One-Pot Directing Group Formation/C?H Bond Functionalization via Copper(I) and Ruthenium(II) Catalysis

Article abstract of DOI:10.1002/adsc.201600735

A copper(I)-catalyzed oxidation leading to the formation of 2-pyridyl ketone directing groups has been efficiently coupled with a ruthenium(II)-catalyzed C(sp²)?H bond arylation transformation without performing any intermediate work-up. This sustainable approach was further extended to sequential three-step transition metal-catalyzed transformations in which up to four new bonds (C–O, C–C, C–H and O–H) are formed in a one-pot fashion. This is the first example in which two different transition metal catalysts are sequentially employed for the directing group formation and the C?H bond functionalization, respectively. (Figure presented.).

Full text of DOI:10.1002/adsc.201600735

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DOI: 10.1002/adsc.201600735
À
One-Pot Directing Group Formation/C H Bond Functionaliza-
tion via Copper(I) and Ruthenium(II) Catalysis
Christian Bruneaua and Rafael Gramage-Doriaa,*
a
Organometallics: Materials and Catalysis Laboratory, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS,
Universitꢀ de Rennes 1, Avenue du Gꢀnꢀral Leclerc 263, 35042 Rennes, France
E-mail: rafael.gramage-doria@univ-rennes1.fr
Received: July 10, 2016; Revised: September 22, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600735.
Abstract: A copper(I)-catalyzed oxidation leading to C, C–H and O–H) are formed in a one-pot fashion.
the formation of 2-pyridyl ketone directing groups This is the first example in which two different tran-
has been efficiently coupled with a ruthenium(II)- sition metal catalysts are sequentially employed for
2
À
À
catalyzed C(sp ) H bond arylation transformation the directing group formation and the C H bond
without performing any intermediate work-up. This functionalization, respectively.
sustainable approach was further extended to se-
À
quential three-step transition metal-catalyzed trans- Keywords: C H bond activation; copper; oxidation;
formations in which up to four new bonds (C–O, C– pyridine; ruthenium
Introduction
ic transformations that generate the directing group
[Eq. (1), Figure 1].[6] From an atom- and cost-econo-
À
Progress in C H bond functionalization has evolved my point of view, an interesting alternative is the uti-
in such a way that nowadays multiple catalytic sys- lization of a single transition metal catalyst for the
À
tems are able to perform extremely selective transfor- formation of the directing group and for the C H
mations in a very efficient manner.[1] Most of the cata- bond functionalization step [Eq. (2), Figure 1). This
À
lysts employed in C H bond functionalization reac- strategy has been elegantly demonstrated for ruthe-
tions are derived from transition metals such as rhodi-
um, palladium, ruthenium and more recently, cobalt.[2]
Since the ultimate goal of catalysis is the straightfor-
ward production of complex molecules from readily
À
available starting materials, C H bond functionaliza-
tion reactions have been successfully coupled with
other chemical transformations without the isolation
of intermediates.[3,4] Such a one-pot approach is par-
ticularly appealing since it reduces the time and costs
devoted to work-up and purification processes, and
also diminishes chemical wastes.[5]
In this context, one of the major drawbacks in the
À
field of transition metal-catalyzed C H bond func-
tionalization is the synthetic effort required for the in-
troduction of the directing group. Interestingly, the di-
recting group synthesis is known to be compatible,
under certain circumstances, with the reaction condi-
À
tions imposed by the further C H bond transforma-
tion, which enables one-pot processes involving these
Figure 1. One-pot catalysis involving directing group forma-
tion and transition metal-catalyzed C H bond functionaliza-
tion. FG=functional group, DG=directing group, E=cou-
pling partner. Non-isolated intermediates are indicated in
À
two important transformations (Figure 1). As such,
C H bond functionalization reactions have been
proven compatible with purely (non-catalyzed) organ- brackets.
À
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nium(II) catalysts where isomerization or dehydro- resent a sustainable synthesis of highly functionalized
genation transformations are followed by C(sp2)–H 2-benzoylpyridine derivatives, which are key motifs
3
[7]
and C(sp ) H bond activation reactions. Surprising- relevant for biological applications[13] as well as for
À
ly, the one-pot utilization of two different transition the design of metal-coordinating ligands.[14] It is rele-
metal catalysts for each step (directing group forma- vant to mention that a few reverse reaction sequences
2
À
À
tion and C H bond activation) has received no atten- involving first C(sp ) H bond activation catalyzed by
tion as yet [Eq. (3), Figure 1].[8] Overcoming such ruthenium(II) have been described.[15]
a challenge clearly offers exponential possibilities to-
wards chemical diversity since multiple catalysts com-
À
patible with C H bond activation could be employed Results and Discussion
for different chemical transformations in a one-pot
fashion. Herein, we present such an approach by Initially, we focused on the search for the optimal re-
means of a one-pot chemical transformation compris- action conditions to obtain 2a from 1 (Table 1). Al-
ing two metal-catalyzed steps without the isolation of though the copper-catalyzed oxidation of 2-benzylpyr-
intermediates. It involves (i) a copper(I)-catalyzed ox- idines (1) was reported to take place in DMSO (di-
idation to form a directing group followed by (ii) methyl sulfoxide) as solvent,[11] this solvent was found
2
À
À
a ruthenium(II)-catalyzed C(sp ) H bond functionali- inappropriate for the ruthenium-catalyzed C H bond
zation [Eq. (3), Figure 1).
functionalization step (0% formation of 2a; Table 1,
entry 1). Interestingly, we found that the oxidation
step successfully took place (almost full conversion of
1 was observed in all cases; Table 1, entries 2–10) with
NMP (N-methyl-2-pyrrolidone) as solvent at a high
concentration of 1M (versus the previously reported
0.5M).[11] This finding is relevant since the best results
À
so far obtained for the C H bond functionalization of
2-benzoylpyridine derivatives (such as 4a) required
the exclusive use of NMP as solvent.[9a] The influence
of the carboxylic acid in the first step was first evalu-
ated keeping the same reaction conditions in the
second step (see reaction conditions in Table 1).
When acetic acid was employed, only 7% of the tar-
geted 2a was obtained (Table 1, entry 2); whereas
2
À
Scheme 1. One-pot directing group formation and C(sp ) H
bond functionalization involving two distinct transition
metal catalysts.
