Regioselective Arene and Heteroarene Functionalization: N-Alkenoxypyridinium Salts as Electrophilic Alkylating Agents for the Synthesis of α-Aryl/α-Heteroaryl Ketones

Article abstract of DOI:10.1021/acs.joc.8b01388

A direct regioselective functionalization of arenes and heteroarenes using N-alkenoxypyridinium salts as electrophilic alkylating agents for the synthesis of α-aryl/heteroaryl ketones has been developed. The method generates alkylating agents from alkynes and N-pyridine oxide followed by site-selective electrophilic substitution with a broad range of arenes and heteroarenes including benzene derivates, phenols, ethers, indoles, pyrroles, furans, and thiophenes in one pot. Kinetic isotope effect measurements and DFT studies reveal that this reaction likely proceeds through a carbon-cation intermediate.

Full text of DOI:10.1021/acs.joc.8b01388

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Article
Regioselective Arene and Heteroarene Functionalization:
N-alkenoxypyridinium Salts as Electrophilic Alkylating
Agents for the Synthesis of #-Aryl/#-Heteroaryl Ketones
Rong Liang Zhai, Yun Sheng Xue, Ting Liang, Jia Jia Mi, and Zhou Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01388 • Publication Date (Web): 18 Jul 2018
Downloaded from http://pubs.acs.org on July 19, 2018
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Regioselective Arene and Heteroarene Functionalization: N-
alkenoxypyridinium Salts as Electrophilic Alkylating Agents for the Syn-
thesis of α-Aryl/α-Heteroaryl Ketones
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Rong L. Zhai, Yun S. Xue, Ting Liang, Jia J. Mi and Zhou Xu*
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University,
Tongshan Road 209, Xuzhou, 221004, People’s Republic of China
Supporting Information Placeholder
ABSTRACT: A direct regioselective functionalization of arenes and heteroarenes using N-alkenoxypyridinium salts as electro-
philic alkylating agents for the synthesis of α-aryl/heteroaryl ketones has been developed. The method generates alkylating agents
from alkynes and N-pyridine oxide followed by site-selective electrophilic substitution with a broad range of arenes and het-
eroarenes including benzene derivates, phenols, ethers, indoles, pyrroles, furans and thiophenes in one pot. KIE measurement and
DFT studies reveal that this reaction likely proceeds through a carbon-cation intermediate.
Introduction
ketones with excellent regioselectivity from commercial or
readily available starting materials.
α-Aryl/α-heteroaryl ketones are essential structures in a
large proportion of small molecule drugs and bioactive mole-
cules which have important applications on organic synthesis
and pharmaceutical chemistry.1 This has led to the develop-
ment of numerous elegant methods for the synthesis of α-aryl
ketones, including the transition-metal (Pd, Ni or Cu) cata-
lyzed coupling reaction of aryl halides or arenes with ketones,
diazo ketones or enol silyl ethers2-4, the reaction of carbonyl
compounds with diaryliodonium salts catalyzed by metal lithi-
um salts,5-6 and the α-arylation of ketones or ketone enolates7-9
(Scheme 1, a). However, there are still some shortcomings
which have limited the utility of these reactions in some cases.
1) The need for prefunctionalized aryl halide substrates and
transition metal catalysts, or reagents; 2) Limited functional-
group tolerance is demonstrated; 3) In most cases, the regiose-
lectivity is not good and in order to offer good selectivity, the
installing of directing group is needed; 4) The reactions are
sensitive to air and water. In addition, some sophisticated
starting materials or potentially explosive diazo β-ketones are
also prerequisites. Therefore, it is quite urgent to develop a
general and efficient method to synthesize α-aryl/heteroaryl
Functionalization of C–H bonds has become a dominant re-
search area in the past decade regarded as an approach to effi-
cient synthesis.10 Direct functionalization of aryl/heteroaryl C-
H bonds, such as the Friedel-Crafts reaction, is one of the most
powerful methods in terms of synthetic application due to the
high prevalence of arene and heteroarene in bioactive com-
pounds. Some progress concerning both Friedel-Crafts acyla-
tion reaction11 and alkylation reactions12 have been reported in
recent years.
Traditionally, Friedel-Crafts alkylation allows the synthesis
of alkylated products via the reaction of arene with alkyl hal-
ides or alkenes. However, since alkyl substituents activate the
arene substrate, polyalkylation always occurs, yielding poor
regioselectivity under the harsh reaction conditions. Thus, the
generation of electrophiles under mild condition is a promising
target. In previous studies on gold-catalyzed reactions of al-
kynes with pyridine-N-oxides,13 we found that N-
alkenoxypyridinium salts could behave as synthetic equiva-
lents of acylcarbenium ions.14 We hoped to expand the utility
of N-alkenoxypyridinium salts and anticipated that it might be
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Scheme 2. Scopes of arenes and heteroarenes.a
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served as an alkylating agent for intermolecular
arene/heteroarene functionalization.
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Scheme 1. Previous methods and our work.
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Results and Discussion
We started our investigation by exploring the reaction of al-
kyne 1a with N-pyridine oxide 2a in the presence of
PPh3AuNTf2 in benzene. After an extensive optimization with
various N-alkenoxypyridinium salts, solvents, temperatures
and et.al, we found that α-phenyl ketone (5a) could be ob-
tained in 63% overall yield (for details, see supporting infor-
mation). As expected, no diarylation or polyalkylation product
was detected by the NMR analysis of the crude reaction mix-
ture. Next we turned to examine the generality of the substrate
scope and the results are summarized in Scheme 2. To our
great delight, wide variety of arenes and heteroarenes are tol-
erated, delivering the α-aryl ketones in moderate to excellent
yields. Naphthalene gave the ortho- and para-isomers (5b) as
the major products with a 2.5/1.0 selectivity ratio (α/β), due to
electronic effects. Potentially reactive functionalities can be
incorporated, such as hydroxyl and amino substituents. The
active hydroxyl group did not need to be protected prior to this
step and was transformed smoothly to the para-product (5c) as
a single isomer, due to a combination of electronic and steric
influence. The same result was also observed with anisole (5d).
Like naphthalene, 1-methoxynaphthalene provided the ortho-
and para-isomers (5e) as the main products with a 2.3/1.0 se-
lectivity ratio. Disubstituted or trisubstituted aromatics are also
suitable substrates for the reaction and undergo functionaliza-
tion in moderate to good yields. For example, the selectivity of
4-chloroanisole or 1,3-dimethoxy benzene is governed by
electronic effects, affording the ortho para-isomers (5f-5g).
Substrates with sterically bulky groups did not retard the reac-
tion and gave good yields, such as 1,3,5-trisubstituted phenols
or 1,3,5-trimethoxyl benzene, which reacted smoothly, provid
ing the desired products in 58% and 65% yield, respectively
(5h-5i).
aReaction conditions: the reaction was conducted with alkyne 1a
(0.2 mmol), 2a (1.1 equiv), PPh3AuNTf2 (2.5 mol%), HFIP (0.3
ml), rt, 3h and then 3a-3i (0.8 ml) or 3j-3y (3.0 equiv.) was added
and reacted. The numbers in the brackets are the over-all isolated
yields. The reaction was carried out at 1.5 mmol scale and the
number in the bracket is the isolated yield.
b
yielding due to their tendency to undergo polymerization un-
der acidic reaction conditions as well as their tendency to un-
dergo multiple alkylations.15 The electrophilicity of the N-
alkenoxypyridinium salt intermediate could also be applied to
furans and pyrroles to provide the corresponding α-heteroaryl
ketones. These substrates underwent electrophilic substitution
exclusively at the C-2 position giving the products with 80-88%
yields at 60oC (5j, 5l-5m). If a substituent group was present
on the C-2 position, the reaction would then take place at the
C-3 position (5k).
Scheme 3. The formation of 5m and 5m’.
