenamide 14a
(175 mg, 0.51 mmol) was treated with DIPEA (0.34 mL, 2.00
mmol) and TMSOTf (0.47 mL, 2.59 mmol) in DCE (13 mL). The
workup was performed by diluting the reaction mixture with EtOAc
(40 mL). After washing with H2O–brine (1:1, 3 × 40 mL), drying
(Na2SO4), and filtration the organic layer was evaporated under re-
duced pressure. The obtained crude product was purified by flash
column chromatography on silica gel (hexanes–EtOAc = 5:1 →
2:1) and washed with Et2O (10 mL) to provide pyrid-2-one 15a (130
mg, 79%) as a colorless solid.
HRMS (ESI-TOF): m/z calcd for C15H18NO [M + H]+: 228.1383;
found: 228.1369.
Anal. Calcd for C15H17NO (227.3): C, 79.26; H, 7.54; N, 6.16.
Found: C, 79.19; H, 7.52; N, 6.17.
Method B: According to general procedure 2, β-ketoenamide 14a
(143 mg, 0.42 mmol) was treated with KOt-Bu (70 mg, 0.62 mmol)
in THF (5 mL). Precipitation provided pyrid-2-one 15a (118 mg,
87%) as a colorless solid; mp >230 °C (sublimation).
TMSOTf-Promoted Cyclization of β-Ketoenamides Followed
by Nonaflation of the Crude Product; General Procedure 3
The reaction was set up according to the general procedure 1. After
performance of the cyclization step and cooling to r.t., the solvent
was carefully evaporated under reduced pressure. The remaining
residue was dissolved in THF (10–20 mL/mmol) under an atmo-
sphere of argon. NaH (5–7 equiv, 60% in mineral oil) was washed
with hexanes (2 ×) under an atmosphere of argon and was suspend-
ed in a small amount of THF. This suspension was slowly trans-
ferred (slow addition was crucial because of vigorous hydrogen
evolution) to the solution of the crude cyclization product. NfF
(2.5–3.0 equiv) was added and the mixture stirred at r.t. overnight.
Sat. aq NH4Cl solution was slowly added and the layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (3 ×) and the
combined organic layers were dried with Na2SO4, filtered, and
evaporated under reduced pressure. The obtained crude product was
purified by flash column chromatography on silica gel.
IR (ATR): 3120–2860 (N–H, =C–H), 1620, 1595, 1575, 1500
(C=C, C=N), 1440, 1355, 1255 cm–1.
1H NMR [CDCl3–CF3CO2D (7:1), 500 MHz]: δ = 7.17–7.20, 7.29–
7.37 (2 m, 4 H, 6 H, C6H5), 7.41 (s, 1 H, 5-H), 7.59–7.63, 7.76–7.77
(2 m, 3 H, 2 H, C6H5).
13C NMR [CDCl3–CF3CO2D (7:1), 126 MHz]: δ = 116.4 (d, C-5),
125.6 (s, C-3), 127.2, 128.68, 128.71, 128.9*, 129.7, 129.9, 130.6,
130.8, 130.9, 132.1, 136.8 (7 d, 2 s, d, s, C6H5), 146.8 (s, C-4),
159.3, 160.7 (2 s, C-2, C-6), * the signal corresponds to two carbon
atoms.
HRMS (ESI-TOF): m/z calcd for C23H18NO [M + H]+: 324.1383;
found: 324.1374.
Anal. Calcd for C23H17NO (323.4): C, 85.42; H, 5.30; N, 4.33.
Found: C, 85.45; H, 5.34; N, 4.35.
Nonaflation of Pyrid-2-ones; General Procedure 4
NaH (3–4 equiv, 60% in mineral oil) was washed twice with hex-
anes (2 ×) under an atmosphere of argon and was suspended in a
small amount of THF. This suspension was slowly transferred (slow
addition is crucial because of vigorous hydrogen evolution) to a
mixture of the pyrid-2-one and THF (10–20 mL/mmol) under an at-
mosphere of argon. NfF (2.5– 3.0 equiv) was added and the mixture
stirred at r.t. for 1 d. The mixture was diluted with CH2Cl2 (or Et2O)
and sat. aq NH4Cl solution was slowly added. The layers were sep-
arated and the aqueous layer was extracted with CH2Cl2 (or Et2O)
(2–3 ×). The combined organic layers were dried with Na2SO4, fil-
tered, and evaporated under reduced pressure. The obtained crude
product was purified by flash column chromatography on silica gel.