For this study, we turned our attention to the reac- 18% of 2a was formed using 2-mesitylcarboxylic acid
tivity of rather flexible 2-benzylpyridine derivatives (MesCO2H), however, 16% of 1 remained unreacted
2
À
(Scheme 1), which are known not to follow C(sp ) H (Table 1, entry 3). A similar result was obtained with
bond activation reactions.[9a] On the other hand, more 1-AdCO2H which provided 2a in a low 20% yield
rigid 2-benzoylpyridine derivatives[9a] have been re- (Table 1, entry 4). Benzoic acid was the most suitable
cently found to participate in ruthenium(II)-catalyzed carboxylic acid leading to full conversion of 1 and
2
À
C(sp ) H bond functionalization reactions via six- 69% of isolated 2a after column chromatography
membered ruthenacycles.[9] Unfortunately, the intro- (Table 1, entry 5). The base employed in the second
duction of the 2-pyridyl ketone directing group re- step had an important impact (Table 1, entries 5–9)
quires the utilization of over-stoichiometric amounts and among the different bases, the best results were
of elemental sulfur (S8) during their synthesis, which found employing K2CO3 (Table 1, entry 5).
makes this strategy not suitable from an atom-econo-
As such, the best conditions found for the one-pot
my point of view.[10] Recently, the groups of Maes and directing group formation/C H bond functionaliza-
Kappe have independently reported very efficient tion of 1 required an atmosphere of O2, 10 mol% of
methods for the oxidation of a large variety of nitro- CuI, benzoic acid (1 equivalent) and NMP as solvent
gen-containing derivatives with copper(I) catalysts in at 1008C for 24 h in the first step. The second step
À
À
the presence of carboxylic acids and environmentally (C H bond functionalization) was carried out at
friendly molecular oxygen.[11] Since copper salts and 1508C for 48 h under an inert atmosphere after
carboxylic acids are in some cases necessary, thus adding to the reaction mixture 5 mol% of [RuCl2(p-
À
compatible, for metal-catalyzed C H bond functional- cymene)]2, K2CO3 (4 equivalents), phenyl bromide
ization reactions,[12] we anticipated that two reactions (1.5 equivalents) and NMP (which was introduced to
involving two different transition metal catalysts dilute the reaction mixture at 0.25M). Under these
(copper and ruthenium) could be coupled in a one- optimized reaction conditions, full conversion of
pot fashion without the isolation of 2-benzoylpyridine 1 was reached and 2a was isolated in 69% yield in
intermediates (Scheme 1). This approach would rep- a one-pot fashion (Table 1, entry 5). Longer reaction
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Table 1. Optimization of the one-pot directing group forma-
tion/C H bond functionalization of 1.
lowing the one-pot directing group formation/C H
[a]
À
bond functionalization transformation (Figure 2). 4-
Alkyl- and 4-aryl-substituted compounds 2b–2g were
obtained in good isolated yields around 70%. The
one-pot transformation is also compatible with 4-
OMe (2h), 4-CN (2i), 4-CF3 (2j), 4-F (2k) and 4-
CO2Me (2l) groups. Unfortunately, 2-CO2Me-substi-
tuted 2m was not formed. In this case, dehalogenation
of the corresponding aryl bromide was observed by
1
GC-MS analysis and H NMR spectroscopy. On the
other hand, 3-CN groups were also well tolerated
(2n). 2-F-substituted 2o was obtained with a poor
51% yield, whereas 2-OMe-substituted 2p gave
a higher yield (70%). This protocol unfortunately
gave poor yields in the case of ketones (2q); and it
was not compatible with aldehyde (2r) and nitro (2s)
functional groups (decomposition of the aryl bromide
employed in the second step was observed by GC-MS
analysis). Interestingly, heteroaromatic derivatives
were also synthesized by the one-pot procedure. For
example, 3-pyridyl-substituted 2t and 2-thiophene-
substituted 2u were isolated in 45% and 74% yield,
respectively. Additionally, if more than two equiva-
lents of 2-bromothiophene were employed in the
second step, a high yield of the corresponding difunc-
tionalized compound 3u (81%) was obtained. The
molecular structures of 2a, 2k and 2u were further
confirmed by X-ray diffraction studies (Figure 3).
Entry Acid
Base
Conversion[b] 2a:3a:4a [%][c]
1[d]
2
PhCO2H
AcOH
K2CO3
K2CO3
>99
98
0:0:100
7:0:91
3
4
MesCO2H K2CO3
1-AdCO2H K2CO3
84
>99
>99
18:0:66
20:0:80
72:8:20 (69)
33:0:67
3:0:97
5
6
7
8
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
K2CO3
Na2CO3 >99
Cs2CO3 >99
KHCO3 >99
NaHCO3 >99
K2CO3
K2CO3
K2CO3
41:5:54
33:1:66
0:0:100
0:0:0
9
10[e]
11[f]
12[h]
>99
<5[g]
92
À
Next, the one-pot directing group formation/C H
13:0:79
bond functionalization of various substituted benzyl-
pyridines (5a–5e) was attempted to demonstrate the
feasibility of the one-pot approach (Figure 4).[11b,16] In
all cases full conversions were observed, and the effi-
ciency of the methodology was governed by the
[a]
Reaction conditions: (i) 1 (0.5 mmol), CuI (0.05 mmol),
acid (0.5 mmol), NMP (0.5 mL), O2, 1008C, 24 h; (ii)
base (2 mmol), [RuCl2(p-cymene)]2 (0.025 mmol), PhBr
(0.75 mmol), NMP (1.5 mL), argon, 1508C, 48 h.
[b]
1
Conversion determined by GC-MS analysis and H NMR
À
second step, that is, the C H bond functionalization
spectroscopy.
step. As such, the sterically demanding 2-Me-substi-
[c]
[d]
[e]
In parenthesis, isolated yield of 2a.
DMSO was used instead of NMP.
Second step was performed under an oxygen atmos-
phere.
First step was performed under an argon atmosphere.
Arylation of 1 was observed in traces amounts.
DMA was used instead of NMP.
tuted 5a was readily oxidized in the first step, howev-
À
er the C H bond functionalization did not proceed so
well (30% yield), in line with previous findings.[9a] The
4-substituted benzylpyridines 5b–5d efficiently gave
rise to the corresponding mono-arylated benzoylpyri-
dines 6b, 6c and 6d in 71%, 55% and 67% isolated
yields, respectively. The 3-CN-susbstituted benzylpyri-
dine 5e also reacted to form 6e in 60% yield. When
[f]
[g]
[h]
times, temperature variation and changing the 2.5 equivalents were employed in the second step,
number of equivalents of acid and base in each step benzylpyridine derivatives 5c and 5d provided the cor-
did not provide significant variations of the overall responding diphenylated benzoylpyridines 7c and 7d
conversion and selectivity. Additional control experi- in 84% and 78% yields, respectively.
ments performing both steps simultaneously under
Finally, in order to further show the potential of
oxygen conditions revealed the exclusive formation of this unique protocol, we explored a one-pot three-
À
4a (Table 1, entry 10); and under argon conditions step oxidation/C H bond functionalization/hydroge-
<5% arylation of 1 was observed (Table 1, entry 11). nation transformation. Inspired by the ability of some
Other polar solvents such as DMA (N,N- ruthenium catalysts to promote hydrogenation reac-
dimethylacet
second step (13% of 2a, Table 1, entry 12).
ACHTUNGTRENNUNG
amide) led to low reactivity in the tions after olefin metathesis,[17] we envisaged that
a similar stepwise procedure might be possible in our
With the optimized conditions in hand, different case. As such, we performed in a one-pot fashion (i)
aryl bromides were reacted with benzylpyridine 1 fol- the copper-catalyzed oxidation followed by (ii)
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Figure 2. Substrate scope and limitations of the one-pot directing group formation/C H bond functionalization. In parenthe-
sis, isolated yields are displayed.