When the reaction temperature was increased to 100oC, pyr-
role gave the condensation product 5m’ as the major product
indicating that the reaction could be tuned by adjusting the
It is well-known that Friedel−Craft alkylation of the parent
five-membered heterocycles pyrrole and furan are low
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these acidic reaction conditions, the terminal chloride or bro-
temperature (Scheme 3). Less-activated heterocycles, such as
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thiophenes can be similarly functionalized at higher tempera-
ture (5n-5p). Indole gave the product in 90% yield, reacting
exclusively at the C-3 position (5q). N-Methyl indole gave a
similar result (5r). Gratifyingly, we found that a variety of N-
unsubstituted indoles were suitable substrates and could afford
the α-heteroaryl ketones with good to excellent yields as single
regio-isomers. Notably, various functional groups including
amino, phenyl, chlorine and bromine are compatible with this
transformation (5s-5x).
Considering benzene is one of the most important raw mate-
rials in industry, we subsequently turned to evaluate the scope
of the alkylation agents which were generated from alkynes
using benzene as a model substrate.
mide didn’t participate into the Friedel-Crafts alkylation,
demonstrating excellent chemio-selectivity.
Indole moieties are found in numerous natural alkaloids
and pharmaceutical substances.16 Therefore, we investigated
the scope of the reaction for a range of functionalized alkyla-
tion agents with indole. As shown in Scheme 5, some func-
tional substituents, such as chlorides, esters, sulfones and am-
ides in the indole are tolerated and afford α-heteroaryl ketones
exclusively at the C-3 position in 72-84% yields at 60oC (5at-
5ax).
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Scheme 5. Scope of alkylating agents with indoles.a
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Scheme 4. Scopes of alkynes.a
aThe reaction was conducted with alkyne 1 (0.3 mmol), 2a (1.1
equiv), PPh3AuNTf2 (2.5 mol%), HFIP (0.2 ml), rt, 3h and then
3o (3.0 equiv.) was added. The numbers in the brackets are the
over-all isolated yields.
We next sought to address the mechanism of the reaction.
NMR studies of crude products for the second step showed
that aside from the major product 5a and protonated pyridine,
there were some other unidentified products. Initially, the pyr-
idine was thought to undergo an electrophilic substitution re-
action. We hope to demonstrate this with experimental evi-
dence. In order to simplify the reaction process, 4a was isolat-
ed and used as the reactant for the second step. Then, we ran a
simple experiment to determine whether 4a was stable under
thermal conditions. To our surprise, 4a decomposed complete-
ly within 2h and 5a’ was obtained and isolated as the sole
product in 78% yield (Scheme 6, a). This observation, sug-
gests to some extent that N-O bond cleavage might occur prior
to the attack by the arene. After N-O bond cleavage, an elec-
trophilic carbocation species is likely produced. KIE studies
for the reaction of 4a and benzene/D6H6 were also performed.
KH/KD was measured to be 1.03, while the measured PH/PD
was 1.13 (Scheme 6, b), indicating the rate-determining step is
likely not the cleavage of the Ar-H bond and the reaction of 4a
and benzene should be an electrophilic aromatic substitution.
Based on the above evidence, two possible pathways for the
reaction are proposed in Scheme 6, c. To gain more insight
into the mechanism, DFT studies were carried out (Fig. 1). To
reduce the computational cost, the nonyl group in 4a was sub-
stituted by ethyl group. The results reveal that the calculated
barrier height in free energy of pathway a is quite high (43.4
kcal/mol), implying this pathway is kinetically unfavourable.
The N-O bond cleavage step in path b needs to overcome a
free energy barrier of 33.5 kcal/mol, whereas the barrier for
aThe reaction was conducted with alkyne 1 (0.2 mmol), 2a (1.1
equiv), PPh3AuNTf2 (2.5 mol%), HFIP (0.2 ml) or benzene (0.2
ml), rt, 3h and then benzene (0.6 ml) was added and reacted at
100oC. The numbers in the brackets are the over-all isolated yields.
b26% cyclized product was observed.
Pleasingly, as revealed in Scheme 4, we found a broad
range of alkynes possessing phenyl moieties bearing a variety
of functional groups such as ether and halides (5y-5ab and
5ak), phenol ethers (5ac-5af), sulfonyl (5ag), acetate (5ah-
5ai), amide (5aj) and hydroxyl groups (5al) are compatible
with the transformation and formed alkylating reagents which
then underwent a Friedel-Crafts-type intermolecular reaction
with benzene in one pot, affording the α-phenyl ketones in
moderate to excellent yields. For alkynes containing a benzene
ring, no cyclization product was observed except for 5am. For
other aliphatic alkynes, the expected products were also ob-
tained (5an-5aq). With 5-chloropent-1-yne or 4-bromo-1-
butyne as the substrate, the α-phenyl ketones were obtained in
81% and 61% isolated yield respectively (5ar-5as). Under
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the second step is only 14.8 kcal/mol, indicating that the first molecular regioselective arene and heteroarene C–H function-
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step is the rate-determining step in path b. It was noted that the
barrier of the first step is much lower than 43.4 kcal/mol for
pathway a. Therefore, from a kinetic point of view, pathway b
should be more facile than pathway a.
alization. Notably, the reaction proceeds in an intermolecular
fashion, without directing groups and the remarkable regiose-
lectivity provides a unique approach to a wide range of struc-
turally diverse α-aryl/α-heteroaryl ketones (up to 51 examples).
Furthermore, the mechanism of the reaction has been elucidat-
ed through isotopic labeling experiments and DFT studies
which reveal that the reaction likely proceeds through a car-
bon-cation intermediate.
Scheme 6. Mechanism studies.
Experimental Section
General Remarks. 1H NMR and 13C NMR spectra were
recorded on ECZ-400S (400 MHz) spectrometers using resi-
due solvent peaks as internal standards (CHCl3, 1H: 7.26 ppm;
13C:77.00 ppm). 19F NMR spectra were recorded on JMTC-
400/54/SS 400 MHz spectrometer calibrated by trifluoroacetic
acid peak (CF3COOH, 19F: -76.55 ppm). Signal positions were
recorded in ppm with the abbreviations s, d, t, q, and m denot-
ing singlet, doublet, triplet, quartet, and multiplet, respectively.
All coupling constants J were quoted in Hz. Data were report-
ed as follows: chemical shift, multiplicity, coupling constant,
and integration. All commercially available reagents were
used as received without further purification. Reactions were
monitored by thin layer chromatography (TLC) using Silicycle
precoated silica gel plates (visualization reagent:
KMnO4/H2SO4). Flash column chromatography was per-
formed over Silicycle silica gel (300-400 mesh). Infrared spec-
tra were recorded with a PerkinElmer Spectrum Two FT-IR
spectrometer and are reported in reciprocal centimeter (cm-1).
Mass spectra were recorded with MicroTof-II using electron
spray ionization (MeOH as solvent) or Waters GCT Premier
time-of-flight mass spectrometer with a field ionization (FI)
ion source.
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Computational details. All calculations were carried out
using the Gaussian 09 program package.17 The structures were
fully optimized by using the M06-2X18 functional coupled
with 6-31G(d,p) basis set. Frequency calculations were per-
formed at the same level of theory to confirm all the stationary
points as minima or transition states. Intrinsic reaction coordi-
nate (IRC) 19 analysis were performed to ensure connectivity
between the transition structures and the intermediates. For the
identified stationary points, we performed additional single-
point calculations using a more extended basis set 6-
311++G(d,p) with M06-2X functional to obtain more accurate
energies. The solvent effects (benzene) were considered by
using the SMD20 solvation model in both geometry optimiza-
tion and single-point calculations. The energies discussed in
the text are Gibbs free energies calculated at 373 K (experi-
mental temperature) unless otherwise stated. To reduce the
computational cost, the nonyl group in 4a was substituted by
ethyl group.
Experimental Procedures. General Procedure for the
Preparation of Product 5a-5ax. Pyridine N-oxide and Tf2NH
were premixed in a molar ratio of 1.2/1.1, then stored in a vial
and used directly for reaction. PPh3AuNTf2 (3.7 mg, 0.25
equiv.) was added into a mixture of undec-1-yne (31.4 mg, 0.2
mmol), premixed salt (82.7 mg, 1.1 equiv.), HFIP (0.2 ml) or
benzene in a vial at room temperature. The reaction mixture
was then stirred at room temperature and the progress of the
reaction was monitored by TLC (PE/EA = 10/1, visualization
reagent: KMnO4/H2SO4). After the reaction was completed
(typically 2.5h), the reaction mixture was added with benzene
(0.6 ml/0.8 ml)/pyrrole (40.2 mg, 3 equiv.). Then the reaction
vial was sealed and heated to 100 oC / 60 oC. The reaction was
Pathway a-TS1 (43.4)
Pathway b-TSN-O (33.5)
Pathway b-TS2 (14.8)
Fig. 1 DFT studies: the optimized structures and the corre-
sponding free energy barrier (in kcal/mol) of the transition
states involving in the two pathways.