3-Methyl-4,6-diphenylpyridin-2(1H)-one (15b)
According to general procedure 1, β-ketoenamide 14b (252 mg,
0.90 mmol) was treated with DIPEA (0.61 mL, 3.59 mmol) and
TMSOTf (0.82 mL, 4.52 mmol) in DCE (23 mL). Workup was per-
formed with sat. aq NH4Cl solution (30 mL) and CH2Cl2 (3 × 30
mL). The obtained crude product was purified by flash column
chromatography on silica gel (hexanes–EtOAc = 1:1) to provide
pyrid-2-one 15b (218 mg, 93%) as a pale brownish solid; mp 243–
245 °C.
IR (ATR): 3120–2800 (N–H), 3030 (=C–H), 2980–2850 (C–H),
1625–1500 (C=C, C=N), 1450, 1375–1265, 1180, 1150 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.14 (s, 3 H, CH3), 6.50 (s, 1 H, 5-
H), 7.37–7.49, 7.79–7.81 (2 m, 8 H, 2 H, C6H5), 12.07 (s br, 1 H,
NH).
13C NMR (CDCl3, 126 MHz): δ = 13.6 (q, CH3), 107.2 (d, C-5),
124.4 (s, C-3), 126.4, 128.0, 128.2, 128.4, 129.0, 129.6, 133.5,
139.8 (6 d, 2 s, C6H5), 142.3 (s, C-6), 151.4 (s, C-4), 165.3 (s, C-2).
2-Benzyl-6-methylpyridin-4-yl Nonaflate (16c) and 4,6-Dimeth-
yl-3-phenylpyridin-2-yl Nonaflate (17c)
According to general procedure 3, β-ketoenamide 14c (217 mg,
1.00 mmol) was treated with DIPEA (0.68 mL, 4.00 mmol) and
TMSOTf (0.91 mL, 5.02 mmol) in DCE (25 mL) using a sealed
tube, followed by nonaflation of the crude product using NaH (300
mg, 7.50 mmol) and NfF (0.54 mL, 3.00 mmol) in THF (15 mL).
Workup was performed with sat. aq NH4Cl solution (20 mL) and
CH2Cl2 (2 × 20 mL). The obtained crude product was purified by
flash column chromatography on silica gel (hexanes–
EtOAc = 30:1) to provide pyridyl nonaflates 17c (15 mg, 3%) and
16c (98 mg, 20%) as yellow oils.
HRMS (ESI-TOF): m/z calcd for C18H16NO [M + H]+: 262.1234;
found: 262.1226.
Anal. Calcd for C18H15NO (261.3): C, 82.73; H, 5.79; N, 5.36.
Found: C, 82.83; H, 5.68; N, 5.31.
4,6-Diethyl-3-phenylpyridin-2(1H)-one (15d)
16c
According to general procedure 2, β-ketoenamide 14d (273 mg,
1.11 mmol) was treated with KOt-Bu (187 mg, 1.67 mmol) in THF
(9 mL). Workup was performed with H2O–brine (1:1, 60 mL) and
CH2Cl2 (4 × 60 mL). The obtained crude product was purified by
flash column chromatography on silica gel (hexanes–EtOAc = 3:1
→ 1:1) to provide β-ketoenamine 13c (16 mg, 11%) as a yellow oil
and pyrid-2-one 15d (203 mg, 81%) as a colorless solid; melting
range 65–70 °C.
IR (ATR): 3085–3030 (=C–H), 2965–2925 (C–H), 1600–1580
(C=N, C=C), 1425, 1235–1195, 1145 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.61 (s, 3 H, CH3), 4.17 (s, 2 H,
CH2), 6.77 (d, J = 2.0 Hz, 1 H, 5-H), 6.92 (d, J = 2.0 Hz, 1 H, 3-H),
7.24–7.32 (m, 5 H, C6H5).
13C NMR (CDCl3, 126 MHz): δ = 24.7 (q, CH3), 44.6 (t, CH2),
112.4 (d, C-5), 112.9 (d, C-3), 126.8, 128.8, 129.1, 138.1 (3 d, s,
C6H5), 157.2, 161.4, 164.0 (3 s, C-2, C-4, C-6).
