Efficient ruthenium-catalyzed α-alkylation of ketones using pyridyl methanols

Article abstract of DOI:10.1016/j.tet.2013.12.065

By employing an easily available [Ru(p-cymene)Cl₂] ₂/Xantphos/t-BuOK catalyst system, the α-alkylation of ketones was demonstrated by using pyridyl methanol as the alkylating reagents. The synthetic protocol allows synthesizing a wid

Full text of DOI:10.1016/j.tet.2013.12.065

Tetrahedron 70 (2014) 1193e1198
Contents lists available at ScienceDirect
Tetrahedron
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Efficient ruthenium-catalyzed a-alkylation of ketones using pyridyl
methanols
,
b
b
b
Feng-Xia Yan b, Min Zhang a , Xiao-Ting Wang , Feng Xie , Meng-Meng Chen ,
*
Huanfeng Jiang a
a South China University of Technol, School of Chemistry & Chemical Engineering, 381 Wushan Rd, Guangzhou 510641, Guangdong, PR China
b Jiangnan University, School of Chemical & Material Engineering, Wuxi 214122, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
By employing an easily available [Ru(p-cymene)Cl2]2/Xantphos/t-BuOK catalyst system, the a-alkylation
Received 19 November 2013
Received in revised form 17 December 2013
Accepted 24 December 2013
Available online 3 January 2014
of ketones was demonstrated by using pyridyl methanol as the alkylating reagents. The synthetic pro-
tocol allows synthesizing a wide range of -pyridyl methylated ketones in reasonable to excellent iso-
lated yields with high atom-efficiency. The transformation is operationally simple, the substrate scope is
wide, and the starting materials are readily-available. There is no need for addition of alkenes as the
hydrogen receptors or the use of stoichiometric amount of base.
a
Keywords:
Ruthenium
Ó 2013 Elsevier Ltd. All rights reserved.
a
-Alkylation
Ketones
Pyridyl methanols
Hydrogen-borrowing
1. Introduction
as the hydrogen acceptor. Yus et al. demonstrated that
RuCl2(DMSO)4 was an efficient catalyst for the a-alkylation of ke-
a
-Alkylation of ketones has been known as an important tool for
tones with benzylic alcohols in the presence of stoichiometric
amount of base.6 Without addition of alkenes, Ishii et al. developed
an efficient [Ir(cod)Cl]2/PPh3/KOH catalytic system to achieve the
similar goal under solvent-free conditions.4a More recently, the Ryu
group described an efficient RuHCl(CO)(PPh3)3/Cs2CO3 system for
the construction of carbonecarbon (CeC) bonds. Conventionally,
such an alkylation can be realized by the reactions of enolates or
enamines derived from ketones with carbon electrophiles, such as
alkyl halides.1,2 However, the drawbacks of the conventional syn-
thesis including the need of pre-functionalization step or the use of
less-environmentally benign halogenated substrates, and the for-
mation of stoichiometric amount of undesirable salts have
prompted the search for green and atom-economical processes to
achieve the related goals. In recent years, much attention has been
a
-alkylation of acetophenones.7 In addition to the homogeneous
catalysis, the development of recyclable heterogeneous catalyst
systems has also been extensively investigated in recent years.8
Drawing from the significant advantages of borrowing-
hydrogen methodology and inspired by the elegant contributions
from the Ryu group, we wish to make a systematical investigation
focused on the transition-metal-catalyzed a-alkylation of ketones
by employing borrowing-hydrogen methodology.3,4 Advanta-
geously, such a process generates water as the only by-product and
there is no need for additional hydrogen source. Additionally, sus-
tainable and abundant alcohols are used as the alternative alky-
lating agents. Among the early reports, Cho et al. reported
on the a-alkylation of ketones using pyridyl methanols as the
alkylating reagents. Based on the related mechanisms, such
a transformation should proceed via the following relay sequences:
1) The dehydrogenation of pyridyl methanol 1 via cooperative ac-
tions of base-initiated deprotonation of hydroxyl group and metal-