Conclusion
In summary, we have developed an efficient, convenient,
and general approach to α-aryl/α-heteroaryl ketones via inter-
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The Journal of Organic Chemistry
monitored by TLC (DCM/MeOH = 50/1, visualization reagent:
31.5 (minor), 30.1, 29.7, 29.4, 29.3, 29.2(8), 29.2, 29.1(8),
29.1, 29.0, 23.8, 23.7, 22.6, 14.1; IR (cm-1): 2922, 2851, 1709,
1455, 806, 745; HRMS (ESI) m/z calcd. for C22H29O2 [M-H]-:
325.2167, found: 325.2164.
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KMnO4 /H2SO4). After the reaction was finished, the mixture
was concentrated and the residue was purified by flash chro-
matography on silica gel (eluent: hexanes/ethyl acetate 10/1)
to afford the desired product 5a-5ax.
1-(5-chloro-2-methoxyphenyl)undecan-2-one (5f). Colorless
oil (40 mg, 65%); 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J =
8.7, 2.7 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.77 (d, J = 8.7 Hz,
1H), 3.76 (s, 3H), 3.61 (s, 2H), 2.42 (t, J = 7.5 Hz, 2H), 1.56-
1-phenylundecan-2-one (5a)21 Colorless oil (236 mg, 63%);
1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 2H), 7.28-7.23
(m, 1H), 7.22-7.15 (m, 2H), 3.67 (s, 2H), 2.42 (t, J = 7.3 Hz,
2H), 1.56-1.47 (m, 2H), 1.35-1.11 (m, 12H), 0.86 (t, J = 6.9
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.7, 134.4, 129.4,
128.7, 126.9, 50.1, 42.0, 31.8, 29.4, 29.4, 29.2, 29.1, 23.7,
22.7, 14.1; IR (cm-1): 2917, 2849, 1708, 1601,1464, 702;
HRMS (ESI) m/z calcd. for C17H25O [M-H]-: 245.1905, found:
245.1906.
1.48 (m, 2H), 1.34-1.13 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 208.2, 156.0, 131.0, 128.0, 125.5,
125.3, 111.5, 55.6, 44.3, 42.2, 31.9, 29.4, 29.3(9), 29.3, 29.1,
23.8, 22.7, 14.1; IR (cm-1): 1922, 2851, 1713, 1492, 1464,
1249; HRMS (ESI) m/z calcd. for C18H26ClO2 [M-H]-:
309.1621, found: 309.1626.
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1-(naphthalen-2-yl)undecan-2-one (5b). Colorless oil (52
1-(2,4-dimethoxyphenyl)undecan-2-one (5g). Colorless oil
1
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mg, 78%); H NMR (400 MHz, CDCl3) δ 7.89-7.78 (m, 4H),
(42 mg, 69%); H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 5.9
7.51 (s, 0.41 H) (minor isomer, Ar-H), 7.50-7.36 (m, 6H), 4.10
(s, 2H) (major isomer), 3.83 (s, 0.83H) (minor isomer), 2.46 (t,
J = 7.5 Hz, 0.83H) (minor isomer), 2.40 (t, J = 7.3 Hz, 2H)
(major isomer), 1.69-1.43 (m, 4H), 1.35-1.06 (m, 21H), 0.86 (t,
J = 6.9 Hz, 5H); 13C NMR (100 MHz, CDCl3) δ 209.1 (major),
208.7 (minor), 133.9 (major), 133.5 (minor), 132.4 (minor),
132.2 (major), 131.9 (minor), 131.2 (major), 128.7 (major),
128.3 (minor), 128.2 (major), 128.0 (minor), 127.9 (major),
127.7 (minor), 127.6 (minor), 127.5 (minor), 126.4 (major),
126.2 (minor), 125.8 (major), 125.7 (minor), 125.5 (major),
123.9 (major), 50.3 (minor), 48.5 (major), 42.1 (minor), 41.5
(major), 31.8 (major), 31.5 (minor), 30.1 (minor), 29.7, 29.3,
29.2(9), 29.2, 29.1, 29.0, 23.7, 22.6, 14.1; IR (cm-1): 2915,
2848, 1712, 1471, 788; HRMS (ESI) m/z calcd. for
C22H30NaO2 [M+Na]+: 349.2143, found: 349.2148.
Hz, 1H), 6.47-6.35 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.57 (s,
2H), 2.38 (t, J = 7.5 Hz, 2H), 1.60-1.46 (m, 2H), 1.40-1.02 (m,
12H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
209.7, 160.1, 158.2, 131.4, 116.1, 104.1, 98.6, 55.4, 55.3, 44.0,
41.8, 37.7, 31.9, 29.4, 29.3, 29.2, 23.9, 22.7, 14.1; IR (cm-1):
2923, 2852, 1711, 1507, 1464, 1208; HRMS (ESI) m/z calcd.
for C19H29O3 [M-H]-: 305.2116, found: 305.2117.
1-(4-hydroxy-2,6-dimethoxyphenyl)undecan-2-one
(5h).
1
Colorless oil (34 mg, 58%); H NMR (400 MHz, CDCl3) δ
6.49 (s, 2H), 3.64 (s, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.15 (s, 6H),
1.68-1.48 (m, 2H), 1.46-0.98 (m, 12H), 0.86 (t, J = 6.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 209.7, 154.1, 138.3,
124.3, 115.0, 43.7, 42.0, 31.8, 29.4, 29.4, 29.2(3), 29.2, 23.4,
22.7, 20.5, 14.1; IR (cm-1): 2915, 2849, 1708, 1506, 1264;
HRMS (ESI) m/z calcd. for C19H29O2 [M-H]-: 289.2168, found:
289.2171.
1-(4-hydroxyphenyl)undecan-2-one (5c). Colorless oil (26
1
mg, 50%); H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.2 Hz,
1-(2,4,6-trimethoxyphenyl)undecan-2-one (5i). Colorless oil
1
2H), 6.77 (d, J = 8.7 Hz, 2H), 5.14 (s, 1H), 3.59 (s, 2H), 2.41
(t, J = 7.3 Hz, 2H), 1.59-1.45 (m, 2H), 1.27-1.14 (m, 12H),
0.86 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.6,
154.7, 130.6, 126.3, 115.6, 49.2, 41.9, 31.8, 29.4, 29.3, 29.2,
29.1, 23.8, 22.6, 14.1; IR (cm-1): 2954, 2848, 2921, 1706, 1517,
1455, 1362; HRMS (ESI) m/z calcd. for C17H26O2 [M-H]-:
261.1854, found: 261.1854.
(44 mg, 65%); H NMR (400 MHz, CDCl3) δ 6.13 (s, 2H),
3.80 (s, 3H), 3.76 (s, 6H), 3.60 (s, 2H), 2.35 (t, J = 7.3 Hz, 2H),
1.56-1.46 (m, 2H), 1.27-1.14 (m, 12H), 0.86 (t, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 210.3, 160.3, 158.8,
104.7, 90.5, 55.7, 55.3, 41.4, 37.4, 31.9, 29.5, 29.4, 29.3, 29.2,
23.9, 22.7, 14.1; IR (cm-1): 2921, 2851, 1712, 1595, 1500,
1455, 1149; HRMS (ESI) m/z calcd. for C20H31O4 [M-H]-:
335.2222, found: 335.2224.
1-(furan-2-yl)undecan-2-one (5j). Colorless oil (38 mg,
80%); 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 1.4 Hz, 1H),
6.33 (q, J = 1.7 Hz, 1H), 6.18 (dd, J = 3.2, 0.9 Hz, 1H), 3.68 (s,
2H), 2.43 (t, J = 7.5 Hz, 2H), 1.54 (t, J = 6.4 Hz, 2H), 1.40-
1.12 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 206.4, 148.4, 142.1, 110.6, 108.1, 42.5, 41.9, 31.8,
29.4, 29.3, 29.2, 29.1, 23.6, 22.7, 14.1; IR (cm-1): 2925, 2856,
1735, 1638, 1491, 1132; HRMS (ESI) m/z calcd. For C15H23O2
[M-H]-: 235.1697; found: 235.1697.