19F NMR (CDCl3, 471 MHz): δ = –125.7, –120.8 (2 mc, 2 F each,
CF2), –108.6 (t, J = 13.6 Hz, 2 F, CF2), –80.5 (t, J = 9.6 Hz, 3 F,
CF3).
IR (ATR): 3130 (N–H), 3075–3025 (=C–H), 2970, 2935, 2870 (C–
H), 1625–1600, 1555 (C=C, C=N), 1495–1440 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 1.04, 1.22 (2 t, J = 7.6 Hz, 3 H
each, CH3), 2.32, 2.51 (2 q, J = 7.6 Hz, 2 H each, CH2), 5.99 (s, 1
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HRMS (ESI-TOF): m/z calcd for C17H13F9NO3S [M + H]+:
482.0467; found: 482.0506.
mL, 1.78 mmol) in THF (5 mL). Workup was performed with sat.
aq NH4Cl solution (30 mL) and Et2O (3 × 30 mL). The obtained
crude product was purified by flash column chromatography on sil-
ica gel (hexanes–EtOAc = 30:1) to provide pyridyl nonaflate 17d
(320 mg, 85%) as a colorless oil.
Anal. Calcd for C17H12F9NO3S (481.3): C, 42.42; H, 2.51; N, 2.91;
S, 6.66. Found: C, 42.40; H, 2.40; N, 2.79; S, 6.53.
4,6-Dimethyl-3-phenylpyridin-2-yl Nonaflate (17c)
IR (ATR): 3085–3030 (=C–H), 2980, 2940–2855 (C–H), 1615,
1545 (C=C, C=N), 1475, 1415, 1245–1200, 1150 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 1.09, 1.34 (2 t, J = 7.6 Hz, 3 H
each, CH2CH3), 2.49, 2.83 (q, J = 7.6 Hz, 2 H each, CH2CH3), 7.15
(s, 1 H, 5-H), 7.21–7.24, 7.40–7.47 (2 m, 2 H, 3 H, C6H5).
13C NMR (CDCl3, 126 MHz): δ = 13.0 (q, 6-CH2CH3), 14.4 (q, 4-
CH2CH3), 26.2 (t, 4-CH2), 30.3 (t, 6-CH2), 122.2 (d, C-5), 125.3 (s,
C-3), 128.3, 128.5, 129.6, 132.4 (3 d, s, C6H5), 153.3 (s, C-2), 157.1
(s, C-4), 161.8 (s, C-6).
19F NMR (CDCl3, 376 MHz): δ = –125.8, –121.1 (2 mc, 2 F each,
CF2), –109.1 (t, J = 13.8 Hz, 2 F, CF2), –80.6 (t, J = 9.2 Hz, 3 F,
CF3).
According to general procedure 4, pyrid-2-one 15c (110 mg, 0.55
mmol) was treated with NaH (100 mg, 2.50 mmol) and NfF (0.30
mL, 1.67 mmol) in THF (5 mL). Workup was performed with sat.
aq NH4Cl solution (20 mL) and CH2Cl2 (4 × 20 mL). The obtained
crude product was purified by flash column chromatography on sil-
ica gel (hexanes–EtOAc = 50:1) to provide pyridyl nonaflate 17c
(188 mg, 71%) as a colorless oil.
IR (ATR): 3070–3035 (=C–H), 2930–2855 (C–H), 1620 (C=N,
C=C), 1420, 1350, 1235–1200, 1140 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.17 (s, 3 H, 4-CH3), 2.54 (s, 3 H,
6-CH3), 7.13 (s, 1 H, 5-H), 7.20–7.23, 7.40–7.47 (2 m, 2 H, 3 H,
C6H5).
13C NMR (CDCl3, 126 MHz): δ = 20.0 (q, 4-CH3), 23.5 (q, 6-CH3),
125.2 (d, C-5), 125.7 (s, C-3), 128.4, 128.5, 129.5, 132.5 (3 d, s,
C6H5), 151.3, 153.1, 156.4 (3 s, C-2, C-4, C-6).
19F NMR (CDCl3, 471 MHz): δ = –125.9, –121.0 (2 mc, 2 F each,
CF2), –109.3 (t, J = 13.7 Hz, 2 F, CF2), –80.6 (t, J = 9.6 Hz, 3 F,
CF3).