À
a ruthenium-catalyzed C H bond functionalization
and (iii) a final hydrogenation step utilizing molecular
hydrogen and the remaining metal catalysts
(Scheme 2). In this manner, 8 was isolated in 64%
yield starting from 2-benzylpyridine 1, showing that
up to three distinct catalysts {CuI for oxidation,
À
[RuCl2(p-cymene)]2 for C H bond functionalization
to introduce a p-styrene moiety and [Ru-H] species
for alkene hydrogenation} can be coupled in a one-
pot fashion. Under these conditions (1 bar of H2 in
the third step), the remaining ruthenium species aris-
ing from the second step selectively hydrogenated the
alkene double bond in the third step, leaving the (2-
pyridyl) ketone directing group intact. Alternatively,
when the hydrogenation step was performed at higher
pressure (40 bar of H2), hydrogenation of the ketone
occurred, as exemplified in the synthesis of 9 in an
isolated yield of 55% (Scheme 2). These two exam-
ples show that, in a one-pot fashion, post-functionali-
zation is doable either in the coupling partner intro-
duced at the C H bond functionalization step (8) or
Figure 3. X-ray molecular structures of 2a (top, left), 2k (top,
right) and 2u (bottom).
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À
Scheme 2. One-pot directing group formation/C H bond
functionalization/hydrogenation employing three distinct
transition metal catalysts. In parenthesis, isolated yields are
displayed (no work-up was performed between each step).
Reaction conditions: (i) 1 (0.5 mmol), CuI (0.05 mmol), ben-
zoic acid (0.5 mmol), NMP (0.5 mL), O2, 1008C, 24 h; (ii)
K2CO3 (2 mmol), [RuCl2(p-cymene)]2 (0.025 mmol), 4-bro-
mostyrene (0.75 mmol), NMP (1.5 mL), argon, 1508C, 48 h;
(iii) H2 (1 bar), 1508C, 12 h; (iv) K2CO3 (2 mmol), [RuCl2(p-
cymene)]2
(0.025 mmol),
1-bromo-4-tert-butylbenzene
(0.75 mmol), NMP (1.5 mL), argon, 1508C, 48 h; (v) H2
(40 bar), 1508C, 12 h.
ates and reducing the costs devoted to work-up opera-
tions. This was ultimately exemplified with one-pot
three-step transition metal-catalyzed transformations
leading to highly functionalized molecules with for-
mation of up to four new bonds in a straightforward
À
Figure 4. One-pot directing group formation/C H bond
functionalization from substituted 2-benzylpyridines 5a–5e.
In parenthesis, isolated yields are displayed.
within the directing group introduced in the first step manner. Complex catalytic systems inspired from the
(9). It is worth noting that compounds bearing the (2- presented one-pot approach are expected to provide
pyridin-2-yl)methanol fragment – as it is the case in 9 new tools to pave the way towards more sustainable
– are key molecules for medicinal applications[18] and transformations involving transition metal-catalyzed
À
the presented methodology enables their synthesis in C H bond functionalization.
a more sustainable and versatile manner.
Experimental Section
Conclusions
General Methods
In summary, we have successfully developed a one-
pot procedure involving two transition metal-cata-
All reagents were obtained from commercial sources and
lyzed reactions in which one of them comprises a sen- used as supplied. NMP was distilled under reduced pressure
À
and stored over molecular sieves under an argon atmos-
phere. 2-Benzylpyridines 5a–5e were prepared according to
literature procedures.[11b,16] Technical grade petroleum ether
(40–608C) and ethyl acetate were used for column chroma-
tography. CDCl3 was stored under nitrogen over molecular
sieves. NMR spectra were recorded on an AVANCE III 400
sitive C H bond activation step. In this case, a cop-
per(I)-catalyzed oxidation forms a 2-pyridyl ketone
directing group that is stepwise followed by a ruthe-
À
nium(II)-catalyzed C H bond functionalization step.
As such, new C=O and C C bonds are efficiently
formed in a one-pot fashion employing 2-benzylpyri-
dine derivatives as substrates. The potential of this ap-
proach relies on the ability to employ multiple transi-
tion metal catalysts compatible with C H bond func-
tionalization reactions without isolation of intermedi- lows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet,
À
1
spectrometer. H NMR spectra were referenced to residual
protiated solvent (d=7.26 ppm for CDCl3) and 13C chemical
shifts are reported relative to deuterated solvents (d=
77.2 ppm for CDCl3). The peak patterns are indicated as fol-
À
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and br. for broad. GC-MS analyses were performed with
a GCMS-QP2010S (Shimadzu) instrument with a GC-2010
equipped with a 30 m capillary column (Supelco, SLBTM-
5 ms, fused silica capillary column, 30 mꢂ0.25 mmꢂ0.25 mm
film thickness), which was used with helium as the vector
gas. The following GC conditions were used: initial temper-
ature 808C for 2 min, then rate 208CminÀ1 until 2808C and
2808C for 28 min. Melting points were performed on
a LEICA VMHB Kofler system. HR-MS were recorded on
a Waters Q-Tof 2 mass spectrometer at the corresponding
facilities of the CRMPO, Centre Rꢀgional de Mesures Phy-
siques de l’Ouest, Universitꢀ de Rennes 1.
1H, J=7.7 Hz), 7.68 (d, 1H, J=7.4 Hz), 7.59 (t, 2H, J=
7.4 Hz), 7.48 (t, 2H, 7.4 Hz), 7.14–7.16 (m, 5H), 1.20 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3): d=198.8, 155.1,
150.1, 148.9, 142.2, 138.6, 137.9, 136.3, 131.1, 129.8, 129.5,
129.1, 127.1, 125.8, 125.0, 123.9, 34.5, 31.3; GC: tR =
15.1 min; MS (EI): m/z=315 (M+, 60), 286 (80), 181 (45),
106 (45), 78 (100), 57 (80): HR-MS (ESI): m/z=338.1524,
calcd, for [M+Na]+ C22H21NONa: 338.15208 (1 ppm).
2-(1-Naphthyl)phenyl 2-pyridyl ketone (2d): Colourless
solid, yield: 110 mg (71%); mp 97–998C; 1H NMR
(400.1 MHz, CDCl3): d=8.06 (d, 1H, J=4.6 Hz), 7.83 (dd,
1H, J=7.5 Hz, J=1.3 Hz), 7.66–7.69 (m, 1H), 7.64 (dd, 1H,
J=7.3 Hz, J=1.6 Hz), 7.60 (dd, 1H, J=7.5 Hz, J=1.4 Hz),
7.56–7.58 (m, 1H), 7.51 (dd, 1H, J=7.4 Hz, J=1.1 Hz),
7.37–7.40 (m, 2H), 7.34–7.36 (m, 2H), 7.18–7.25 (m, 2H),
6.90–6.93 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): d=
198.1, 154.7, 148.0, 140.1, 139.8, 138.3, 135.8, 133.2, 131.6,
131.1, 130.6, 129.5, 128.0, 127.7, 127.5, 126.6, 125.8, 125.6,
125.1, 124.7, 122.7; GC: tR =16.5 min; MS (EI): m/z=309
(M+, 90), 280 (100), 231 (97), 202 (98), 101 (35), 78 (20), 51
(20); HR-MS (ESI): m/z=332.1046, calcd. for [M+Na]+
C22H15NONa: 332.10458 (0 ppm), m/z=292.1119, calcd. for
[MÀH2O+H]+ C22H14N: 292.11207 (1 ppm).