1-(4-methoxyphenyl)undecan-2-one (5d). Colorless oil (44
1
mg, 80%); H NMR (400 MHz, CDCl3) δ 7.30-7.19 (m, 1H),
7.16-7.05 (m, 1H), 6.91 (td, J = 7.3, 0.9 Hz, 1H), 6.88-6.81 (m,
1H), 3.79 (s, 3H), 3.65 (s, 2H), 2.40 (t, J = 7.5 Hz, 2H), 1.54 (t,
J = 7.3 Hz, 2H), 1.31-1.15 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 209.4, 131.2, 128.4, 120.6,
110.4, 55.3, 44.7, 41.9, 31.9, 29.5, 29.4, 29.3, 29.2, 23.8, 22.7,
14.1;
IR
(cm-1):
2920,
1709,
1247,
1066;
HRMS (ESI) m/z calcd. for C18H27O2 [M-H]-: 275.2011, found:
275.2010.
1-(5-methoxynaphthalen-2-yl)undecan-2-one (5e). Colorless
1-(2,5-dimethylfuran-3-yl)undecan-2-one (5k). Colorless oil
1
1
oil (57 mg, 88%); H NMR (400 MHz, CDCl3) δ 7.80 (t, J =
(39 mg, 73%); H-NMR (400 MHz, CDCl3) δ 5.80 (s, 1H),
8.0 Hz, 3H), 7.75-7.72 (m, 0.7H) (minor isomer), 7.53-7.30 (m,
3.84H), 7.17-7.07 (m, 1H), 4.14 (s, 2H) (major), 4.04 (s,
0.82H) (minor), 3.96 (s, 3H) (major), 3.91 (s, 1.21H) (minor),
2.37 (q, J = 6.9 Hz, 2.81H), 1.54-1.48 (m, 2.7H), 1.29-1.16 (m,
19H), 0.94-0.77 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
209.9 (major), 209.6 (minor), 158.2 (minor), 154.8 (major),
133.4 (major), 130.2 (major), 129.9 (minor), 129.3 (minor),
129.1 (major), 129.0 (major), 128.8 (major), 128.5 (major),
127.7, 126.9 (major), 123.5 (major), 123.3 (minor), 123.0,
118.5, 116.4, 113.0, 102.5, 56.4 (major), 55.3 (minor), 49.3
(minor), 41.3 (major), 41.1 (minor), 40.3 (major), 31.8 (major),
3.55 (s, 2H), 2.52 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.91 (s, 3H),
1.65-1.49 (m, 2H), 1.41-1.15 (m, 12H), 0.87 (t, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 205.3, 155.4, 141.7,
117.6, 108.4, 41.8, 32.0, 29.6, 29.5, 29.4, 29.3, 29.0, 28.2,
28.0, 22.8, 14.2, 10.0; IR (cm-1): 2923, 2853, 1713, 1505, 1405,
798; HRMS (ESI) m/z calcd. For C17H27O2 [M-H]-: 263.2010;
found: 263.2005.
1-(1-methyl-1H-pyrrol-2-yl)undecan-2-one (5l). Colorless
1
oil (43 mg, 85%); H-NMR (400 MHz, CDCl3) δ 6.59 (t, J =
2.3 Hz, 1H), 6.08 (t, J = 3.2 Hz, 1H), 6.00 (q, J = 1.7 Hz, 1H),
3.64 (s, 2H), 3.50 (s, 3H), 2.43 (t, J = 7.5 Hz, 2H), 1.53 (t, J =
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The Journal of Organic Chemistry
Page 6 of 10
7.1 Hz, 2H), 1.40-1.10 (m, 12H), 0.87 (t, J = 6.9 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 208.2, 125.5, 122.6, 108.7, 107.1,
41.5, 41.4, 33.9, 31.9, 29.4, 29.3(6), 29.2, 29.1, 23.7, 22.7,
14.1; IR (cm-1): 2923, 2853, 1712, 1455, 705; HRMS (ESI)
m/z calcd. For C16H26NO [M-H]-: 248.2014; found: 248.2013.
1-(1H-pyrrol-2-yl)undecan-2-one (5m). Colorless oil (41
39.7, 32.7, 31.8, 29.4, 29.3(7), 29.2, 29.1, 23.8, 23.7, 22.6,
14.0; IR (cm-1): 2922, 2853, 1708, 1614, 1550, 1455, 740;
1
2
3
4
5
6
7
8
HRMS (ESI) m/z calcd. for C20H29NONa [M+Na]+: 322.2141;
found: 322.2150.
1-(2-methyl-1H-indol-3-yl)undecan-2-one (5s). Colorless oil
1
(55 mg, 91%);. H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H),
1
mg, 88%); H-NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 6.78-
7.54-7.39 (m, 1H), 7.28 (dd, J = 6.7, 1.5 Hz, 1H), 7.19-7.01
6.60 (m, 1H), 6.13 (dd, J = 5.9, 2.7 Hz, 1H), 6.03-5.85 (m, 1H),
3.71 (s, 2H), 2.48 (t, J = 7.3 Hz, 2H), 1.72-1.41 (m, 2H), 1.36-
1.15 (m, 12H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 209.0, 124.0, 117.7, 108.2, 107.2, 42.5, 41.0, 31.8,
29.4, 29.3(5), 29.2, 29.1, 23.7, 22.7, 14.1; IR (cm-1): 3338,
2919, 2851, 1704, 718; HRMS (ESI) m/z calcd. For C15H24NO
[M-H]-: 234.1857; found: 234.1854.
(m, 2H), 3.71 (s, 2H), 2.47-2.40 (m, 3H), 2.39 (s, 3H), 1.56-
1.45 (m, 2H), 1.42-1.03 (m, 12H), 0.87 (t, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 209.5, 135.2, 132.5, 128.5, 121.3,
119.6, 117.8, 110.2, 104.9, 41.1, 39.2, 31.8, 29.4, 29.3, 29.2,
29.1, 23.8, 22.6, 14.0, 11.7; IR (cm-1): 3384, 2922, 2853, 1701,
1433, 737; HRMS (ESI) m/z calcd. For C20H28NO [M-H]-:
298.2170; found: 298.2178.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(thiophen-3-yl)undecan-2-one (5n). Colorless oil (36 mg,
1-(2-phenyl-1H-indol-3-yl)undecan-2-one (5t). Colorless oil
1
1
71%); H NMR (400 MHz, CDCl3) δ 7.28 (q, J = 2.6 Hz,
(56 mg, 78%); H-NMR (400 MHz, CDCl3) δ 8.17 (s, 1H),
0.48H) (minor), 7.20 (dd, J = 5.0, 1.4 Hz, 1H) (major), 7.08 (d,
J = 1.8 Hz, 0.47H) (minor), 7.00-6.92 (m, 1H) (major), 6.90-
6.84 (m, 1H) (major), 3.87 (s, 2H) (major), 3.70 (s, 1H), 2.48
(t, J = 7.5 Hz, 2H) (major), 2.43 (t, J = 7.3 Hz, 1H) (minor),
1.69-1.46 (m, 3H), 1.25 (d, J = 16.5 Hz, 20H), 0.86 (t, J = 6.9
Hz, 5H); 13C NMR (100 MHz, CDCl3) δ 208.1 (minor), 207.0
(major), 135.4 (major), 134.0(minor), 128.5 (major), 126.9
(minor), 126.6 (major), 125.8 (minor), 124.9 (major), 122.7
(minor), 44.3, 43.5 (minor), 41.9, 41.7, 31.8, 29.3, 29.3, 29.2,
29.0, 23.7, 22.6, 14.1; IR (cm-1): 2917, 2850, 1709, 1464, 1407,
1247, 799; HRMS (ESI) m/z calcd. for C15H23OS [M-H]-:
251.1469, found: 251.1475.