a RuCl2(PPh3)2-catalyzed
a
-alkylation of ketones with primary al-
induced
hyde A (See Scheme 1, from 1 to A).9 2) Aldehyde A then condenses
with the nucleophilic -methylene group of the ketone 2 to give
b-hydride elimination, leads to in situ generation of alde-
cohols.5 In order to avoid the generation of
a
-alkylated alcohols via
further hydrogenation of alkylated ketones, 1-dodecene was added
a
enone B. 3) Finally, the hydrogenation of B via insertion of CeC
double bond into the MeH bond and protonation by BH, releases
the
a-pyridyl methylated product and regenerates the catalyst after
* Corresponding author. Tel.: þ86 020 22236518; e-mail address: minzhang@
a reductive elimination step. Interestingly, the hydrogen required
scut.edu.cn (M. Zhang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.065

1194
F.-X. Yan et al. / Tetrahedron 70 (2014) 1193e1198
Table 1
R1
Screening of optimized reaction conditions for the synthesis of 3aa
Catalyst/Base
[M]
R2
B-
O
R1
OH
B-
R3
1
OH
O
3
ligand (1 mol%), solvent, 16h
1a
O
N
N
+
3a
OH
M
R1
B-H
Cat (1 mol%), t-BuOK (40 mol%)
hydrogenation
R1
R2
dehydrogenation
R1
R1
O
OM
O
R3
R2
2a
N
3a'
O
[M-H]
Entry
Catalyst
Ligand
Solvent
3a Yield (%)b
R3
1
2
3
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Cat 6
Cat 7
Cat 8
Cat 9
Cat 8
Cat 8
Cat 8
Cat 8
Cat 8
Cat 8
Cat 8
Cat 8
Cat 8
d
d
d
d
d
d
d
d
d
L1
L2
L3
L4
L1
L1
L1
L1
L1
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
t-amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
tert-Amyl alcohol
Toluene
trace
69
21
53
70
11
23
76
68
92
42
84
76
52
83
72
23
<10
B
A
R3
O
H2O
R2
4b
5
elimination
of water
2
aldol
condensation
6
7
R1 = Pyridyl group; B- = Base anion
8c
9
Scheme 1. Possible pathway for a-alkylation of ketones using pyridyl methanols.
10
11
12
13
14d
15e
16
17
18
for the final hydrogenation step is completely generated from the
dehydrogenation of the pyridyl methanol. Hence, there is no need
for additional hydrogen source (see Scheme 1).
However, such a process that generates a-pyridyl methylated
1,4-Dioxane
DMSO
ketones, a very useful class of intermediates for the preparation of
complex heterocycles and bioactive compounds,10a,12 has been
scarcely explored. Presumably, the challenging points for such
a synthetic goal are associated with following factors: 1) The pyr-
idyl group may reduce the catalyst activity by blocking necessary
coordination sites on the metal center. 2) Ketone 2 might undergo
homo-aldol condensation prior to the dehydrogenation of pyridyl
methanol under alkaline or at elevated reaction temperature. Thus
the cross-aldol condensation (Scheme 1, from A to B), a key step for
the formation of product 3 is prohibited. Herein, we wish to de-
velop a suitable catalyst system that could provide an efficient
a
Unless otherwise specified, all reactions were carried out with 1a (1.2 mmol,
130 mg), 2a (1 mmol, 120 mg), cat (0.01 mmol), t-BuOK (0.4 mmol) and ligand
(0.01 mol) in tert-amyl alcohol (1 mL) at 120 ꢀC for 16 h.
b
Catalyst loading: 0.34 mmol%.
Catalyst loading: 0.5 mmol%.
Reaction temperature: 110 ꢀC.
c
d
e
Base loading: 0.3 mmol.
[RuCl2(COD)]n
(Cp*RuCl2)n
Ru3(CO)12
RuCl3
RuCl2(PPh3)3
Cp*RuCl(COD)
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Cat 6
method for synthesis of a-pyridyl methylated ketones from readily-
available ketones and pyridyl methanols.
Cl
Cl
P
O
P
Cl
Ru
Ru
Cl
Ru
Ru
PPh3
O
Cl
2. Results and discussion
Cl
Cl
PPh3
Cat 7
Cat 8: [RuCl2(p-Cymene)]2
Cat 9
In order to determine an effective catalyst system, the reaction
of acetophenone 1a with 3-(Hydroxymethyl)pyridine 2a that gen-
erates 3-(3-Pyridinyl)-1-phenylpropan-1-one 3a was chosen as
a model reaction to evaluate the influence of various ruthenium
catalysts, ligands and solvents. On the basis of recently reported
contributions, t-BuOK has been proven to be highly effective for
alcohol dehydrogenation.10a By employing this base, the model
reaction was initially conducted at 120 ꢀC for 16 h by introducing
1 mol % of ruthenium catalyst with respect to the amount of metal.