General Procedure for the One-Pot Directing Group
À
Formation and C H Bond Functionalization of 2-
Benzylpyridines 1 and 5a–5e
CuI (0.05 mmol, 0.0095 g, 0.1 equiv.), benzoic acid
(0.5 mmol, 0.061 g, 1 equiv.), 2-benzylpyridine derivatives
(0.5 mmol, 1 equiv.) and NMP (0.5 mL) were introduced in
a dry Schlenk tube and flushed with O2 for 1 min. The
Schlenk tube was connected to a balloon filled with O2. The
reaction mixture was stirred at 1008C during 24 h. Then, the
reaction mixture was cooled down to room temperature and
flushed with vacuum/argon over 3–5 cycles. Under an argon
atmosphere, K2CO3 (2 mmol, 0.276 g, 4 equiv,), [RuCl2(p-
cymene)]2 (0.025 mmol, 0.015 g, 0.05 equiv,), aryl bromide
(0.75 mmol, 1.5 equiv.) and NMP (1.5 mL) were introduced.
The reaction mixture was stirred at 1508C for 48 h. The re-
action mixture was diluted with dichloromethane and fil-
tered over a pad of Celite. After solvent evaporation under
vacuum, the desired product 2 (or 6) was purified by silica
gel column chromatography with a mixture of petroleum
ether and ethyl acetate as the eluent.
2-Biphenyl 2-pyridyl ketone (2a): Colourless solid, yield:
89 mg (69%); mp 108–1108C; 1H NMR (400.1 MHz,
CDCl3): d=8.44 (d, 1H, J=4.5 Hz), 7.82 (d, 1H, J=8.1 Hz),
7.70–7.59 (m, 3H), 7.54–7.48 (m, 2H), 7.28–7.11 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3): d=198.4, 154.6, 148.7,
141.9, 140.7, 138.4, 136.3, 130.9, 129.8, 129.3, 129.1, 128.0,
127.1, 127.0, 125.9, 123.7; GC: tR =13.1 min; MS (EI): m/z=
259 (M+, 40), 230 (90), 181 (85), 152 (100), 78 (20), 51 (25);
HR-MS (ESI): m/z=282.0889, calcd. for [M+Na]+
C18H13NONa: 282.08893 (0 ppm). Crystals suitable for single
crystal X-ray diffraction studies were grown by slow diffu-
sion of n-hexane into a concentrated solution of 2a in ethyl
acetate at room temperature.[19]
2-(2-Naphthyl)phenyl 2-pyridyl ketone (2e): Colourless
solid, yield: 114 mg (74%); mp 98–1008C; 1H NMR
(400.1 MHz, CDCl3): d=8.35 (d, 1H, J=4.0 Hz), 7.77 (d,
1H, J=8.0 Hz), 7.46–7.73 (m, 9H), 7.39–7.42 (m, 3H), 7.06
(ddd, 1H, J=7.5 Hz, J=4.8 Hz, J=1.0 Hz); 13C{1H} NMR
(100 MHz, CDCl3): d=198.4, 154.6, 148.6, 141.8, 138.5,
138.2, 136.2, 132.8, 132.1, 130.9, 130.0, 129.5, 128.3, 127.9,
127.7, 127.4, 127.2, 127.1, 126.1, 125.9, 125.8, 123.5; GC: tR =
17.6 min; MS (EI): m/z=309 (M+, 90), 280 (100), 231 (97),
202 (98), 101 (35), 78 (20), 51 (20); HR-MS (ESI): m/z=
332.1048, calcd. for [M+Na]+ C22H15NONa: 332.10513
(1 ppm).
2-(p-Terphenyl 2-pyridyl ketone (2f): Colourless solid,
1
yield: 117 mg (70%); mp 113–1158C; H NMR (400.1 MHz,
CDCl3): d=8.44 (d, 1H, J=4.1 Hz), 7.83 (d, 1H, J=7.8 Hz),
7.69 (d, 1H, J=7.7 Hz), 7.59–7.65 (m, 2H), 7.52 (d, 2H, J=
7.2 Hz), 7.48–7.50 (m, 2H), 7.38–7.42 (m, 4H), 7.30–7.34 (m,
3H), 6.59 (ddd, 1H, J=7.7 Hz, J=4.6 Hz, J=0.9 Hz);
13C{1H} NMR (100 MHz, CDCl3): d=198.3, 154.6, 148.7,
141.5, 140.5, 139.7, 139.7, 138.3, 136.3, 130.9, 129.7, 129.5,
129.4, 128.7, 127.2, 127.1, 126.8, 126.7, 125.9, 123.7; GC: tR =
21.5 min; MS (EI): m/z=335 (M+, 90), 306 (100), 257 (90),
228 (60), 152 (20), 78 (20), 51 (20); HR-MS (ESI): m/z=
358.1202, calcd. for [M+Na]+ C24H17NONa: 358.12023
(0 ppm).
2-(p-Tolyl)phenyl 2-pyridyl ketone (2b): Colourless solid,
1
2-(p-Styryl)phenyl 2-pyridyl ketone (2g): Colourless solid,
yield: 98 mg (72%); mp 109–1118C; H NMR (400.1 MHz,
1
yield: 94 mg (66%); mp 108–1108C; H NMR (400.1 MHz,
CDCl3): d=8.45 (d, 1H, J=4.3 Hz), 7.81 (d, 1H, J=7.7 Hz),
7.67–7.62 (m, 2H), 7.59–7.55 (m, 1H), 7.48–7.44 (m, 2H),
7.424–7.21 (m, 1H), 7.13 (d, 2H, J=8.0 Hz), 6.96 (d, 2H,
J=7.7 Hz), 2.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
d=198.7, 154.8, 149.0, 142.1, 138.5, 138.0, 137.0, 136.5, 131.0,
130.0, 129.5, 129.1, 128.9, 127.0, 126.1, 124.0, 21.2; GC: tR =
13.7 min; MS (EI): m/z=273 (M+, 60), 244 (100), 195 (88),
165 (55), 152 (75), 78 (20), 51 (20); HR-MS (ESI): m/z=
296.1051, calcd. for [M+Na]+ C19H15NONa: 296.10513
(0 ppm).
CDCl3): d=8.43 (d, 1H, J=4.7 Hz), 7.83 (d, 1H, J=7.8 Hz),
7.64–7.67 (m, 2H), 7.59 (td, 1H, J=7.6 Hz, J=1.2 Hz),
7.45–7.50 (m, 2H), 7.22–7.24 (m, 1H), 7.20 (s, 4H), 6.59 (dd,
1H, J=17.6 Hz, J=10.9 Hz), 5.65 (d, 1H, J=17.6 Hz), 5.18
(d, 1H, J=10.9 Hz); 13C{1H} NMR (100 MHz, CDCl3): d=
198.3, 154.5, 148.8, 141.5, 140.2, 138.3, 136.4, 136.3, 136.3,
130.9, 129.7, 129.3, 129.2, 127.1, 126.0, 125.9, 123.8,
113.9 ppm. GC: tR =14.4 min. MS (EI): m/z=285 (M+, 80),
256 (100), 178 (75), 152 (35), 127 (20), 78 (20), 51 (20); HR-
MS
(ESI):
m/z=308.1051,
calcd.
for
[M+Na]+
2-(p-tert-Butylphenyl)phenyl 2-pyridyl ketone (2c): Col-
1
ourless solid, yield: 107 mg (68%); mp 112–1148C; H NMR
C20H15NONa: 308.10458 (2 ppm); m/z=268.1124, calcd. for
(400.1 MHz, CDCl3): d=8.39 (d, 1H, J=3.8 Hz), 7.73 (d,
[MÀH2O+H]+ C20H14N: 268.11207 (1 ppm).