7.58-7.43 (m, 5H), 7.42-7.33 (m, 2H), 7.24-7.18 (m, 1H), 7.15
(t, J = 7.5 Hz, 1H), 3.90 (s, 2H), 2.42 (t, J = 7.3 Hz, 2H), 1.62-
1.44 (m, 2H), 1.43-0.97 (m, 12H), 0.86 (t, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 209.8, 136.0, 135.8, 132.5, 129.0,
129.0, 128.1, 128.0, 122.6, 120,1, 118.9, 110.9, 106.1, 41.6,
39.7, 31.8, 29.4, 29.3(5), 29.2, 29.1, 23.8, 22.6, 14.1; IR (cm-1):
3366, 2923, 2853, 1698, 1457, 738, 697; HRMS (ESI) m/z
calcd. For C25H30NO [M-H]-: 360.2327; found: 360.2327.
1-(3-methyl-1H-indol-2-yl)undecan-2-one (5u). Colorless
oil (38 mg, 64%); 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H),
7.51 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.22-7.02
(m, 2H), 3.81 (s, 2H), 2.50 (t, J = 7.3 Hz, 2H), 2.27 (s, 3H),
1.56 (t, J = 7.1 Hz, 2H), 1.35-1.15 (m, 12H), 0.87 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.4, 135.6, 128.6,
127.0, 121.6, 119.1, 118.3, 110.6, 108.6, 42.6, 39.7, 31.8, 29.4,
29.3(7), 29.2, 29.0, 23.5, 22.6, 14.0, 8.5; IR (cm-1): 3351, 2922,
2853, 1703, 14511, 741; HRMS (ESI) m/z calcd. for
C20H29NONa [M+Na]+: 322.2141; found: 322.2140.
1-(7-methyl-1H-indol-3-yl)undecan-2-one (5v). Colorless
oil (49 mg, 81%); 1H-NMR (400 MHz, CDCl3) δ 8.01 (s, 1H),
7.39 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.06 (t, J =
7.5 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 3.79 (s, 2H), 2.51-2.42
(m, 5H), 1.62-1.46 (m, 2H), 1.38-1.06 (m, 12H), 0.86 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.5, 135.7,
126.8, 122.8, 122.7, 120.3, 119.9, 116.4, 109.4, 41.4, 40.0,
31.8, 29.3, 29.2, 29.1, 23.8, 22.6, 16.5, 14.0; IR (cm-1): 3397,
2915, 2850, 1701, 1433, 785; HRMS (ESI) m/z calcd. For
C20H28NO [M-H]-: 298.2170; found: 298.2173.
1-(5-chloro-1H-indol-3-yl)undecan-2-one (5w). Colorless
oil (51 mg, 80%); 1H-NMR (400 MHz, CDCl3) δ 8.13 (s, 1H),
7.49 (d, J = 1.8 Hz, 1H), 7.25 (s, 1H), 7.14 (dd, J = 8.7, 1.8 Hz,
2H), 3.76 (s, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.60-1.50 (m, 2H),
1.35-1.13 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 208.8, 134.4, 128.4, 125.5, 124.4, 122.6,
118.2, 112.2, 108.7, 41.7, 39.4, 31.8, 29.4, 29.3(6), 29.2, 29.1,
23.8, 22.6, 14.09; IR (cm-1): 3344, 2916, 2850, 1704, 1455,
799; HRMS (ESI) m/z calcd. For C19H25ClNO [M-H]-:
318.1624; found: 318.1626.
1-(4-bromo-1H-indol-3-yl)undecan-2-one (5x). Colorless
oil (55 mg, 75%); 1H-NMR (400 MHz, CDCl3) δ 8.30 (s, 1H),
7.24-7.18 (m, 2H), 7.02 (d, J = 2.7 Hz, 1H), 6.97 (t, J = 8.0 Hz,
1H), 4.08 (s, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.74-1.49 (m, 2H),
1.49-1.04 (m, 12H), 0.87 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 209.8, 137.5, 125.3, 124.0, 122.9, 114.0,
110.7, 109.7, 42.2, 40.3, 31.8, 29.4, 29.2, 23.7, 22.6, 14.1; IR
(cm-1): 3334, 2952, 2919, 2849, 1706, 1054, 729; HRMS (ESI)
1-(3,4-dimethoxythiophen-2-yl)undecan-2-one (5o). Color-
1
less oil (48 mg, 77%); H-NMR (400 MHz, CDCl3) δ 6.05 (s,
1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.70 (s, 2H), 2.46 (t, J = 7.3 Hz,
2H), 1.63-1.54 (m, 2H), 1.34-1.16 (m, 12H), 0.86 (t, J = 5.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 207.1, 150.4, 144.5,
118.0, 94.2, 60.6, 57.1, 41.7, 40.3, 31.8, 29.4, 29.3, 29.2, 29.1,
23.7, 22.6, 14.1; IR (cm-1): 2924, 2853, 1713, 1495, 1400,
1044; HRMS (ESI) m/z calcd. for C17H28O3SNa [M+Na]+:
335.1651; found: 335.1660.
1-(2,5-dimethylthiophen-3-yl)undecan-2-one (5p). Colorless
oil (47 mg, 83%); 1H-NMR (400 MHz, CDCl3) δ 5.80 (s, 1H),
3.55 (s, 2H), 2.52 (t, J = 7.5 Hz, 2H), 2.10 (s, 3H), 1.91 (s, 3H),
1.65-1.49 (m, 2H), 1.41-1.15 (m, 12H), 0.87 (t, J = 6.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 205.3, 155.4, 141.7,
117.5, 108.3, 41.7, 31.9, 29.5, 29.4, 29.3, 29.2, 28.9, 28.1,
28.0, 22.7, 14.1, 9.9; IR (cm-1): 2923, 2853, 1713, 1505, 1405,
798; HRMS (ESI) m/z calcd. For C17H27O2 [M-H]-: 263.2010;
found: 263.2005.
1-(1H-indol-3-yl)undecan-2-one (5q). Colorless oil (51 mg,
90%); 1H-NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.55 (d, J =
7.8 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.21 (td, J = 7.5, 1.2 Hz,
1H), 7.17-7.10 (m, 2H), 3.81 (s, 2H), 2.47 (t, J = 7.5 Hz, 2H),
1.55 (t, J = 6.6 Hz, 2H), 1.46-1.03 (m, 12H), 0.87 (t, J = 6.9
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.4, 136.1, 127.3,
123.0, 122.2, 119.7, 118.7, 111.1, 108.9, 41.5, 39.8, 31.8, 29.4,
29.3 (6), 29.2, 29.1, 23.8, 22.6, 14.0; IR (cm-1): 3383, 2923,
2853, 1703, 1457, 736; HRMS (ESI) m/z calcd. For C19H26NO
[M-H]-: 284.2014; found: 284.2020.
1-(1-methyl-1H-indol-3-yl)undecan-2-one (5r). Colorless oil
(54 mg, 90%); 1H-NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.8
Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H),
7.12 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H), 3.78 (s, 2H), 3.76 (s, 3H),
2.46 (t, J = 7.3 Hz, 2H), 1.54 (t, J = 7.1 Hz, 2H), 1.37-1.10 (m,
12H), 0.86 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
209.5, 136.9, 127.7, 121.7, 119.1, 118.8, 109.2, 107.2, 41.4,
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The Journal of Organic Chemistry
m/z calcd. For C19H25BrNO [M-H]-: 362.1119; found:
362.1110.
7-phenoxy-1-phenylheptan-2-one (5af). Colorless oil (38
mg, 67%); H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz,
1
1
1-(benzyloxy)-3-phenylpropan-2-one (5y). Colorless oil (30
2H), 7.29-7.22 (m, 3H), 7.19 (d, J = 7.3 Hz, 2H), 6.92 (t, J =
7.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 3.90 (t, J = 6.4 Hz, 2H),
3.67 (s, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.81-1.68 (m, 2H), 1.67-
1.57 (m, 2H), 1.48-1.34 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 208.3, 158.9, 134.2, 129.4, 129.3(7), 128.7, 126.9, 120.5,
114.4, 67.4, 50.2, 41.7, 29.0, 25.5, 23.3; IR (cm-1): 2930, 1708,
1602, 1473, 1478, 748, 692; HRMS (ESI) m/z calcd. for
C19H21O2 [M-H]-: 281.1541, found: 281.1550.