HRMS (ESI-TOF): m/z calcd for C19H17F9NO3S [M + H]+:
510.0780; found: 510.0770.
Anal. Calcd for C19H16F9NO3S (509.4): C, 44.80; H, 3.17; N, 2.75;
S, 6.29. Found: C, 44.93; H, 3.15; N, 2.89; S, 6.39.
2,6-Dimethylpyridin-4-yl Nonaflate (16e)
According to general procedure 3, β-ketoenamide 14e (300 mg,
2.13 mmol) was treated with DIPEA (1.45 mL, 8.50 mmol) and
TMSOTf (1.93 mL, 10.1 mmol) in DCE (53 mL) using a reflux con-
denser, followed by nonaflation of the crude product using NaH
(425 mg, 10.6 mmol) and NfF (0.95 mL, 5.31 mmol) in THF (20
mL). Workup was performed with sat. aq NH4Cl solution (30 mL)
and CH2Cl2 (3 × 30 mL). The obtained crude product was purified
by flash column chromatography on silica gel (hexanes–
EtOAc = 20:1 → 5:1) to provide pyridyl nonaflate 16e (282 mg,
33%) as a pale yellow oil.
HRMS (ESI-TOF): m/z calcd for C17H13F9NO3S [M + H]+:
482.0467; found: 482.0486.
Anal. Calcd for C17H12F9NO3S (481.3): C, 42.42; H, 2.51; N, 2.91;
S, 6.66. Found: C, 42.56; H, 2.31; N, 2.61; S, 6.59.
2-Benzyl-6-ethyl-3-methylpyridin-4-yl Nonaflate (16d) and 4,6-
Diethyl-3-phenylpyridin-2-yl Nonaflate (17d)
According to general procedure 3, β-ketoenamide 14d (320 mg,
1.30 mmol) was treated with DIPEA (0.85 mL, 5.00 mmol) and
TMSOTf (1.18 mL, 6.50 mmol) in DCE (33 mL) using a sealed
tube, followed by nonaflation of the crude product using NaH (364
mg, 9.10 mmol) and NfF (0.70 mL, 3.90 mmol) in THF (16 mL).
After evaporation of THF under reduced pressure, the remaining
residue was dissolved in CH2Cl2 (40 mL) and washed with H2O (3
× 40 mL). The organic layer was dried with Na2SO4, filtered, and
evaporated to dryness under reduced pressure. The obtained crude
product was purified by flash column chromatography on silica gel
(hexanes–EtOAc = 50:1 → 20:1) to provide pyridyl nonaflates 17d
(41 mg, 6%) and 16d (200 mg, 30%) as pale yellow oils.
IR (ATR): 3080 (=C–H), 2970–2855 (C–H), 1600, 1585 (C=C,
C=N), 1430, 1350, 1235–1115 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.58 (s, 6 H, CH3), 6.90 (s, 2 H, 3-
H, 5-H).
13C NMR (CDCl3, 101 MHz): δ = 24.7 (q, CH3), 112.5 (d, C-3, C-
5), 157.0 (s, C-4), 161.2 (s, C-2, C-6).
19F NMR (CDCl3, 376 MHz): δ = –125.8, –120.8 (2 mc, 2 F each,
CF2), –108.7 (t, J = 13.7 Hz, 2 F, CF2), –80.6 (t, J = 9.6 Hz, 3 F,
CF3).
HRMS (ESI-TOF): m/z calcd for C11H9F9NO3S [M + H]+:
406.0154; found: 406.0203.
16d
IR (ATR): 3090–3030 (=C–H), 2970, 2925, 2875–2850 (C–H),
1605, 1560, 1545 (C=C, C=N), 1430, 1235–1145 cm–1.
Anal. Calcd for C11H8F9NO3S (405.2): C, 32.60; H, 1.99; N, 3.46;
S, 7.91. Found: C, 32.64; H, 1.93; N, 3.50; S, 8.21.
1H NMR (CDCl3, 500 MHz): δ = 1.32 (t, J = 7.7 Hz, 3 H, CH2CH3),
2.20 (s, 3 H, 3-CH3), 2.85 (q, J = 7.7 Hz, 2 H, CH2CH3), 4.24 (s, 2
H, CH2Ph), 6.98 (s, 1 H, 5-H), 7.16–7.21, 7.25–7.28 (2 m, 3 H, 2 H,
C6H5).