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2-(p-Anisyl)phenyl 2-pyridyl ketone (2h): Colourless
solid, yield: 108 mg (75%); mp 101–1038C; 1H NMR
(400.1 MHz, CDCl3): d=8.43 (d, 1H, J=4.2 Hz), 7.79 (d,
1H, J=7.7 Hz), 7.62–7.66 (m, 2H), 7.56 (td, 1H, J=7.6 Hz,
J=1.2 Hz), 7.42–7.47 (m, 2H), 7.19–7.23 (m, 1H), 7.15 (d,
2H, J=8.6 Hz), 6.68 (d, 2H, J=8.6 Hz), 3.70 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=198.6, 158.7, 154.6,
148.7, 141.4, 138.2, 136.3, 133.1, 130.8, 130.2, 129.7, 129.2,
126.7, 125.9, 123.7, 113.5, 55.1; GC: tR =14.7 min; MS (EI):
m/z=289 (M+, 90), 274 (5), 260 (80), 246 (10), 231 (100),
196 (10), 183 (15), 168 (50), 139 (70), 109 (30), 78 (20); HR-
2-(p-Methyl benzoate)phenyl 2-pyridyl ketone (2l): Col-
ourless solid, yield: 109 mg (69%); mp 118–1208C; H NMR
1
(400.1 MHz, CDCl3): d=8.41 (d, 1H, J=4.6 Hz), 7.86 (d,
1H, J=7.5 Hz), 7.83 (d, 2H, J=8.2 Hz), 7.65–7.69 (m, 2H),
7.61 (td, 1H, J=7.4 Hz, J=1.1 Hz), 7.53 (td, 1H, J=7.4 Hz,
J=0.6 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.32 (d, 2H, J=8.2 Hz),
7.22–7.25(m, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=197.9, 166.8, 154.3, 148.8, 145.5, 140.9, 138.3,
136.5, 131.0, 129.7, 129.6, 129.3, 129.1, 127.8, 126.3, 126.2,
123.7, 52.0; GC: tR =16.3 min; MS (EI): m/z=317 (M+, 35),
306 (100), 257 (90), 228 (60), 152 (20), 78 (20), 51 (20); HR-
MS
(ESI):
m/z=290.1198,
calcd.
for
[M+Na]+
MS
(ESI):
m/z=340.0945,
calcd.
for
[M+Na]+
C19H15NO2Na: 290.11810 (6 ppm).
C20H15NO3Na: 340.09441 (0 ppm).
2-(p-Cyanophenyl)phenyl 2-pyridyl ketone (2i): Colourless
solid, yield: 108 mg (76%); mp 109–1118C; 1H NMR
(400.1 MHz, CDCl3): d=8.44 (d, 1H, J=4.5 Hz), 7.90 (d,
1H, J=7.9 Hz), 7.73 (td, 1H, J=7.7 Hz, J=1.6 Hz), 7.67 (d,
1H, J=7.6 Hz), 7.63 (td, 1H, J=7.6 Hz, J=1.1 Hz), 7.54
(td, 1H, J=7.5 Hz, J=0.8 Hz), 7.47 (d, 2H, J=8.1 Hz), 7.43
(d, 1H, J=7.9 Hz), 7.36 (d, 2H, J=8.2 Hz), 7.29–7.32 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3): d=197.4, 154.1,
148.8, 145.7, 140.1, 138.2, 136.7, 131.8, 131.1, 129.8, 129.7,
129.6, 128.1, 126.5, 123.8, 118.6, 110.8; GC: tR =15.0 min;
MS (EI): m/z=284 (M+, 25), 255 (100), 206 (60), 178 (30),
151 (50), 114 (10), 78 (15), 51 (10); HR-MS (ESI): m/z=
307.0844, calcd. for [M+Na]+ C19H12N2ONa: 307.08418
(1 ppm).
2-(p-Trifluoromethylphenyl)phenyl 2-pyridyl ketone (2j):
Colourless solid, yield: 110 mg (67%); mp 86–888C;
1H NMR (400.1 MHz, CDCl3): d=8.44 (d, 1H, J=4.3 Hz),
7.86 (d, 1H, J=7.7 Hz), 7.69 (td, 1H, J=7.7 Hz, J=1.7 Hz),
7.67 (dd, 1H, J=7.7 Hz, J=1.2 Hz), 7.62 (td, 1H, J=7.6 Hz,
J=1.4 Hz), 7.53 (td, 1H, J=7.5 Hz, J=1.2 Hz), 7.45 (dd,
1H, J=8.0 Hz, J=0.6 Hz), 7.42 (d, 2H, J=8.2 Hz), 7.36 (d,
2H, J=8.2 Hz), 7.24–7.28 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): d=197.7, 154.3, 148.8, 144.4, 140.5,
2-(m-Cyanophenyl)phenyl 2-pyridyl ketone (2n): Colour-
less solid, yield: 84 mg (59%); mp 94–968C; 1H NMR
(400.1 MHz, CDCl3): d=8.46 (d, 1H, J=4.4 Hz), 7.91 (d,
1H, J=7.8 Hz), 7.73 (td, 1H, J=7.8 Hz, J=1.7 Hz), 7.68
(dd, 1H, J=7.5 Hz, J=0.8 Hz), 7.61–7.65 (m, 1H), 7.53–7.57
(m, 2H), 7.48 (d, 1H, J=7.8 Hz), 7.42 (d, 2H, J=7.7 Hz),
7.28–7.31 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): d=
197.4, 154.2, 148.9, 142.2, 139.6, 138.2, 136.7, 133.4, 132.4,
131.2, 130.6, 129.8, 129.8, 128.8, 128.0, 126.5, 123.8, 118.5,
112.2; GC: tR =15.0 min; MS (EI): m/z=284 (M+, 25), 255
(100), 206 (60), 178 (30), 151 (50), 114 (10), 78 (15), 51 (10);
HR-MS (ESI): m/z=307.0844, calcd. for [M+Na]+
C19H12N2ONa: 307.08418, (1 ppm).
2-(o-Fluorophenyl)phenyl 2-pyridyl ketone (2o): Colour-
less solid, yield: 71 mg (51%); mp 129–1318C; 1H NMR
(400.1 MHz, CDCl3): d=8.50 (d, 1H, J=4.3 Hz), 7.87 (d,
1H, J=7.8 Hz), 7.73 (dd, 1H, J=7.6 Hz, J=1.0 Hz), 7.69
(td, 1H, J=7.8 Hz, J=1.6 Hz), 7.61 (td, 1H, J=7.6 Hz, J=
1.3 Hz), 7.51 (td, 1H, J=7.6 Hz, J=1.2 Hz), 7.47 (t, 1H, J=
7.6 Hz), 7.24–7.28 (m, 1H), 7.23 (td, 1H, J=7.6 Hz, J=
1.7 Hz), 7.09–7.15 (m, 1H), 7.00 (td, 1H, J=7.5 Hz, J=
1.1 Hz), 6.83–6.88 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): d=196.7, 159.0 (d, JC,F =244.9 Hz), 154.4, 148.7,
138.2, 136.4, 135.7, 131.5 (d, JC,F =3.1 Hz), 131.0, 130.8,
129.8, 129.3 (d, JC,F =8.4 Hz), 128.4 (d, JC,F =15.5 Hz), 127.6,
126.0, 123.9 (d, JC,F =3.2 Hz), 123.8, 115.2 (d, JC,F =22.4 Hz);
19F{1H} NMR (376 MHz, CDCl3): d=À115.8; GC: tR =
13.1 min; MS (EI): m/z=277 (M+, 30), 248 (97), 230 (35),
199 (100), 170 (95), 151 (25), 129 (30), 78 (25), 51 (27); HR-
138.3, 136.6, 131.0, 129.8, 129.6, 129.3, 129.1 (q, JC,F
31.8 Hz), 127.8, 126.3, 124.9 (q, JC,F =3.4 Hz), 124.0 (q, JC,F
=
=
270.9 Hz), 123.8; 19F{1H} NMR (376 MHz, CDCl3): d=
À62.7; GC: tR =12.5 min; MS (EI): m/z=327 (M+, 30), 298
(100), 249 (80), 201 (65), 152 (55), 78 (25), 51 (25); HR-MS
(ESI): m/z=350.07687, calcd. for [M+Na]+ C19H12NOF3Na:
350.0772 (1 ppm); m/z=328.0950, calcd. for [M+H]+
C19H13NOF3: 328.09492 (0 ppm); m/z=308.0880, calcd. for
[MÀHF+H]+.C19H12NOF2: 308.0887 (2 ppm).