2
3
4
5
6
7
8
9
1
mg, 63%); H NMR (400 MHz CDCl3) δ 7.44-7.25 (m, 8H),
7.23-7.13 (m, 2H), 4.55 (s, 2H), 4.11 (s, 2H), 3.77 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 206.0, 137.0, 133.3, 129.4, 128.7,
128.5, 128.0, 127.9, 127.0, 74.3, 73.3, 46.2; IR (cm-1): 2917,
1724, 1495, 1453, 1094, 695; HRMS (ESI) m/z calcd. for
C16H15O2 [M-H]-: 239.1067, found: 239.1062.
1-((2-chloro-5-fluorobenzyl)oxy)-3-phenylpropan-2-one
1
(5z). Colorless oil (37 mg, 63%); H NMR (400 MHz CDCl3)
1-phenyl-4-(phenylsulfonyl)butan-2-one (5ag). Colorless oil
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 7.39-7.25 (m, 4H), 7.24-7.13 (m, 3H), 6.94 (td, J = 8.3, 3.0
Hz, 1H), 4.60 (s, 2H), 4.22 (s, 2H), 3.80 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 205.3, 162.7, 160.3, 137.3 (d, J = 6.7 Hz),
133.1, 130.4 (d, J = 7.6 Hz), 129.4, 128.8, 127.2, 115.8 (d, J =
6.7 Hz), 115.6 (d, J = 8.6 Hz), 75.1, 69.9, 46.3; 19F NMR: δ-
114.70; IR (cm-1): 2921, 1725, 1472, 1154, 699; HRMS (ESI)
m/z calcd. for C16H14ClFO2Na [M+Na]+: 315.0558, found:
315.0548.
(37 mg, 64%); H NMR (400 MHz, CDCl3) δ 7.88-7.80 (m,
2H), 7.68-7.62 (m, 1H), 7.58-7.50 (m, 2H), 7.38-7.26 (m, 3H),
7.18-7.09 (m, 2H), 3.70 (s, 2H), 3.34 (t, J = 7.5 Hz, 2H), 2.94
(t, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 203.6,
138.9, 133.9, 133.1, 129.3, 128.9, 127.9, 127.4, 50.5, 50.0,
34.2; IR (cm-1): 2917, 1718, 1305, 699; HRMS (ESI) m/z
calcd. for C16H16O3SNa [M+Na]+: 311.0712, found: 311.0701.
2-oxo-3-phenylpropyl acetate (5ah). Colorless oil (25 mg,
66%); 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 3H), 7.24-
7.17 (m, 2H), 4.69 (s, 2H), 3.74 (s, 2H), 2.15 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.2, 170.1, 132.7, 129.3, 128.8,
127.4, 67.4, 46.4, 20.4; IR (cm-1): 2932, 1716, 1498, 699;
HRMS (ESI) m/z calcd. for C11H12O3Na [M+Na]+: 215.0678,
found: 215.0679.
diethyl 2-(2-oxo-3-phenylpropyl)malonate (5ai). Colorless
oil (47 mg, 80%); 1H-NMR (400 MHz, CDCl3) δ 7.36-7.29 (m,
2H), 7.29-7.25 (m, 1H), 7.23-7.16 (m, 2H), 4.16 (qd, J = 7.1,
3.0 Hz, 4H), 3.83 (t, J = 7.1 Hz, 1H), 3.74 (s, 2H), 3.04 (d, J =
7.3 Hz, 2H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 204.8, 168.7, 133.5, 129.4, 128.7, 127.1, 61.7, 49.8,
47.0, 40.5, 13.9; IR (cm-1): 2957, 1722, 1333, 1177, 700;
HRMS (ESI) m/z calcd. for C16H20O5 [M-H]-: 291.1227, found:
291.1224.
1-(1-(4-(methylsulfonyl)phenyl)ethoxy)-3-phenylpropan-2-
1
one (5aa). Colorless oil (43 mg, 65%); H NMR (400 MHz,
CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H),
7.36-7.26 (m, 3H), 7.22-7.11 (m, 2H), 4.50 (q, J = 6.4 Hz, 1H),
3.98 (d, J = 5.6 Hz, 2H), 3.74 (s, 2H), 3.04 (s, 3H), 1.48 (d, J =
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.4, 149.0,
139.8, 133.1, 129.3, 128.7, 127.8, 127.2, 127.0, 77.8, 46.4,
44.4, 23.7; IR (cm-1): 2985, 1725, 1305, 1047, 699; HRMS
(ESI) m/z calcd. for C18H20O4SNa [M+Na]+: 355.0980; found:
355.0975.
1-(2,4-dichlorophenethoxy)-3-phenylpropan-2-one (5ab).
1
Colorless oil (52 mg, 80%); H NMR (400 MHz, CDCl3) δ
7.36 (d, J = 2.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.22 (d, J = 8.7
Hz, 2H), 7.19-7.10 (m, 3H), 4.07 (s, 2H), 3.71 (s, 2H), 3.66 (t,
J = 6.9 Hz, 2H), 3.01 (t, J = 6.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 206.0, 134.6, 133.3, 132.8, 132.0, 129.4, 129.2,
128.7, 127.1, 127.0, 75.0, 70.2, 46.1, 33.3; IR (cm-1): 2933,
1722, 1242, 1104, 699; HRMS (ESI) m/z calcd. For
C17H15Cl2O2 [M-H]-: 321.0448; found: 321.0445.
4-phenoxy-1-phenylbutan-2-one (5ac). Colorless oil (25 mg,
53%); 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.30-
7.25 (m, 3H), 7.24-7.18 (m, 2H), 6.98-6.90 (m, 1H), 6.89-6.80
(m, 2H), 4.20 (t, J = 6.4 Hz, 2H), 3.77 (s, 2H), 2.91 (t, J = 6.4
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 206.0, 158.4, 133.7,
129.5, 129.4, 128.8, 127.1, 120.9, 114.4, 62.8, 50.7, 41.2; IR
(cm-1): 2927, 1702, 1498, 1392, 1245, 1038, 744, 691;
HRMS (ESI) m/z calcd. for C16H15O2 [M-H]-: 239.1071, found:
239.1077.
2-(4-oxo-5-phenylpentyl)isoindoline-1,3-dione (5aj). Color-
1
less oil (44 mg, 71%); H NMR (400 MHz, CDCl3) δ 7.83 (q,
J = 2.9 Hz, 2H), 7.71 (q, J = 2.9 Hz, 2H), 7.34-7.27 (m, 2H),
7.26-7.20 (m, 1H), 7.20-7.15 (m, 2H), 3.67 (m, 4H), 2.52 (t, J
= 7.1 Hz, 2H), 2.02-1.80 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 207.0, 168.4, 134.1, 133.9, 132.0, 129.4, 128.6, 126.9, 123.2,
50.0, 38.9, 37.1, 22.6; IR (cm-1): 2923, 1770, 1703, 1437, 1394,
699; HRMS (ESI) m/z calcd. for C19H16NO3 [M-H]-: 306.1129,
found: 306.1130.
1-(pentyloxy)-3-phenylpropan-2-one (5ak). Colorless oil
1
(28 mg, 64%); H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m,
2H), 7.28-7.25 (m, 1H), 7.24-7.18 (m, 2H), 4.06 (s, 2H), 3.77
(s, 2H), 3.43 (t, J = 6.6 Hz, 2H), 1.68-1.56 (m, 2H), 1.40-1.26
(m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 206.6, 133.5, 129.4, 128.6, 127.0, 75.4, 71.9, 46.1, 29.2, 28.1,
22.4, 14.0; IR (cm-1): 2955, 2931, 1723, 1454, 1100, 730, 698;
HRMS (ESI) m/z calcd. for C14H20O2 [M-H]-: 219.1379, found:
219.1374.
1-((2,4-dichlorobenzyl)oxy)-3-phenylpropan-2-one (5ad).
1
Colorless oil (33 mg, 53%); H NMR (400 MHz, CDCl3) δ
7.43-7.37 (m, 2H), 7.37-7.27 (m, 3H), 7.26-7.19 (m, 3H), 4.61
(s, 2H), 4.21 (s, 2H), 3.80 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 205.4, 134.1, 133.7, 133.6, 133.5, 133.1, 129.9, 129.4, 129.1,
128.7, 127.2, 74.8, 69.7, 46.3; IR (cm-1): 2922, 1728, 1474,
1057, 1043, 816; HRMS (ESI) m/z calcd. for C16H14Cl2O2Na
[M+Na]+: 331.0263; found: 331.0259.