Among 9 ruthenium catalyst precursors tested (Table 1, entries 1e9
and see Scheme 2), [RuCl2(p-Cymene)]2 (Cat 8) showed to be an
excellent catalyst and the product was afforded in best yield (Table
1, entry 8). Considering the bidentate phosphine ligands signifi-
cantly influence the catalyst activity,10 we then tried to further
improve the reaction efficiency by using the combinations of four
diphosphine ligands with [RuCl2(p-Cymene)]2 (Cat 8) (Table 1,
entries 10e13 and see Scheme 2). Gratifyingly, the use of [RuCl2(p-
Cymene)]2 and Xantphos (L1) gave product 3a in almost quanti-
tative yield upon GC analysis (Table 1, entry 10), which might be
attributed to the Xantphos acts as a P^O^P ligand that form an active
pincer ruthenium species.11 However, the decrease of reaction
temperature from 120 ꢀC to 110 ꢀC (Table 1, entry 14) or decreasing
the base loading (Table 1, entry 15) would lead to decreased
product yields. Changing the solvent to toluene, 1,4-dioxane, and
PPh2
PPh2
PCy2
Fe
Ph2P
Cy2P
O
PPh2
PPh2
PPh2
L1
L2
L3
L4
(COD = cyclooctadiene, Cp* = C5Me5)
Scheme 2. Ruthenium catalyst precursors and ligands tested for optimizing the re-
action conditions.
DMSO resulted in lower yields of 3a (Table 1, entries 16e18). Hence,
the best reaction conditions are summarized as follows: 0.5 mol %
of [RuCl2(p-Cymene)]2 catalyst, 1 mol % of Xantphos (L1), tert-amyl
alcohol as the reaction solvent, and at 120 ꢀC (Table 1, entry 10).
Notably, in all the cases tested, the side product 3a0 arising from
hydrogenation of 3a was also detected that less than 10% of yields
were observed by means of GC and GCeMS analysis.
With the optimized reaction conditions in hand, we then ex-
amined the generality and the limitations of this ruthenium-
catalyzed synthetic protocol. Firstly, the reactions of pyridyl
methanol substrates in combination with a variety of acetophe-
nones have been examined. As shown in Table 2, the acetophenones
were efficiently alkylated to yield
moderate to excellent yields upon isolation (Table 2, entires 1e14).
a-pyridyl methylated products in

F.-X. Yan et al. / Tetrahedron 70 (2014) 1193e1198
Table 2 (continued)
1195
Table 2
Ruthenium-catalyzed a
-alkylation of ketonesa
yield % b
Entry
12
1
2
Product 3
O
O
[RuCl2-(p-cymene)]2 (0.5 mol%)
R3
R3
R2
R1
OH
+
R2
O
O
N
Xantphos (1 mol%), t-BuOK (40 mol%)
t-amyl alcohol, N2,16h
1
2
3
2a
73
O
O
R1
2b: R2 = Ph, R3 = H;
2a: R2 = Ph, R3 = H;
N
OH
2d: R2 = 4-Cl-C6H4, R3 = H;
2c: R2 = 4-Me-C6H4, R3 = H;
2e: R2 = 4-F-C6H4, R3 = H;
2g: R2 = Ph, R3 = Ph;
3l
2f: R2 = 4-NO2-C6H4, R3 = H;
1d
2h: R2 = 4-MeO-C6H4, R3 = 4-MeO-C6H4;
O
O
13
14
O
2b
77
O
N
O
OH
3m
N
1d
2i:
2j
O
2d
2f
62
-
O
yield % b
Entry
1
2
Product 3
N
Cl
OH
N
3n
O
1
1d
2a
78
15e
16
NO2
OH
OH
OH
N
N
1a
OH
N
N
N
3a
O
1c
O
3o
2
2b
80
2a
-
1a
1a
N
OH
N
N
N
3b
O
O
3
3p
1e
1c
2c
82
17c
18c
O
Ph
70
72
N
N
2g
2h
OH
N
O
Ph
3c
N
4b
O
3q
2d
66
OMe
OH
OH
OH
O
1a
1b
1b
OH
N
Cl
N
3d
1c
N
O
5
6
MeO
N
N
2a
2b
70
78
N
3r
19d
20
2i
2j
40
42
3e
O
OH
OH
N
N
N
N
N
1c
1c
O
3s
N
O
3f
N
O
7
2c
2a
80
72
OH
OH
3t
N
1b
1c
aAll the reactions were carried out with 1 (1.2 mmol), 2 (1
mmol), [RuCl2(p-Cymene)]2 (0.01 mmol), t-BuOK (0.4 mmol)
and ligand (0.01 mol) in t-amyl alcohol (1 mL) at 120 oC for 16h.
bIsolated yield..
OMe
OMe
3g
3h
8
9
N
O
N
N
cReaction time: 10h.
d2.4 equivalent of 1c was added.