13C NMR (CDCl3, 126 MHz): δ = 11.7 (q, 3-CH3), 13.7 (q,
CH2CH3), 31.2 (t, OCH2), 42.6 (t, CH2Ph), 112.2 (d, C-5), 121.6 (s,
C-3), 126.5, 128.6*, 138.1 (2 d, s, C6H5), 156.0 (s, C-4), 161.9 (s,
C-2), 162.9 (s, C-6), * the signal corresponds to two carbon atoms.
19F NMR (CDCl3, 376 MHz): δ = –125.7, –120.7 (2 mc, 2 F each,
CF2), –109.3 (t, J = 12.6 Hz, 2 F, CF2), –80.5 (t, J = 9.2 Hz, 3 F,
CF3).
HRMS (ESI-TOF): m/z calcd for C19H17F9NO3S [M + H]+:
510.0780; found: 510.0767.
2-Ethyl-6-methylpyridin-4-yl Nonaflate (16f)
According to general procedure 3, β-ketoenamide 14f (155 mg, 1.00
mmol) was treated with DIPEA (0.68 mL, 4.00 mmol) and TMS-
OTf (0.91 mL, 5.02 mmol) in DCE (25 mL) using a sealed tube, fol-
lowed by nonaflation of the crude product using NaH (300 mg, 7.50
mmol) and NfF (0.54 mL, 3.00 mmol) in THF (15 mL). Workup
was performed with sat. aq NH4Cl solution (20 mL) and CH2Cl2 (3
× 20 mL). The obtained crude product was purified by flash column
chromatography on silica gel (hexanes–EtOAc = 30:1) to provide
pyridyl nonaflate 16f (217 mg, 52%) as a pale yellow oil.
IR (ATR): 2975, 2940–2885 (C–H), 1600–1575 (C=C, N=C), 1430,
1350, 1235–1200, 1140–1120 cm–1. Due to their weak intensity an
unambiguous assignment of the =C–H signals was not possible.
1H NMR (CDCl3, 500 MHz): δ = 1.30 (t, J = 7.6 Hz, 3 H, CH2CH3),
2.58 (s, 3 H, CH3), 2.84 (q, J = 7.6 Hz, 2 H, CH2), 6.89, 6.90 (2 d,
Anal. Calcd for C19H16F9NO3S (509.4): C, 44.80; H, 3.17; N, 2.75;
S, 6.29. Found: C, 44.76; H, 3.09; N, 2.84; S, 6.32.
4,6-Diethyl-3-phenylpyridin-2-yl Nonaflate (17d)
According to general procedure 4, pyrid-2-one 15d (169 mg, 0.74
mmol) was treated with NaH (90 mg, 2.25 mmol) and NfF (0.32
J
AB ≈ 1.9 Hz, 1 H each, 3-H, 5-H).
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Synthesis of Pyrid-4-yl and Pyrid-2-yl Nonaflates
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13C NMR (CDCl3, 126 MHz): δ = 13.6 (q, CH2CH3), 24.7 (q, CH3),
31.5 (t, CH2), 111.2 (d, C-3), 112.6 (d, C-5), 157.1 (s, C-6), 161.2
(s, C-2), 166.6 (s, C-4).
19F NMR (CDCl3, 376 MHz): δ = –125.7, –120.8 (2 mc, 2 F each,
CF2), –108.7 (t, J = 13.9 Hz, 2 F, CF2), –80.6 (t, J = 9.6 Hz, 3 F,
CF3).
Anal. Calcd for C12H10F9NO4S (435.3): C, 33.11; H, 2.32; N, 3.22;
S, 7.37. Found: C, 33.09; H, 2.16; N, 3.29; S, 7.24.
17h
IR (ATR): 3010 (=C–H), 2940–2845 (C–H), 1615 (C=N, C=C),
1485, 1415, 1320, 1235–1195, 1145 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.33 (s, 3 H, 4-CH3), 2.43 (s, 3 H,
6-CH3), 3.84 (s, 3 H, OCH3), 7.02 (s, 1 H, 5-H).