11-hydroxy-1-phenylundecan-2-one (5al). Colorless oil (26
1
mg, 50%); H NMR (400 MHz, CDCl3) δ 7.36-7.28 (m, 2H),
7.28-7.22 (m, 1H), 7.22-7.15 (m, 2H), 3.66 (s, 2H), 3.62 (t, J =
6.6 Hz, 2H), 2.42 (t, J = 7.3 Hz, 2H), 1.65-1.45 (m, 2H), 1.35-
1.15 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 208.6, 134.3,
129.3, 128.6, 126.9, 63.0, 50.1, 41.9, 32.7, 29.3, 29.2(9), 29.2,
29.0, 25.6, 23.7; IR (cm-1): 3357, 2923, 2848, 1705, 1074, 699;
HRMS (ESI) m/z calcd. for C17H25O2 [M-H]-: 261.1854, found:
261.1848.
1-hydroxy-3-phenylpropan-2-one
(5ae).
1
Colorless oil (22 mg, 72%); H NMR (400 MHz, CDCl3) δ
7.42-7.27 (m, 3H), 7.25-7.18 (m, 2H), 4.30 (s, 2H), 3.73 (s,
2H), 3.02 (t, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
207.2, 132.6, 129.2, 128.9, 127.4, 67.6, 45.7; IR (cm-1): 3421,
1718, 1403, 1047, 699; HRMS (ESI) m/z calcd. for
C9H10O2Na [M+Na]+: 173.0573; found: 173.0571.
1,5-diphenylpentan-2-one (5am). Colorless oil (19 mg,
40%); 1H NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 2H), 7.29-
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7.22 (m, 3H), 7.21-7.16 (m, 3H), 7.12-7.05 (m, 2H), 3.65 (s, diethyl 2-(3-(1H-indol-3-yl)-2-oxopropyl)malonate (5au).
1
2
3
4
5
6
7
8
2H), 2.56 (t, J = 7.5 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 1.94-
1.73 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 208.0, 141.5,
134.2, 129.3, 128.6, 128.4, 128.3, 126.9, 125.8, 50.1, 41.0,
34.9, 25.1; IR (cm-1): 2928, 1710, 1495, 1463, 697;
HRMS (ESI) m/z calcd. for C17H17O [M-H]-: 237.1279, found:
237.1283.
Colorless oil (52 mg, 78%); 1H-NMR (400 MHz, CDCl3) δ
8.10 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H),
7.20 (td, J = 7.5, 1.2 Hz, 1H), 7.17-7.09 (m, 2H), 4.14 (qd, J =
7.2, 1.7 Hz, 4H), 3.87 (s, 2H), 3.83 (t, J = 3.7 Hz, 1H), 3.08 (d,
J = 7.3 Hz, 2H), 1.22 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 205.6, 168.9, 136.1, 127.2, 123.2, 122.3, 119.9,
118.6, 111.2, 108.2, 61.6, 47.0, 40.0, 39.7, 13.9; IR (cm-1):
3398, 2933, 1717, 1178, 744; HRMS (ESI) m/z calcd. For
C18H20NO5 [M-H]-: 330.1341; found: 330.1339.
1-phenylhexan-2-one (5an). Colorless oil (23 mg, 65%); 1H-
NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 2H), 7.29-7.23 (m,
1H), 7.23-7.16 (m, 2H), 3.68 (s, 2H), 2.44 (t, J = 7.5 Hz, 2H),
1.59-1.48 (m, 2H), 1.31-1.21 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 208.6, 134.3, 129.3, 128.6,
126.9, 50.1, 41.7, 25.8, 22.2, 13.8; IR (cm-1): 2957, 2931, 1710,
1495, 1465, 697; HRMS (ESI) m/z calcd. for C12H16ONa
[M+Na]+: 199.1093, found:199.1084.
9
4-(1H-indol-3-yl)-1-tosylbutan-2-one (5av). Colorless oil
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(49 mg, 72%); H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H),
7.67 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.37 (d, J =
8.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.8 Hz, 1H),
7.14-7.08 (m, 2H), 3.82 (s, 2H), 3.30 (t, J = 7.5 Hz, 2H), 2.95
(t, J = 7.5 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 204.5, 144.8, 136.1, 135.9, 129.9, 127.9, 127.0, 123.3, 122.5,
120.0, 118.5, 111.3, 107.7, 50.7, 40.0, 33.7, 21.6; IR (cm-1):
3387, 2923, 1712, 1285,720; HRMS (ESI) m/z calcd. For
C19H18NO3S [M-H]- : 340.1007; found: 340.1006.
1-(1H-indol-3-yl)-5-phenylpentan-2-one (5aw). Colorless
oil (44 mg, 80%); 1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H),
7.52 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.24-7.18
(m, 3H), 7.18-7.12 (m, 2H), 7.12-7.09 (m, 1H), 7.07 (d, J =
7.3 Hz, 2H), 3.78 (s, 2H), 2.57-2.47 (m, 4H), 1.92-1.83 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 208.8, 141.6, 136.1,
128.4, 128.2, 127.3, 125.8, 123.0, 122.3, 119.8, 118.7, 111.1,
108.8, 40.5, 39.9, 34.9, 25.2; IR (cm-1): 3289, 2927, 743, 699 ;
HRMS (ESI) m/z calcd. For C19H18NO [M-H]-: 276.1388;
found: 276.1386.
4-cyclohexyl-1-phenylbutan-2-one (5ao). Colorless oil (36
1
mg, 79%); H-NMR (400 MHz, CDCl3) δ 7.39-7.29 (m, 2H),
7.29-7.23 (m, 1H), 7.22-7.17 (m, 2H), 3.66 (s, 2H), 2.32 (d, J
= 6.9 Hz, 2H), 1.92-1.76 (m, 1H), 1.69-1.54 (m, 6H), 1.31-
1.18 (m, 4H), 0.93-0.80 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 208.1, 134.29, 129.4, 128.6, 126.9, 50.7, 49.6, 33.7, 33.1,
29.6, 26.1, 26.0; IR (cm-1): 2957, 2917, 1735, 1193, 852, 755;
HRMS (ESI) m/z calcd. for C16H21O [M-H]-: 229.1592, found:
229.1592.
1,10-diphenyldecane-2,9-dione (5ap). Colorless oil (32 mg,
50%); 1H-NMR (400 MHz, CDCl3) δ 7.36-7.28 (m, 4H), 7.27-
7.22 (m, 2H), 7.21-7.15 (m, 4H), 3.65 (s, 4H), 2.39 (t, J = 7.3
Hz, 4H), 1.54-1.38 (m, 4H), 1.28-1.08 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 208.4, 134.3, 129.3, 128.6, 126.9, 50.1, 41.7,
28.7, 23.4; IR (cm-1): 2931, 1706, 1498, 1455, 696;
HRMS (ESI) m/z calcd. for C22H25O2 [M-H]-: 321.1854, found:
321.1850.
1,4-diphenylbutan-2-one (5aq). Colorless oil (27 mg, 60%);
1H NMR (400 MHz, CDCl3) δ 7.37-7.22 (m, 5H), 7.20-7.07
(m, 5H), 3.65 (s, 2H), 2.97-2.81 (m, 2H), 2.80-2.63 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 207.4, 140.8, 134.0, 129.3,
128.7, 128.4, 128.2, 127.0, 126.0, 50.3, 43.4, 29.7; IR (cm-1):
2929, 1708, 1497, 1364, 700; HRMS (ESI) m/z calcd. for
C16H15O [M-H]-: 223.1122, found: 223.1122.
5-chloro-1-phenylpentan-2-one (5ar). Colorless oil (32 mg,
81%); 1H NMR (400 MHz, CDCl3): δ 7.39-7.31 (m, 2H), 7.30-
7.26 (m, 1H), 7.25-7.18 (m, 2H), 3.71 (s, 2H), 3.53 (t, J = 6.4
Hz, 2H), 2.65 (t, J = 6.9 Hz, 2H), 2.19-1.92 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 207.2, 133.9, 129.3, 128.7, 127.1, 50.2,
44.3, 38.5, 26.2; IR (cm-1): 2921, 2850, 1710, 1495, 1448, 698;
HRMS (ESI) m/z calcd. for C11H12ClO [M-H]+: 195.0576,
found:195.0576.