Halogens (Cle, Fe) as well as electron-donating substituents (Mee,
MeOe) are well tolerated in the reactions. It was found that the
substitution patterns of pyridyl methanol substrates have little in-
fluence on the formation of desired products (Table 2, see 1aed).
However, the substituents having different electronic properties on
the aryl ring of acetophenones affected the reaction yields signifi-
cantly. In general, acetophenones possessing electron-donating
groups gave the corresponding products in higher yields (Table 2,
entries 2, 3, 6, 7, 9, and 13) comparing to electron-poor ones (Table
2, entries 4, 10, 11, and 14). Notably, acetophenone containing
a strong electron-withdrawing group (such as eNO2) led to
a complex reaction system and failed to yield the expected products
(Table 2, entry 15). On the basis of GCeMS analysis, this result can
be attributed to the decomposition of acetophenones under the
standard reaction conditions. Moreover, 1-(pyridin-3-yl)ethanol
OH
OH
N
2c
75
66
O
1c
1c
3i
2d
Cl
F
10
11
N
N
N
O
3j
2e
52
OH
N
1c
O
3k

1196
F.-X. Yan et al. / Tetrahedron 70 (2014) 1193e1198
reacted with acetophenone could not yield trace amount of ex-
pected product even at elevated reaction temperature or with large
excess of base (Table 2, entry 16). It is conceivable that the in situ
formed ketone derived from dehydrogenation of 1e is less reactive
than that of aryl aldehydes arising from primary alcohols. Fur-
thermore, the steric effect of substrates should also play a key role
in the formation of products.
temperature, the reaction mixture was filtered, then it was purified
by preparative TLC on silica, eluting with petroleum ether
(60e90 ꢀC): ethyl acetate (3:1) to give 3-(3-Pyridinyl)-1-
phenylpropan-1-one 3a as a white solid (164 mg, 78%).
4.2.1. 3-(3-Pyridinyl)-1-phenylpropan-1-one (3a). Yield: 78%; white
solid; mp:86e88 ꢀC mp 84e86 ꢀC; 1H NMR (400 MHz, CDCl3):
In addition to the acetophenones employed, benzylic ketones as
well as simple cyclic and bridged cyclic ketones were also employed
for the a-alkylation reactions. Benzylic ketones were proven to be
d
3.09 (t, J¼7.4 Hz, 2H), 3.33 (t, J¼7.4 Hz, 2H), 7.23 (m, 1H), 7.47 (t,
J¼7.6 Hz, 2H), 7.56e7.61 (m, 2H), 7.95 (dd, J¼1.37 Hz, 2H), 8.46 (d,
J¼4.0 Hz, 1H), 8.52e8.54 (m, 1H); 13C NMR (100 MHz, CDCl3):
excellent coupling partners, the reactions completed in only 10 h
and 1,2,3-triaryl substituted propanone 3q and r were obtained in
70% and 72% yields, respectively (Table 2, entries 17 and 18). Cy-
clohexanone 2i yielded a dialkylated product exclusively in a rela-
tively low yield (Table 2, entry 19), indicating that the alkyl alkyl
ketones are less reactive than the tested acetophenones under the
same reaction conditions. Interestingly, bicyclo[2.2.1]heptan-2-one
2i has been successfully employed for the synthetic protocol, and
d 198.50, 150.23, 147.70, 136.68, 136.07, 133.28, 128.69, 128.02,
123.44, 39.77, 27.14; IR (neat): 3028, 2929, 1682, 1595, 1577, 1447,
1424, 1364, 1293, 1207, 748, 717, 692; HRMS calcd for C21H15N3:
309.1266, found: 309.125.
4.2.2. 3-(Pyridin-3-yl)-1-p-tolylpropan-1-one (3b). Yield: 80%;
white solid; mp: 59e62 ꢀC; 1H NMR (400 MHz, CDCl3):
d 2.40 (s,
3H), 3.07 (t, J¼7.4 Hz, 2H), 3.29 (t, J¼7.4 Hz, 2H), 7.20e7.26 (m, 3H),
the
a-pyridyl methylated product 3t was obtained in 41% yield
7.58 (d, J¼7.6 Hz, 1H), 7.85 (d, J¼8.0 Hz, 2H), 8.45 (dd, J¼2.1 Hz, 1H),
(Table 2, entry 20).
8.53 (d, J¼1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 198.19, 148.82,
144.09, 136.43, 134.16, 129.38, 128.15, 123.41, 77.39, 77.07; IR (neat):
3028, 2934, 2899, 1678, 1606, 1573, 1480, 1446, 1363, 799, 716;
HRMS calcd for C15H15NO: 225.11536, found: 225.1133.