13C NMR (CDCl3, 126 MHz): δ = 15.7 (q, 4-CH3), 23.1 (q, 6-CH3),
61.2 (q, OCH3), 126.6 (d, C-5), 142.9 (s, C-3), 144.9 (s, C-4), 148.1
(s, C-2), 151.8 (s, C-6).
HRMS (ESI-TOF): m/z calcd for C12H11F9NO3S [M + H]+:
420.0310; found: 420.0323.
Anal. Calcd for C12H10F9NO3S (419.3): C, 34.38; H, 2.40; N, 3.34;
S, 7.65. Found: C, 34.46; H, 2.25; N, 3.29; S, 7.64.
19F NMR (CDCl3, 471 MHz): δ = –125.7, –120.8 (2 mc, 2 F each,
CF2), –109.1 (t, J = 13.7 Hz, 2 F, CF2), –80.5 (t, J = 9.7 Hz, 3 F,
CF3).
HRMS (ESI-TOF): m/z calcd for C12H10F9NNaO4S [M + Na]+:
458.0085; found: 458.0075.
2-Methyl-6-(2-phenylethyl)pyridin-4-yl Nonaflate (16g)
According to general procedure 3, β-ketoenamide 14g (231 mg,
1.00 mmol) was treated with DIPEA (0.68 mL, 4.00 mmol) and
TMSOTf (0.91 mL, 5.02 mmol) in DCE (25 mL) using a sealed
tube, followed by nonaflation of the crude product using NaH (300
mg, 7.50 mmol) and NfF (0.54 mL, 3.00 mmol) in THF (15 mL).
Workup was performed with sat. aq NH4Cl solution (20 mL) and
CH2Cl2 (3 × 20 mL). The obtained crude product was purified by
flash column chromatography on silica gel (hexanes–
EtOAc = 30:1) to provide pyridyl nonaflate 16g (374 mg, 76%) as
a pale yellow oil.
Pd-Catalyzed Coupling of Pyridyl Nonaflates with Boronic
Acids; General Procedure 5
DMF (~5 mL/mmol) was purged with argon for 30 min. The solvent
was then transferred to a Schlenk-tube that was charged with the
pyridyl nonaflate (1 equiv), Pd(PPh3)4 (5 mol%), K2CO3 (1 equiv)
and the boronic acid (1.1 equiv) under an atmosphere of argon. The
mixture was stirred at 80 °C for the indicated time. After cooling to
r.t., the mixture was diluted with EtOAc and washed with an equal
volume of a mixture of H2O and brine (1:1, 3 ×). The organic layer
was dried with Na2SO4, filtered, and evaporated under reduced
pressure. The obtained crude product was purified by flash column
chromatography.
IR (ATR): 3085–3030 (=C–H), 2965–2865 (C–H), 1600–1580
(C=C, C=N), 1425, 1240–1200, 1140 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.61 (s, 3 H, CH3), 3.05, 3.10 (2
mc, 2 H each, CH2CH2), 6.78 (d, J = 1.9 Hz, 1 H, 5-H), 6.91 (d,
J = 1.9 Hz, 1 H, 3-H), 7.16–7.20, 7.25–7.28 (2 m, 3 H, 2 H, C6H5).
13C NMR (CDCl3, 126 MHz): δ = 24.7 (q, CH3), 35.6, 40.1 (2 t,
CH2CH2), 112.2 (d, C-5), 112.8 (d, C-3), 126.2, 128.3, 128.4, 140.7
(3 d, s, C6H5), 156.9 (s, C-4), 161.4 (s, C-2), 164.2 (s, C-6).
19F NMR (CDCl3, 471 MHz): δ = –125.7, –120.7 (2 mc, 2 F each,
CF2), –108.6 (t, J = 13.6 Hz, 2 F, CF2), –80.5 (t, J = 9.6 Hz, 3 F,
CF3).
2-Benzyl-6-methyl-4-phenylpyridine (18)
According to general procedure 5, pyridyl nonaflate 16c (350 mg,
0.73 mmol) was treated with phenylboronic acid (97 mg, 0.80
mmol), Pd(PPh3)4 (40 mg, 0.04 mmol), and K2CO3 (100 mg, 0.73
mmol) in DMF (3.5 mL) for 4 h. Workup was performed with
EtOAc (40 mL) and H2O–brine (1:1, 3 × 40 mL). The obtained
crude product was purified by flash column chromatography on sil-
ica gel (hexanes–EtOAc = 10:1) to provide pyridine 18 (183 mg,
97%) as a yellow oil.