2-(5-(1H-indol-3-yl)-4-oxopentyl)isoindoline-1,3-dione
(5ax).Colorless oil (58 mg, 84%); 1H-NMR (400 MHz, CDCl3)
δ 8.06 (s, 1H), 7.81 (q, J = 2.9 Hz, 2H), 7.69 (q, J = 2.7 Hz,
2H), 7.51 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.21-
7.14 (m, 1H), 7.14-7.04 (m, 2H), 3.81 (s, 2H), 3.65 (t, J = 6.6
Hz, 2H), 2.54 (t, J = 7.3 Hz, 2H), 2.00-1.84 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 207.8, 168.4, 136.1, 133.8, 132.0, 123.2,
123.1, 122.2, 119.8, 118.7, 111.1, 108.7, 39.8, 38.4, 37.2, 22.7;
IR (cm-1): 3383, 2917, 1769, 1698, 1395, 715; HRMS (ESI)
m/z calcd. For C21H17N2O3 [M-H]-: 345.1238; found: 345.1235.
Synthetic procedure and characterization data of com-
pounds 5a’. Pyridine N-oxide and Tf2NH were premixed in a
molar ratio of 1.2/1.1, then stored in a vial and used directly
for reaction. PPh3AuNTf2 (3.7 mg, 0.25 equiv.) was added into
a mixture of undec-1-yne (31.4 mg, 0.2 mmol), premixed salt
(82.7 mg, 1.1 equiv.), HFIP (0.2 mL) or benzene in a vial at
room temperature. The reaction mixture was then stirred at
room temperature and the progress of the reaction was moni-
4-bromo-1-phenylbutan-2-one (5as). Colorless oil (28 mg,
61%); 1H-NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.31-
7.27 (m, 1H), 7.24-7.17 (m, 2H), 3.72 (s, 2H), 3.52 (t, J = 6.9
Hz, 2H), 3.03 (t, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 205.1, 133.3, 129.4, 128.8, 127.3, 50.4, 44.3, 25.2; IR (cm-1):
2922, 1716, 1495, 1454, 699; HRMS (ESI) m/z calcd. for
C10H11BrONa [M+Na]+: 248.9885, found: 248.9886.
tored by TLC (PE/EA
= 10/1, visualization reagent:
KMnO4/H2SO4). After the reaction was completed (typically
o
2.5h), Then the reaction vial was heated to 100 C for 1h. The
reaction was monitored by TLC (DCM/MeOH = 20/1. After
the reaction was finished, the mixture was concentrated and
the residue was purified by flash chromatography on silica gel
(eluent: DCM/MeOH = 30/1) to afford the desired product 5a’.
1-(2-oxoundecyl)pyridin-1-ium triflimide (5a’). Colorless
5-chloro-1-(1H-indol-3-yl)pentan-2-one (5at). Colorless oil
1
(38 mg, 81%); H-NMR (400 MHz, CDCl3) δ 8.10 (s, 1H),
1
7.54 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (td, J =
7.5, 1.1 Hz, 1H), 7.17-7.07 (m, 2H), 3.83 (s, 2H), 3.56-3.46 (m,
2H), 2.67 (t, J = 7.1 Hz, 2H), 2.08-1.92 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 207.9, 136.1, 127.2, 123.1, 122.4, 119.9,
118.6, 111.2, 108.6, 44.4, 40.1, 37.9, 26.4; IR (cm-1): 3350,
1708, 1455, 742; HRMS (ESI) m/z calcd. For C13H13ClNO
[M-H]-: 234.0685; found: 234.0679.
oil (39 mg, 78%); H NMR (400 MHz, CDCl3) δ 8.59 (d, J =
5.5 Hz, 2H), 8.54-8.46 (m, 1H), 8.08-7.99 (m, 2H), 5.66 (s,
2H), 2.70 (t, J = 7.5 Hz, 2H), 1.69-1.60 (m, 2H), 1.43-1.14 (m,
12H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
199.7, 145.7, 145.6, 121.2, 118.3, 68.2, 40.1, 31.8, 29.3, 29.2,
29.1, 28.9, 22.9, 22.6, 14.0; IR (cm-1): 2925, 2856, 1735, 1638,
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The Journal of Organic Chemistry
1491, 1348, 1132; HRMS (ESI) m/z calcd. for C16H26NO [M]+:
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nier Dit Chabert, J.; Bennett, E.; Nettles, J.; Snyder, J. P.; Lawrence,
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Agarwal, R.; Adepally, U.; Sen, S. A Novel Library of α-Arylketones
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Cyclohexanones with Diaryl Iodonium Salts: Application to the Syn-
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248.2009; found: 248.2009.
Synthetic procedure and characterization data of com-
pounds 5m’. Pyridine N-oxide and Tf2NH were premixed in a
molar ratio of 1.2/1.1, then stored in a vial and used directly
for reaction. PPh3AuNTf2 (3.7 mg, 0.25 equiv.) was added into
a mixture of undec-1-yne (31.4 mg, 0.2 mmol), premixed salt
(82.7 mg, 1.1 equiv.), HFIP (0.2 mL) or benzene in a vial at
room temperature. The reaction mixture was then stirred at
room temperature and the progress of the reaction was moni-
9
tored by TLC (PE/EA
= 10/1, visualization reagent:
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KMnO4/H2SO4). After the reaction was completed (typically
2.5h), the reaction mixture was added with pyrrole (40.2 mg, 3
equiv.). Then the reaction vial was sealed and heated to 90 oC.
The reaction was monitored by TLC (DCM/MeOH = 50/1,
visualization reagent: KMnO4/H2SO4). After the reaction was
finished, the mixture was concentrated and the residue was
purified by flash chromatography on silica gel (eluent: hex-
anes/ethyl acetate 10/1) to afford the desired product 5m’.
3,3',3''-(undecane-1,2,2-triyl)tris(1H-pyrrole) (5m’). Color-
less oil (42 mg, 60%);1H-NMR (400 MHz, CDCl3) δ 7.74 (s,
2H), 7.10 (s, 1H), 6.68-6.55 (m, 2H), 6.51-6.41 (m, 1H), 6.17
(q, J = 2.9 Hz, 2H), 6.15-6.08 (m, 2H), 6.03 (q, J = 2.9 Hz,
1H), 5.91 (t, J = 3.4 Hz, 1H), 3.24 (s, 2H), 1.98-1.72 (m, 2H),
1.35-1.02 (m, 12H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 136.3, 128.5,117.1, 117.0, 108.1, 107.9, 107.4,
105.7, 43.5, 39.3, 37.4, 31.8, 30.0, 29.5, 29.5, 29.2, 24.2, 22.6,
14.1; IR (cm-1): 3385, 2923, 2853, 1455, 713; HRMS (ESI)
m/z calcd. For C23H32N3 [M-H]-: 350.2595; found: 350.2611.
ASSOCIATED CONTENT
*Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: xx.xxxx/acs.joc.xxxxxx.
Screening of catalysts and conditions optimization, Determi-
nation of rate determining step by kinetic isotopic effect, cop-
1
ies of HNMR and 13C NMR spectra for all products were
performed (PDF).
AUTHOR INFORMATION
Corresponding Author
*E-mail: xuzhou@xzhmu.edu.cn
ORCID
Zhou Xu: 0000-0002-9703-8245
Author Contributions
Mr. Zhai and Dr. Xue contribute equally to this work.
(8) (a) Miyoshi, T.; Miyakawa, T.; Ueda, M.; Miyata, O. Nucleo-
philic α-Arylation and α-Alkylation of Ketones by Polarity Inversion
of N-Alkoxyenamines: Entry to the Umpolung Reaction at the α-
Carbon Position of Carbonyl Compounds. Angew. Chem., Int. Ed.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank National Natural Science Foundation of China
(Grant No. 21602191) and Natural Science Foundation of Jiangsu
Province (Grants No. BK 20171175) and the Project of Science
and Technology of Xuzhou Government (No. KC16SG250). The
work is also sponsored by Qing Lan Project of Jiangsu Province
and Jiangsu Six Talent Peaks Program (YY-042).
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