Synthesis of the ortho / meta / para isomers of relevant pharmaceutical compounds by coupling a Sonogashira reaction with a regioselective hydration

Article abstract of DOI:10.1021/cs401075z

Aryl ketones substituted in ortho, meta, and para position are prepared by a palladium-catalyzed Sonogashira reaction followed by a regioselective hydration of the so-formed alkyne with triflimidic acid or a gold catalyst, under catalytic conditions. This methodology opens a way to obtain substituted aryl alkyl ketones from readily available starting materials, haloarenes, and terminal alkynes. The syntheses of the different regioisomers of haloperidol, melperone, pipamperone, and ibuprofen are presented. Structure-activity relationships for these compounds are studied with dopaminergic and cyclooxigenase binding assays.

Full text of DOI:10.1021/cs401075z

Research Article
pubs.acs.org/acscatalysis
Synthesis of the ortho/meta/para Isomers of Relevant Pharmaceutical
Compounds by Coupling a Sonogashira Reaction with a
Regioselective Hydration
Antonio Leyva-Perez,*,† Jose R. Cabrero-Antonino,† Paula Rubio-Marques,† Saud I. Al-Resayes,‡
́
́
and Avelino Corma*,†
†Instituto de Tecnología Química, Universidad Politec
Naranjos s/n, 46022 Valencia, Spain
́
nica de Valencia-Consejo Superior de Investigaciones Científicas, Avda. de los
‡Chemistry Department, College of Science, King Saud University, B.O. BOX 2455, Riyadh 11451, Saudi Arabia
S
* Supporting Information
ABSTRACT: Aryl ketones substituted in ortho, meta, and
para position are prepared by a palladium-catalyzed Sonoga-
shira reaction followed by a regioselective hydration of the so-
formed alkyne with triflimidic acid or a gold catalyst, under
catalytic conditions. This methodology opens a way to obtain
substituted aryl alkyl ketones from readily available starting
materials, haloarenes, and terminal alkynes. The syntheses of
the different regioisomers of haloperidol, melperone, pipam-
perone, and ibuprofen are presented. Structure−activity relationships for these compounds are studied with dopaminergic and
cyclooxigenase binding assays.
KEYWORDS: butyrophenones, antipsychotics, NSAIDs, Sonogashira reaction, regioselective hydration
Scheme 1. Friedel-Crafts Acylation and the Methodology
Presented Here
INTRODUCTION
■
The acid-catalyzed Friedel−Crafts acylation of aromatic rings is
a fundamental process in the fine chemical industry and has
allowed the synthesis of acyl arenes during the last century.1
Many pharmaceuticals, flavors, fragrances, dyes, agrochemicals,
and natural products, some of them manufactured in
multikilogram quantities, are obtained through Friedel−Crafts
intermediates. These intermediates are generally para-sub-
stituted due to the electronics of the Friedel−Crafts reaction,
and this regioselectivity ultimately dictates the biological and
chemical properties of the final compound. This inherent
limitation of the Friedel−Crafts reaction has not been
significantly alleviated by any synthetic method to date,2 and
the corresponding ortho- and meta-substituted isomers must be
prepared by alternative methods, which hinders their wide-
spread exploration. Therefore, synthetic methodologies to
prepare ortho- and meta-substituted aryl ketones are of
interest.3,4
Scheme 1 shows the synthetic procedure used here to
prepare ortho-, meta-, and para-substituted aryl alkyl ketones
consisting of a palladium-catalyzed Sonogashira reaction
followed by a Brønsted (triflimidic acid) or Lewis (gold)
acid-catalyzed Markovnikov hydration of the alkyne product. It
is widely reported that the Sonogashira reaction allows the easy
formation of new carbon−carbon bonds on substituted
aromatic rings5,6 and that the regioselective hydration of
alkynes proceeds with different acid catalysts at the gram
scale.7−9 Both reactions have separately been implemented in
industrial processes and multigram synthetic programs.
Previous works have shown the possibility of engaging the
Sonogashira coupling and the hydration of the so-formed
alkyne to form aryl ketones.10 The regioselectivity of hydration
across the triple bond is due to electronic reasons, and in the
case of arylalkynes containing electron withdrawing groups, the
regioselectivity can be poor. Neighboring groups can speed up
the process or invert the inherent regioselectivitiy expected for
aryl alkynes,10e,f whereas the methodology here presented with
triflimidic acid does not require of any anchimeric assistance
(see Table S1 in Supporting Information for a complete set of
data comparing the different methods). Overall, we will show
Received: August 23, 2013
Revised: January 10, 2014
Published: January 17, 2014
© 2014 American Chemical Society
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here that the two-step Sonogashira-hydration procedure with
triflimidic acid is regioselective, starts from widely available
materials, is fully catalyzed and group-tolerant, operates under
mild conditions, and provides an eco-friendly system for the