HRMS (ESI-TOF): m/z calcd for C18H15F9NO3S [M + H]+:
496.0631; found: 496.0616.
Anal. Calcd for C18H14F9NO3S (495.4): C, 43.64; H, 2.85; N, 2.83;
S, 6.47. Found: C, 43.73; H, 2.64; N, 2.72; S, 6.23.
IR (ATR): 3055–3025 (=C–H), 2920–2845 (C–H), 1600–1550
(C=C, C=N), 1495–1450, 1400, 1075 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.63 (s, 3 H, CH3), 4.21 (s, 2 H,
CH2), 7.10, 7.21 (2 d, J = 1.1 Hz, 1 H each, 3-H, 5-H), 7.22–7.24,
7.31–7.32, 7.39–7.45, 7.54–7.55 (4 m, 1 H, 4 H, 3 H, 2 H, C6H5).
13C NMR (CDCl3, 126 MHz): δ = 24.6 (q, CH3), 44.8 (t, CH2),
118.2 (d, C-3), 118.9 (d, C-5), 126.3, 127.0, 128.5, 128.7, 128.9,
129.1, 138.7, 139.6 (6 d, 2 s, C6H5), 149.2 (s, C-4), 158.3 (s, C-6),
160.9 (s, C-2).
2-(Methoxymethyl)-6-methylpyridin-4-yl Nonaflate (16h) and
3-Methoxy-4,6-dimethylpyridin-2-yl Nonaflate (17h)
According to general procedure 3, β-ketoenamide 14h (171 mg,
1.00 mmol) was treated with DIPEA (0.68 mL, 4.00 mmol) and
TMSOTf (0.91 mL, 5.02 mmol) in DCE (25 mL) using a sealed
tube, followed by nonaflation of the crude product using NaH (300
mg, 7.50 mmol) and NfF (0.54 mL, 3.00 mmol) in THF (15 mL).
Workup was performed with sat. aq NH4Cl solution (20 mL) and
CH2Cl2 (3 × 25 mL). The obtained crude product was purified by
flash column chromatography on silica gel (hexanes–EtOAc = 20:1
→ 10:1) to provide pyridyl nonaflates 17h (28 mg, 6%) and 16h (51
mg, 12%) as brownish oils.
HRMS (ESI-TOF): m/z calcd for C19H18N [M + H]+: 260.1441;
found: 260.1451.
4-(4,6-Diethyl-3-phenylpyridin-2-yl)benzonitrile (19)
16h
According to the general procedure 5, pyridyl nonaflate 17d (272
mg, 0.53 mmol) was treated with 4-cyanophenylboronic acid (86
mg, 0.59 mmol), Pd(PPh3)4 (31 mg, 0.03 mmol), and K2CO3 (74
mg, 0.54 mmol) in DMF (3 mL) for 6 h. Workup was performed
with EtOAc (40 mL) and H2O–brine (1:1, 3 × 40 mL). The obtained
crude product was purified by flash column chromatography on sil-
ica gel (hexanes–EtOAc = 10:1) to provide pyridine 19 (156 mg,
94%) as a colorless solid; mp 90–92 °C.
IR (ATR): 3085 (=C–H), 2990–2825 (C–H), 1620–1585 (C=C),
1430, 1235–1200, 1140–1120 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 2.60 (s, 3 H, CH3), 3.49 (s, 3 H,
OCH3), 4.58 (s, 2 H, OCH2), 6.98 (d, J = 1.9 Hz, 1 H, 3-H), 7.20 (d,
J = 1.9 Hz, 1 H, 5-H).
13C NMR (CDCl3, 126 MHz): δ = 24.5 (q, CH3), 58.9 (q, OCH3),
74.7 (t, OCH2), 110.4 (d, C-5), 113.9 (d, C-3), 157.5 (s, C-2), 161.3
(s, C-6), 161.9 (s, C-4).
19F NMR (CDCl3, 471 MHz): δ = –125.7, –120.7 (2 mc, 2 F each,
CF2), –108.6 (t, J = 13.7 Hz, 2 F, CF2), –80.5 (t, J = 9.6 Hz, 3 F,
CF3).