3. Conclusion
In conclusion, we have demonstrated an efficient ruthenium-
catalyzed
able [RuCl2(p-Cymene)]2/t-BuOK/Xantphos catalyst system, which
allows assembling a wide range -pyridyl methylated products in
moderate to excellent isolated yields. The transformation is oper-
ationally simple, the substrate scope is wide, and the starting ma-
terials are readily-available. There is no need for addition of alkenes
as the hydrogen acceptors or the use of stoichiometric amount
bases. Comparing to the previously reported hydrogen-borrowing
procedures for CeC bond formations, this synthetic protocol is an
a
-pyridyl alkylation of ketones by using an easily avail-
4.2.3. 1-(4-Methoxyphenyl)-3-(pyridin-3-yl)propan-1-one
(3c). Yield: 82%; white solid; mp: 73e75 ꢀC; 1H NMR (400 MHz,
a
CDCl3):
d
3.00 (t, J¼7.4 Hz, 2H), 3.20 (t, J¼7.4 Hz, 2H), 3.80 (s, 3H),
6.86 (d, J¼4.8 Hz, 2H), 7.15 (m, 1H), 7.50 (d, J¼7.6 Hz, 1H), 7.79 (d,
J¼8.8 Hz, 2H), 8.38 (m, 1H), 8.46(d, J¼1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3):
d 197.39, 163.50, 149.98, 147.64, 136.81, 130.30,
129.78, 123.37, 113.82, 55.49, 39.41, 27.31; IR (neat): 3029, 2958,
2935,1668,1603,1575,1509,1423,1261,1028, 841, 803; HRMS calcd
for C15H15NO2: 241.1103, found: 241.1089.
important complement to the
a series of advantages, the synthetic method is of practical value in
preparation of -pyridyl methylated ketones.
a-alkylation of ketones. Based on
4.2.4. 1-(4-Chlorophenyl)-3-(pyridin-3-yl)propan-1-one (3d). Yield:
a
66%; colorless oil; 1H NMR (400 MHz, CDCl3):
d
3.00 (t, J¼7.4, 2H),
3.21 (t, J¼7.4 Hz, 2H), 7.13e7.16 (m, 1H), 7.35 (d, J¼8.8 Hz, 2H), 7.50
4. Experimental section
4.1. General
(d, J¼7.6 Hz,1H), 7.80 (d, J¼8.8 Hz, 2H), 8.37 (dd, J¼2.13 Hz,1H), 8.43
(d, J¼2.00 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 197.22, 149.90,
147.73, 139.76, 136.45, 136.10, 134.94, 129.13, 129.01, 123.44, 39.73,
27.03; IR (neat): 3030, 2914, 2854, 1686, 1589, 1573, 1488, 1423,
1400, 1291, 1204, 1091, 1013, 979, 833, 801, 714; HRMS calcd for
All the obtained products were characterized by melting points
(mp), 1H NMR, 13C NMR, infrared spectra (IR) and high-resolution
C14H12ClNO: 245.0607, found: 245.0601.
€
mass spectra (HRMS). Melting points were measured on an BUCHI
B-545 microscopy digital melting point apparatus and are un-
corrected; IR spectra were recorded on a FTLA2000 spectrometer;
1H NMR spectra were obtained on Bruker Advance 400 and ꢁ300;
High-resolution mass spectra (HRMS) were recorded on a JEOL
JMS-600 spectrometer. Chemical shifts were reported in parts per
4.2.5. 1-Phenyl-3-(pyridin-4-yl)propan-1-one (3e). Yield: 70%;
white solid; mp: 64e67 ꢀC; 1H NMR (400 MHz, CDCl3):
3.00
d
(t, J¼7.4 Hz, 2H), 3.25 (t, J¼7.4 Hz, 2H), 7.10 (d, J¼5.2 Hz, 2H), 7.39
(t, J¼7.6 Hz, 2H), 7.50 (t, J¼7.4 Hz, 1H), 7.86e7.89 (m, 2H), 8.87 (dd,
J¼4.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 198.25, 150.36, 149.60,
million (ppm,
d) downfield from tetramethylsilane. Proton coupling
136.53, 133.36, 128.73, 128.02, 123.91, 38.85, 29.18; IR (neat): 3062,
3018, 2924,1684,1600,1580,1494,1449,1415,1364,1292,1221,1069,
994, 813, 746; HRMS calcd for C14H13NO: 211.0997, found: 211.0991.
patterns are described as singlet (s), doublet (d), triplet (t), multi-
plet (m); TLC was performed using commercially prepared
100e400 mesh silica gel plates (GF254), and visualization was
effected at 254 nm; All the reagents were purchased from com-
mercial sources (J&KChemic, TCI, Fluka, Acros, SCRC), and used
without further purification.