MS
(ESI):
m/z=300.0795,
calcd.
for
[M+Na]+
C18H12NOFNa: 300.07951 (0 ppm).
2-(o-Anisyl)phenyl 2-pyridyl ketone (2p): Colourless
solid, yield: 101 mg (70%); mp 102–1048C; 1H NMR
(400.1 MHz, CDCl3): d=8.51 (d, 1H, J=4.3 Hz), 7.84 (d,
1H, J=7.8 Hz), 7.65–7.69 (m, 2H), 7.57 (td, 1H, J=7.6 Hz,
J=1.2 Hz), 7.41–7.45 (m, 2H), 7.23–7.26 (m, 2H), 7.11 (td,
1H, J=7.9 Hz, J=1.6 Hz), 6.89 (td, 1H, J=7.4 Hz, J=
0.8 Hz), 6.59 (d, 1H, J=8.2 Hz), 3.41 (s. 3H); 13C{1H} NMR
(100 MHz, CDCl3): d=196.0, 155.1, 154.5, 148.6, 138.0,
138.0, 136.2, 131.0, 131.0, 130.9, 129.6, 129.2, 128.9, 126.8,
125.7, 123.7, 120.7, 110.0, 54.4; GC: tR =14.1 min; MS (EI):
m/z=289 (M+, 90), 274 (5), 260 (80), 246 (10), 231 (100),
196 (10), 183 (15), 168 (50), 139 (70), 109 (30), 78 (20); HR-
2-(p-Fluorophenyl)phenyl 2-pyridyl ketone (2k): Colour-
less solid, yield: 90 mg (65%); mp 131–1338C; 1H NMR
(400.1 MHz, CDCl3): d=8.46 (d, 1H, J=4.5 Hz), 7.83 (d,
1H, J=7.7 Hz), 7.74–7.70 (m, 2H), 7.59 (td, 1H, J=7.5 Hz,
J=1.2 Hz), 7.49 (td, 1H, J=7.5 Hz, J=0.7 Hz), 7.42 (d, 1H,
J=7.6 Hz), 7.23–7.25 (m, 1H), 7.18–7.21 (m, 2H), 6.84 (t,
2H, J=8.6 Hz); 13C{1H} NMR (100 MHz, CDCl3): d=198.3,
162.0 (d, JC,F =245.0 Hz), 154.5, 148.8, 140.8, 138.4, 136.8 (d,
J
C,F =3.2 Hz), 136.5, 130.9, 130.6 (d, JC,F =8.3 Hz), 129.8,
129.3, 127.2, 126.1, 123.7, 114.9 (d, JC,F =21.4 Hz); 19F{1H}
NMR (376 MHz, CDCl3): d=À115.4; GC: tR =12.9 min;
MS (EI): m/z=277 (M+, 60), 248 (100), 199 (85), 170 (80),
151 (20), 78 (20), 51 (22); HR-MS (ESI): m/z=300.0802,
calcd. for [M+Na]+ C18H12NOFNa: 300.08006 (0 ppm).
Crystals suitable for single crystal X-ray diffraction studies
were grown by slow evaporation of a concentrated solution
of 2e in chloroform at room temperature.
MS
(ESI):
m/z=312.0997,
calcd.
for
[M+Na]+
C19H15NO2Na: 312.0995 (1 ppm); m/z=272.1071, calcd. for
[MÀH2O+H]+ C19H14NO: 272.10699 (0 ppm); m/z=
290.1178, calcd. for [M+H]+ C19H16NO2: 290.11755 (1 ppm).
2-(m-Pyridyl)phenyl 2-pyridyl ketone (2t): Pale yellow
solid, yield: 59 mg (45%); mp 126–1288C; 1H NMR
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(400.1 MHz, CDCl3): d=8.51 (br s, 1H), 8.44 (d, 1H, J=
4.7 Hz), 8.37 (br s, 1H), 7.90 (d, 1H, J=7.7 Hz), 7.75 (d,
1H, J=7.5 Hz), 7.70 (d, 1H, J=7.5 Hz), 7.64 (t, 1H, J=
7.3 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.40–7.49 (m, 2H), 7.25–
7.28 (m, 1H), 7.09 (dd, 1H, J=7.7 Hz, J=5.0 Hz); 13C{1H}
NMR (100 MHz, CDCl3): d=197.6, 154.2, 149.5, 148.9,
148.1, 138.4, 138.2, 136.7, 136.2, 131.1, 130.0, 128.5, 127.9,
126.8, 126.4, 123.8, 122.7; GC: tR =13.8 min; MS (EI): m/z=
260 (M+, 10), 231 (100), 182 (45), 154 (10), 127 (40), 102
(10), 77 (10), 51 (10); HR-MS (ESI): m/z=260.1022, calcd.
for [M+H]+ C17H13N2O: 261.10224 (0 ppm).
2-(o-Thiophenyl)phenyl 2-pyridyl ketone (2u): Pale red
solid, yield: 98 mg (74%); mp 123–1258C; 1H NMR
(400.1 MHz, CDCl3): d=8.46 (d, 1H, J=4.6 Hz), 7.88 (d,
1H, J=7.8 Hz), 7.69 (td, 1H, J=7.7 Hz, J=1.6 Hz), 7.61 (d,
1H, J=7.4 Hz), 7.52–7.56 (m, 2H), 7.46–7.50 (m, 1H), 7.24–
7.27 (m, 1H), 7.10 (dd, 1H, J=5.0 Hz, J=0.7 Hz), 6.80 (dd,
1H, J=3.5 Hz, J=0.8 Hz), 6.74 (dd, 1H, J=4.9 Hz, J=
3.6 Hz); 13C{1H} NMR (100 MHz, CDCl3): d=198.2, 154.3,
149.0, 142.1, 138.7, 136.4, 133.8, 130.7, 130.0, 129.0, 127.7,
127.7, 127.2, 126.2, 126.1, 123.6; GC: tR =13.3 min; MS (EI):
m/z=265 (M+, 55), 236 (60), 187 (55), 159 (10), 115 (100),
78 (10), 51 (10); HR-MS (ESI): m/z=288.0455, calcd. for
[M+Na]+ C16H11NOSNa: 288.04536 (0 ppm). Crystals suita-
ble for single crystal X-ray diffraction studies were grown by
slow diffusion of n-hexane into a concentrated solution of
2u in ethyl acetate at room temperature.