IR (ATR): 3060, 3030 (=C–H), 2970, 2935, 2875 (C–H), 2230
(C≡N), 1605, 1590, 1545 (C=C, C=N), 1465, 1440, 1385 cm–1.
1H NMR (CDCl3, 500 MHz): δ = 1.09, 1.39 (2 t, J = 7.6 Hz, 3 H
each, CH2CH3), 2.49, 2.90 (2 q, J = 7.6 Hz, 2 H each, CH2CH3),
7.02–7.06 (m, 2 H, C6H5), 7.17 (s, 1 H, 5'-H), 7.26–7.29 (m, 3 H,
C6H5), 7.33–7.36, 7.41–7.44 (2 m, 2 H each, 2-H, 3-H).
HRMS (ESI-TOF): m/z calcd for C12H11F9NO4S [M + H]+:
436.0267; found: 436.0265.
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Synthesis 2013, 45, 3288–3294

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P. Hommes et al.
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J.; Shin, H.; Lee, S.-g. J. Org. Chem. 2009, 74, 7556. For
reactions with isocyanates leading to pyrimidin-2,4-diones,
see: (d) Chun, Y. S.; Xuan, Z.; Kim, J. H.; Lee, S.-g. Org.
Lett. 2013, 15, 3162.
13C NMR (CDCl3, 126 MHz): δ = 14.0 (q, 6′-CH2CH3), 14.5 (q, 4′-
CH2CH3), 26.2 (t, 4′-CH2), 31.2 (t, 6′-CH2), 110.6 (s, C-1), 119.0 (s,
CN), 121.1 (d, C-5′), 127.3, 128.3 (2 d, C6H5), 130.3, 130.5, 131.3
(3 d, C6H5, C-2, C-3), 133.2 (s, C6H5), 137.5 (s, C-3′), 145.8 (s, C-
4), 152.6 (s, C-4′), 154.8 (s, C-2′), 162.5 (s, C-6′).
HRMS (ESI-TOF): m/z calcd for C22H20N2Na [M + Na]+: 335.1519;
found: 335.1525.
(8) Hommes, P.; Jungk, P.; Reissig, H.-U. Synlett 2011, 2311.
(9) For a review summarizing the advantages of alkenyl and aryl
nonaflates in transition-metal-catalyzed reactions, see:
Högermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
2747.
(10) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 2004, 2nd ed.
(11) For recent examples utilizing pyrid-4-yl nonaflates, see:
(a) Bera, M. K.; Hommes, P.; Reissig, H.-U. Chem. Eur. J.
2011, 17, 11838. (b) Eidamshaus, C.; Hommes, P.; Reissig,
H.-U. Synlett 2012, 23, 1670. (c) Gholap, S. L.; Hommes, P.;
Neuthe, K.; Reissig, H.-U. Org. Lett. 2013, 15, 318.
(d) Bera, M. K.; Gholap, S. L.; Hommes, P.; Neuthe, K.;
Trawny, D.; Rabe, J. P.; Lentz, D.; Zimmer, R.; Reissig, H.-U.
Adv. Synth. Catal. 2013, 355, in press; DOI
Anal. Calcd for C22H20N2 (312.4): C, 84.58; H, 6.45; N, 8.97.
Found: C, 84.67; H, 6.47; N, 8.90.
Acknowledgment
Generous support of this work by the Deutsche Forschungsgemein-
schaft (GK 1582 and RE 514/14) and Bayer HealthCare is most
gratefully acknowledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are experimental procedures for the synthesis of compounds 14a–d
and 14f–h as well as copies of 1H and 13C NMR spectra for all new
10.1002/adsc.201306613.
(12) (a) Gewald, K.; Rehwald, M.; Müller, H.; Bellmann, P.
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(13) An analogous reaction leading to 2-quinolones are known
for structurally related o-acyl(aminoacyl)benzenes:
(a) Blackburn, T. P.; Cox, B.; Guildford, A. J.; Le Count, D.
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S.; Chasanov, M. I.; Fedotov, A. N.; Zefirov, N. S. Chem.
Heterocycl. Compd. 2011, 47, 1105.
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Synthesis 2013, 45, 3288–3294
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