4.2.6. 3-(Pyridin-4-yl)-1-p-tolylpropan-1-one (3f). Yield: 78%; col-
orless oil; 1H NMR (400 MHz, CDCl3):
d
2.34 (s, 3H), 3.00 (t, J¼7.4,
2H), 3.23 (t, J¼7.4 Hz, 2H), 7.11 (dd, J¼6.0 Hz, 2H), 7.19 (d, J¼8.0 Hz,
2H)7.78 (dd, J¼8.4 Hz, 2H), 8.43 (d, J¼5.2 Hz, 2H); 13C NMR
4.2. Typical procedure for the synthesis of 3a
(100 MHz, CDCl3): d 197.75, 149.65, 144.18, 134.2, 129.30, 127.98,
123.90, 38.64, 29.68, 21.34; IR (neat):3027, 2924, 2854, 1682, 1604,
1573, 1559, 1414, 1257, 1221, 1180, 975, 806; HRMS calcd for
t-BuOK (0.4 mmol, 44.8 mg), Xantphos (0.01 mmol, 5.8 mg) and
[RuCl2(p-cymene)]2 (0.005 mmol, 3.2 mg) were added in a Schlenk
tube, then 3-(Hydroxymethyl)pyridine 1a (1.2 mmol, 130 mg),
acetophenone 2a (1 mmol, 120 mg) were dissolved in tert-amyl
alcohol (1 mL), and the resulting liquid mixture was added to the
Schlenk tube under N2 atmosphere. The Schlenk tube was closed
and stirred at 120 ꢀC for 16 h. After cooling down to room
C15H15NO: 225.1154, found: 225.1152.
4.2.7. 1-(4-Methoxyphenyl)-3-(pyridin4-yl)propan-1-one
(3g). Yield: 80%; white solid; mp: 80e82 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
3.00 (t, J¼7.4 Hz, 2H), 3.21 (t, J¼7.4 Hz, 2H), 3.80 (s, 3H),
6.86 (dd, J¼9.2 Hz, 2H), 7.11 (d, J¼6.0 Hz, 2H), 7.87 (dd, J¼8.8 Hz,

F.-X. Yan et al. / Tetrahedron 70 (2014) 1193e1198
1197
2H), 8.43 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
196.82,
J¼8.4 Hz, 2H), 8.03 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
196.82,
163.67, 150.60, 149.88, 130.31, 129.68, 123.83, 113.84, 55.53, 38.48,
29.45; IR (neat): 3070, 3024, 2937, 2842, 1672, 1603, 1576, 1509,
1416, 1260, 1026, 841, 807, 777; HRMS calcd for C15H15NO2:
241.1103, found: 241.1102.
163.67, 150.41, 149.88, 130.31, 129.58, 123.96, 113.84, 55.26, 38.52,
29.04; IR (neat): 2997, 2958, 2925, 2855, 1680, 1608, 1558, 1474,
1410,1357, 1302,1260, 1231, 1215, 1180, 1097, 1057, 803; HRMS calcd
for C17H18ClNO2: 303.1026, found: 303.1026.
4.2.8. 1-Phenyl-3-(pyridin-2-yl)propan-1-one (3h). Yield: 72%; Yel-
4.2.15. 1,2-Diphenyl-3-(pyridin-2-yl)propan-1-one (3q). Yield: 70%;
low oil; 1H NMR (400 MHz, CDCl3):
d
2.91 (t, J¼7.2 Hz, 2H), 3.20 (t,
J¼7.2 Hz, 2H), 6.96e7.06 (m, 2H), 7.23e7.29 (m, 4H), 7.67e7.89 (m,
2H), 8.43e8.62 (m, 1H); 13C NMR (100 MHz, CDCl3):
198.2, 160.3,
Yellow oil; 1H NMR (400 MHz, CDCl3):
d
3.12 (dd, J¼6.0 Hz,1H), 3.65
(dd, J¼8.4 Hz, 1H), 5.26 (dd, J¼6.4 Hz, 1H), 6.90e6.94 (m, 2H),
7.04e7.08 (m, 1H), 7.12e7.16 (m, 2H), 7.19e7.25 (m, 4H), 7.29e7.37
(m, 2H), 7.84e7.87 (m, 2H), 8.36e8.38 (m, 1H); 13C NMR (100 MHz,
d
149.5, 136.6, 136.3, 128.6, 128.3, 122.8, 121.2, 37.3, 32.3; IR (neat):
3021, 2942, 2866, 1663, 1601, 1581, 1502, 1423, 1261, 1032, 797, 777,
726; HRMS calcd for C14H13NO: 211.0997, found: 211.0995.