2,6-Bis(o-thiophenyl)phenyl 2-pyridyl ketone (3u): Pale
red solid, yield: 173 mg (81%); mp 135–1378C; 1H NMR
(400.1 MHz, CDCl3): d=8.51 (d, 1H, J=4.4 Hz), 7.81 (d,
1H, J=7.8 Hz), 7.66 (td, 1H, J=7.7 Hz, J=1.6 Hz), 7.49–
7.55 (m, 3H), 7.24–7.27 (m, 1H), 7.15 (dd, 2H, J=5.0 Hz,
J=0.7 Hz), 6.88 (dd, 2H, J=3.4 Hz, J=0.9 Hz), 6.82 (dd,
2H, J=5.0 Hz, J=3.7 Hz); 13C{1H} NMR (100 MHz,
CDCl3): d=198.9, 154.4, 149.2, 141.1, 139.0, 136.4, 133.1,
130.0, 129.1, 127.8, 127.1, 126.4, 126.2, 122.9; GC: tR =
18.6 min; MS (EI): m/z=347 (M+, 70), 318 (100), 269 (80),
240 (35), 208 (35), 157 (20), 78 (15), 51 (10); HR-MS (ESI):
m/z=370.0332, calcd. for [M+Na]+ C20H13NOS2Na:
370.03308 (0 ppm).
m/z=296.1046, calcd. for [M+Na]+ C19H15NONa: 296.10458
(0 ppm).
2-Phenyl-4-methoxyphenyl 2-pyridyl ketone (6c): Colour-
less solid, yield: 80 mg (55%); mp 95–978C; 1H NMR
(400.1 MHz, CDCl3): d=8.40 (d, 1H, J=4.4 Hz), 7.75 (d,
1H, J=7.8 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.61 (td, 1H, J=
7.6 Hz, J=0.6 Hz), 7.23 (d, 1H, J=7.4 Hz), 7.09–7.19 (m,
4H), 7.00 (dd, 1H, J=8.4 Hz, J=2.3 Hz), 6.95 (d, 1H, J=
2.3 Hz), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=
197.2, 161.6, 155.2, 148.5, 144.6, 140.8, 136.6, 132.1, 130.6,
129.0, 128.0, 127.1, 125.6, 123.8, 115.4, 112.6, 55.5; GC: tR =
15.0 min; MS (EI): m/z=289 (M+, 20), 260 (50), 211 (100),
168 (20), 139 (35), 78 (10), 51 (10); HR-MS (ESI): m/z=
312.0995, calcd. for [M+Na]+ C19H15NO2Na: 312.0995
(0 ppm).
2-Phenyl-4-fluorophenyl 2-pyridyl ketone (6d): Colourless
solid, yield: 93 mg (67%); mp 126–1288C; 1H NMR
(400.1 MHz, CDCl3): d=8.39 (d, 1H, J=4.6 Hz), 7.81 (d,
1H, J=7.9 Hz), 7.62–7.70 (m, 2H), 7.11–7.23 (m, 8H);
13C{1H} NMR (100 MHz, CDCl3): d=197.2, 163.9 (d, JC,F
=
250.7 Hz), 154.5, 148.7, 144.9 (d, JC,F =8.5 Hz), 139.7, 136.4,
134.5 (d, JC,F =2.6 Hz), 131.9 (d, JC,F =9.2 Hz), 128.9, 128.2,
127.6, 126.1, 123.7, 116.8 (d, JC,F =22.2 Hz), 114.2 (d, JC,F
=
21.8 Hz); 19F{1H} NMR (376 MHz, CDCl3): d=À109.0; GC:
tR =12.8 min; MS (EI): m/z=277 (M+, 40), 248 (95), 199
(100), 170 (75), 151 (15), 78 (10), 51 (15); HR-MS (ESI):
m/z=300.0794, calcd. for [M+Na]+ C18H12NOFNa:
300.07951 (0 ppm).
2-Phenyl-3-cyanophenyl 2-pyridyl ketone (6e): 60% purity
according to 1H NMR spectroscopy and GC-MS analysis.
This compound could not be separated from the correspond-
ing bis-phenylated derivative 7e [GC: tR =20.9 min; MS
(EI): m/z=360 (M+, 40), 331 (100), 282 (70), 253 (30), 226
(20), 207 (50), 151 (10), 78 (20) 51 (10)]. As such, only se-
lected data are provided for 6e: 1H NMR (400.1 MHz,
CDCl3): d=8.40 (d, 1H, J=4.5 Hz), 7.84 (dd, 1H, J=
8.0 Hz, J=1.6 Hz,), 7.70 (td, 1H, J=7.7 Hz, J=1.5 Hz), 7.58
(d, 1H, J=8.0 Hz), 7.27–7.29 (m, 1H), 7.18–7.23 (m, 7H);
13C{1H} NMR (100 MHz, CDCl3): d=196.3, 153.4, 148.8,
146.1, 139.5, 139.0, 136.7, 133.7, 132.8, 130.6, 128.8, 128.3,
128.2, 126.7, 123.6, 118.2, 111.2; GC: tR =15.1 min; MS (EI):
m/z=284 (M+, 30), 255 (100), 206 (40), 177 (25), 151 (45),
114 (10), 78 (15), 51 (15).
2-Phenyl-6-methylphenyl 2-pyridyl ketone (6a): 30%
1
purity according to H NMR spectroscopy and GC/MS anal-
ysis. This compound could not be separated from the corre-
sponding non-phenylated benzoylpyridine derivative 10a.[20]
2,6-Diphenyl-4-methoxyphenyl 2-pyridyl ketone (7c): Col-
1
1
As such, only selected data are provided for 6a: H NMR
ourless solid, yield: 153 mg (84%); mp 134–1368C; H NMR
(400.1 MHz, CDCl3): d=8.50 (d, 1H, J=4.4 Hz), 7.76 (d,
1H, J=7.8 Hz), 7.864 (td, 1H, J=7.6 Hz, J=1.5 Hz), 7.09–
7.48 (m, 9H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): d=200.1, 154.7, 140.7, 140.4, 138.7, 136.4, 135.5,
129.3, 129.2, 129.1, 127.8, 127.1, 126.9, 126.2, 123.0, 19.8;
GC: tR =13.1 min; MS (EI): m/z=272 (M+, 35), 244 (100),
195 (40), 165 (45), 152 (50), 129 (20), 80 (25), 51 (10).
2-Phenyl-4-methylphenyl 2-pyridyl ketone (6b): Colour-
less solid, yield: 97 mg (71%); mp 99–1018C; 1H NMR
(400.1 MHz, CDCl3): d=8.41 (d, 1H, J=4.3 Hz), 7.78 (d,
1H, J=7.8 Hz), 7.61 (td, 1H, J=7.8 Hz, J=1.5 Hz), 759 (d,
1H, J=7.6 Hz), 7.27–7.31 (m, 2H), 7.06–7.23 (m, 6H), 7.24–
2.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): d=198.3,
154.9, 148.6, 142.1, 141.3, 140.8, 136.2, 135.5, 130.6, 129.7,
129.0, 127.9, 127.8, 126.9, 125.7, 123.7, 21.54; GC: tR =
13.7 min; MS (EI): m/z=273 (M+, 45), 244 (100), 195 (95),
165 (65), 152 (85), 115 (25), 78 (25), 51 (30); HR-MS (ESI):
(400.1 MHz, CDCl3): d=8.44 (d, 1H, J=4.8 Hz), 7.56 (d,
1H, J=7.8 Hz), 7.50 (td, 1H, J=7.7 Hz, J=1.5 Hz), 7.27–
7.30 (m, 4H), 7.12–7.20 (m, 7H), 6.96 (s, 2H), 3.90 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): d=199.2, 159.7, 155.7,
148.6, 143.0, 140.6, 136.1, 131.3, 129.0, 127.9, 127.1, 125.7,
123.0, 114.6, 55.4; GC: tR =20.4 min; MS (EI): m/z=365
(M+, 25), 336 (50), 287 (100), 272 (10), 244 (10), 215 (30), 78
(10); HR-MS (ESI): m/z=388.1306, calcd. for [M+Na]+
C25H19NO2Na: 388.1308 (0 ppm).
2,6-Diphenyl-4-fluorophenyl 2-pyridyl ketone (7d): Col-
1
ourless solid, yield: 137 mg (78%); mp 125–1278C; H NMR
(400.1 MHz, CDCl3): d=8.45 (d, 1H, J=4.8 Hz), 7.58 (d,
1H, J=7.8 Hz), 7.52 (td, 1H, J=7.6 Hz, J=1.3 Hz), 7.25–
7.27 (m, 4H), 7.13–7.20 (m, 9H); 13C{1H} NMR (100 MHz,
CDCl3): d=198.7, 162.2 (d, JC,F =250.7 Hz), 155.1, 148.7,
143.5 (d, JC,F =8.4 Hz), 139.5, 136.2, 134.7 (d, JC,F =2.7 Hz),
128.9, 128.0, 127.5, 126.0, 122.9, 115.8 (d, JC,F =21.9 Hz);
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8
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19C{1H} NMR (376 MHz, CDCl3): d=À111.8; GC: tR =
16.5 min; MS (EI): m/z=353 (M+, 20), 324 (70), 275 (100),
246 (20), 226 (25), 78 (10), 51 (10); HR-MS (ESI): m/z=
376.1109, calcd. for [M+Na]+ C24H16NOFNa: 376.11081
(0 ppm); m/z=336.1184, calcd. for [MÀH2O+H]+
C24H15NF: 336.1183 (0 ppm).
pressure was slowly released followed by H2 flushing over
5 min. Then, the autoclave was pressurized with H2 (40 bar)
and the reaction mixture was stirred at 1508C for 12 h. Back
down at room temperature, the pressure was slowly released
and the reaction mixture was diluted with dichloromethane
prior to being filtered over a pad of Celite. After solvent
evaporation under vacuum, the desired product 9 was puri-
fied by silica gel column chromatography with a mixture of
petroleum ether and ethyl acetate as the eluent and ob-
tained as a colourless solid; yield: 87 mg (55%); mp 108–
Synthesis and Characterization of 2-(p-Ethylphenyl)-
phenyl 2-Pyridyl Ketone (8)
1
1108C. H NMR (400.1 MHz, CDCl3): d=8.53 (d, 1H, J=
CuI (0.05 mmol, 0.0095 g, 0.1 equiv.), benzoic acid
(0.5 mmol, 0.061 g, 1 equiv.), 2-benzylpyridine derivative
1 (0.5 mmol, 1 equiv.) and NMP (0.5 mL) were introduced
in a dry Schlenk tube and flushed with O2 for 1 min. The
Schlenk tube was connected to a balloon filled with O2. The
reaction mixture was stirred at 1008C during 24 h. Then, the
reaction mixture was cooled down to room temperature and
flushed with vacuum/argon over 3–5 cycles. Under an argon
atmosphere, K2CO3 (2 mmol, 0.276 g, 4 equiv.), [RuCl2(p-
cymene)]2 (0.025 mmol, 0.015 g, 0.05 equiv.), 4-bromostyrene
(0.75 mmol, 1.5 equiv.) and NMP (1.5 mL) were introduced.
The reaction mixture was stirred at 1508C for 48 h. Then,
the Schlenk tube was capped with balloon filled with H2 and
the reaction mixture was stirred at 1508C for 12 h. Back
down to room temperature, the pressure was slowly released
and the reaction mixture was diluted with dichloromethane
prior to being filtered over a pad of Celite. After solvent
evaporation under vacuum, the desired product 8 was puri-
fied by silica gel column chromatography with a mixture of
petroleum ether and ethyl acetate as the eluent and ob-
tained as a colourless solid; yield: 92 mg (64%); mp 102–
4.7 Hz), 7.54 (td, 1H, J=7.7 Hz, J=1.4 Hz), 7.41–7.46 (m,
4H), 7.27–7.32 (m, 3H), 7.20–7.22 (m, 1H), 7.13–7.17 (m,
1H), 6.84 (d, 1H, J=7.9 Hz), 5.93 (s, 1H), 5.39 (br s, 1H),
1.37 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): d=161.3,
150.0, 147.3, 142.0, 140.6, 137.8, 136.7, 130.1, 129.3, 128.2,
127.8, 127.6, 125.2, 122.2, 121.8, 70.7, 34.6, 31.4; GC: tR =
15.2 min; MS (EI): m/z=317 (M+, 70), 284 (15), 243 (45),
165 (20), 108 (30), 80 (100), 57 (50), 52 (15); HR-MS (ESI):
m/z=340.1671, calcd. for [M+Na]+ C22H23NONa: 340.16718
(0 ppm).
CCDC 1471276 (2a), CCDC 1471277 (2k), and CCDC
1471278 (2u) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
1
Dr. T. Roisnel is acknowledged for performing X-ray diffrac-
tions studies. The authors wish to thank CNRS and Universitꢀ
de Rennes 1 for financial support, and the contribution of the
COST Action CA15106 (C–H Activation in Organic Synthe-
sis, CHAOS).
1048C. H NMR (400.1 MHz, CDCl3): d=8.42 (d, 1H, J=
4.2 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.56–7.66 (m, 3H), 7.47 (t,
2H, J=7.4 Hz), 7.18–7.21 (m, 1H), 7.14 (d, 2H, J=8.0 Hz),
6.97 (d, 2H, J=8.0 Hz), 2.51 (q, 2H, J=7.6 Hz), 1.12 (t, 3H,
J=7.6 Hz); 13C{1H} NMR (100 MHz, CDCl3): d=198.5,
154.8, 148.7, 143.1, 142.0, 138.3, 138.0, 136.2, 130.9, 129.8,
129.3, 129.1, 127.5, 126.9, 125.8, 123.8, 28.4, 15.5; GC: tR =
14.2 min; MS (EI): m/z=287 (M+, 50), 258 (100), 209 (15),
181 (55), 152 (30), 122 (10), 78 (15), 51 (10); HR-MS (ESI):
m/z=310.1203, calcd. for [M+Na]+ C20H17NONa: 310.12023
(0 ppm); m/z=270.1275, calcd. for [MÀH2O+H]+ C20H16N:
270.12772 (1 ppm).
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One-Pot Directing Group Formation/C H Bond
Functionalization via Copper(I) and Ruthenium(II)
Catalysis
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Christian Bruneau, Rafael Gramage-Doria*
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