CDCl3):
d 199.5, 159.5, 149.2, 139.3, 136.8, 136.1, 132.8, 129.0, 128.9,
128.5, 128.4, 127.2, 124.1, 121.3, 53.2, 42.3; IR (neat): 2983, 2832,
1723, 1603, 1523, 1412, 1343, 1221, 1176, 1065, 802, 763, 731, 707;
HRMS calcd for C20H17NO: 287.1310, found: 287.1313.
4.2.9. 1-(4-Methoxyphenyl)-3-(pyridin-2-yl)propan-1-one
(3i). Yield: 75%; Yellow oil; 1H NMR (300 MHz, CDCl3):
d 3.15
(t, J¼7.2 Hz, 2H), 3.38 (t, J¼7.2 Hz, 2H), 3.78 (s, 3H), 6.84 (dd, J¼3.9 Hz,
2H), 7.01e7.06 (m, 1H), 7.17e7.20 (m, 1H), 7.49e7.55 (m, 1H), 7.90
(dd, J¼2.8 Hz, 2H), 8.43e8.45 (m, 1H); 13C NMR (100 MHz, CDCl3):
4.2.16. 1,2-Bis(4-methoxyphenyl)-3-(pyridin-2-yl)propan-1-one
(3r). Yield: 72%; Yellow oil; 1H NMR (300 MHz, CDCl3):
d 3.09 (dd,
J¼6.6 Hz, 1H), 3.57 (dd, J¼5.7 Hz, 1H), 3.61 (s, 3H), 3.67 (s, 3H), 5.14
(dd, J¼7.2 Hz, 1H), 6.65e6.74 (m, 4H), 6.91e6.94 (m, 2H), 7.08e7.18
(m, 2H), 7.32e7.38 (m, 1H), 7.83e7.88 (m, 2H), 8.37e8.40 (m, 1H);
d
197.8, 163.4, 160.9, 149.1, 136.5, 130.4, 130.0, 123.4, 121.2, 113.7, 55.4,
37.5, 32.2; IR (neat): 2951, 1683, 1601, 1581, 1529, 1426, 1381, 1163,
1024, 855, 772; HRMS calcd for C15H15NO2: 241.1103, found: 241.1106.
13C NMR (75 MHz, CDCl3):
d 198.1, 163.2, 159.7, 158.6, 149.1, 136.2,
131.6, 131.1, 129.6, 129.3, 124.2, 121.2, 114.3, 113.6, 55.4, 55.1, 52.1,
42.3; IR (neat): 2961, 2872, 1703, 1621, 1532, 1442, 1381, 1376, 1221,
1165, 1132, 812, 783, 721, 717, 702; HRMS calcd for C22H21NO3:
347.1521, found: 347.1524.
4.2.10. 1-(4-Chlorophenyl)-3-(pyridin-2-yl)propan-1-one
(3j). Yield: 66%; Yellow oil; 1H NMR (300 MHz, CDCl3):
d 3.16 (t,
J¼5.1 Hz, 2H), 3.41 (t, J¼5.1 Hz, 2H), 7.01e7.05 (m, 1H), 7.12e7.19 (m,
1H), 7.33e7.35 (m, 2H), 7.49e7.54 (m, 1H), 7.84e7.87 (m, 2H),
8.42e8.44 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
198.2,160.5, 149.3,
4.2.17. 2,6-Bis(pyridin-2-ylmethyl)cyclohexanone (3s). Yield: 40%;
139.5, 136.5, 135.3, 129.6, 128.9, 123.4, 121.4, 37.7, 32.0; IR (neat):
2933, 1703, 1612, 1582, 1533, 1421, 1263, 1017, 853,,766, 723, 707;
HRMS calcd for C14H12ClNO: 245.0607, found: 245.0603.
Light yellow oil; 1H NMR (300 MHz, CDCl3):
d 1.63e2.02 (m, 6H),
2.51 (q, J¼7.2 Hz, 2H), 2.90e2.97 (m, 2H), 3.26 (dd, J¼6.3 Hz, 2H),
6.98e7.04 (m, 2H), 7.12e7.20 (m, 2H), 7.47e7.55 (m, 2H), 8.40e8.44
(m, 2H); 13C NMR (75 MHz, CDCl3):
d 212.6,160.4,149.1,136.3,124.2,
4.2.11. 1-(4-Fluorophenyl)-3-(pyridin-2-yl)propan-1-one
121.1, 50.8, 37.9, 28.2, 25.3; IR (neat): 2971, 2942, 2883, 1712, 1644,
1521, 1432, 1221, 1118, 842, 763, 713; HRMS calcd for C18H20N2O:
280.1576, found: 280.1573.
(3k). Yield: 52%; Yellow oil; 1H NMR (400 MHz, CDCl3):
d 3.15 (t,
J¼7.2 Hz, 2H), 3.40 (t, J¼7.2 Hz, 2H), 7.01e7.05 (m, 3H), 7.16e7.20
(m, 1H), 7.48e7.53 (m, 1H), 7.92e7.96 (m, 2H), 8.42e8.44 (m, 1H);
13C NMR (100 MHz, CDCl3):
d
197.8, 165.7 (JCeF¼244 Hz), 160.6,
4.2.18. 3-(Pyridin-2-ylmethyl)bicyclo[2.2.1]heptan-2-one
149.3, 136.4, 133.4, 130.8 (JCeF¼9 Hz), 123.4, 121.3, 115.6
(JCeF¼21.8 Hz), 37.7, 32.0; IR (neat): 2956, 1701, 1632, 1581, 1418,
1233, 1112, 852, 782, 732, 721; HRMS calcd for C14H12FNO:
229.0903, found: 229.0902.
(3t). Yield: 42%; Yellow oil; 1H NMR (300 MHz, CDCl3):
d 1.40e1.57
(m, 3H), 1.62e1.80 (m, 3H), 2.18e2.42 (m, 1H), 2.43e2.63 (m, 3H),
2.97e3.21 (m, 1H), 7.02e7.21 (m, 2H), 7.49e7.56 (m, 1H), 8.44e8.47
(m, 1H); 13C NMR (75 MHz, CDCl3):
d 219.0, 160.2, 149.4, 136.4,
123.2, 121.3, 54.0, 50.5, 38.6, 37.0, 34.7, 25.6, 21.4; IR (neat): 2961,
2922, 2878, 1732, 1612, 1509, 1432, 1221, 1106, 821, 733, 712; HRMS
calcd for C13H15NO: 201.1154, found: 201.1153.
4.2.12. 3-(4-Methoxy-3,5-dimethylpyridin-2-yl)-1-phenylpropan-1-
one (3l). Yield: 73%; white solid; mp: 66e68 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
2.14 (s, 3H), 2.20 (s, 3H), 3.10 (t, J¼7.4 Hz, 2H), 3.42 (t,
J¼7.4 Hz, 2H), 3.67 (s, 3H), 7.38 (t, J¼7.6 Hz, 2H), 7.47 (t, J¼7.4 Hz,
Acknowledgements
1H), 7.95 (d, J¼7.2 Hz, 2H), 8.06 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
199.91, 163.70, 158.56, 148.70, 137.12, 132.92, 128.53, 128.18,
The authors are grateful to the funds of the ‘National Natural
Science Foundation of China (21101080)’, ‘Natural Science Foun-
dation of Jiangsu Province (BK2011144)’, ‘Fundamental Research
Funds for the Central Universities of China (2014ZZ0047)’, and ‘333
Talent Project of Jiangsu Province’.
124.29, 123.98, 59.88, 36.57, 28.79, 13.06, 11.04; IR (neat): 2907,
1684,1595,1560,1450,1397,1253,1205,1093,1051, 762, 689; HRMS
calcd for C17H19NO2: 269.1416, found: 269.1416.
4.2.13. 3-(4-Methoxy-3,5-dimethylpyridin-2-yl)-1-p-tolylpropan-1-
one (3m). Yield: 77%; white solid; mp: 58e60 ꢀC; 1H NMR
Supplementary data
(400 MHz, CDCl3):
d 2.14 (s, 3H), 2.20 (s, 3H), 2.33 (s, 3H), 3.09 (t,
J¼7.4 Hz, 2H), 3.39 (t, J¼7.4 Hz, 2H), 3.67 (s, 3H), 7.18 (d, J¼8.0 Hz,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.12.065.
2H), 7.85 (d, J¼8.0 Hz, 2H), 8.06 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
199.58, 163.67, 158.73, 148.73, 143.65, 134.61, 129.21, 128.29,
124.28, 123.93, 59.87, 36.62, 28.98, 21.56, 13.20, 11.15; IR (neat):
2925, 1676, 1607, 1560, 1475, 1414, 1395, 1301, 1233, 1181, 1053, 997,
184; HRMS calcd for C18H21NO2: 283.1572, found: 283.1575.
References and notes
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