synthesis of aryl alkyl ketones.
RESULTS AND DISCUSSION
■
The synthesis of some para-substituted aryl ketones used as
antipsychotics, haloperidol 1, melperone 2, and pipamperone 3,
together with the corresponding ortho/meta regioisomers and
other halogenated derivatives, was attempted using the
proposed methodology. The structures of these drugs are
shown in Scheme 2. The para-substituted fluorobutyro-
Scheme 2. Representative Examples of Widely Used Drugs
Containing Aromatic Rings with para-Fluoro Ketone
Derivatives
Figure 1. Halo-aromatic butyrophenones obtained by a Sonogashira-
hydration−nucleophilic substitution reaction sequence. Combined
isolated yields after three steps.
hindered amine for pipamperone derivatives reacts slowly.
Nominal water from the reactants can also compete as
nucleophile under these basic conditions. In any case, the
isolated yields of poly-halo-substituted butyrophenones 1a−d,
2a−c, and 3a−c after three synthetic steps range within the
accepted values for other antipsychotic drugs such as
olanzapine (48%)15 and clozapine (50%)16,17 and also for
other drugs and natural products such as praziquantel (45%,
drug to treat schistosomiasis and also on the WHO List of
Essential Medicines),18 verapamil (57%, clinical use for
hypertension),19 arundic acid (61%, phase II trials for acute
ischemic stroke and clinical development for treatment of
Parkinson’s and Alzheimer’s disease),20 or trimethylresveratrol
(54%, higher activity against several human cancer cell lines
than resveratrol itself),21 all of them prepared in three synthetic
steps.
phenones are prepared by Friedel−Crafts acylation of
fluorobenzene, and the corresponding ortho-, meta-, and
polysubstituted fluoro derivatives have not been prepared to
date.11 Haloperidol 1 is a “core” medicine in the World Health
Organization (WHO) List of Essential Medicines, and in
general, para-fluorinated compounds are very common in
Pharma. For instance, the current first top-selling drug
atorvastatin 4 and others such as escitalopram 5 contain this
moiety (see also Scheme 2).
The results in Figure 1 show that para-fluorinated drugs 1−3
and an array of analogues 1a−d, 2a−c, and 3a−c can be
prepared in three steps from readily available polihaloben-
zenes12,13 in reasonable yields, following the Sonogashira-
hydration reaction sequence.
The results show that the Sonogashira coupling is fast and
gives good yields of isolated alkynes 6a−d. The coupling must
be stopped at 30 min reaction time, because otherwise, the
excess of Et3N removes the terminal chloride and forms the
quaternary ammonium salt, which then undergoes Hoffmann
elimination. Lesser amounts of Et3N or other alternative amines
do not solve this problem and tend to hamper the final yield of
the coupling. The hydration also proceeds well, with moderate
to good isolated yields of ketones 7a−d, and the combined
isolated yields for the two reactions are >50%. Notice that there
are very few reported examples of application in drugs or
natural products of the Markovnikov hydration of asymmetric
internal alkynes without anchimeric assistance.14
The final iodide-catalyzed nucleophilic substitution with the
amine is somewhat less effective and gives variable yields
depending on the substitution pattern and the amine employed.
For instance, the nucleophilic aromatic substitution of the
fluoride atom competes with the desired substitution at the
terminal position in the ortho-fluoro derivatives, and the
We have evaluated here the binding affinity toward D1 and
D2 dopaminergic receptors of some of the compounds prepared
in the form of hydrochloride salt,22 and the results are shown in
Table 1.
The results in Table 1 show that the selectivity for D2
receptors (D1/D2 value) increases significantly for ortho- and
meta-halobutyrophenones. Notice that the extrapyramidal
effects observed for these drugs are associated with the low
selectivity for D2 sites, and any increment in the selectivity for
these centers may be reflected in a reduction of the undesired
secondary symptoms associated with these drugs. For instance,
the ortho derivative 1b increases the selectivity 5 times
compared to haloperidol 127 while maintaining an acceptable
activity, <100 nM (entry 3). The introduction of a chloro atom
in meta position, compound 1c, also improves the selectivity,
and this is consistent for the three drugs (compounds 1c−3c,
see entries 4, 8, and 11). In particular, 3c increases 1 order of
magnitude the selectivity of D1/D2 compared to pipamperone 3
and maintains a comparable activity (entries 9 and 11), as also
shown in Figure 2 (for additional binding assays, see
Supporting Information).
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Table 1. Affinity Values (Ki, μM) and Selectivity (Ratio of Ki
D1/Ki D2) for Dopaminergic Receptors, in Mice, of Fluoro-
Substituted Butyrophenones
entry
compd
D1, Ki (μM)
D2, Ki (μM)
D1/D2
b
b
b
1
2
1
1a
1b
1c
1d
2
0.025 0.007
0.005 0.0002
0.554 0.100
0.099 0.049
0.254 0.067
0.541 0.127
5.0
2.192 0.104
2.726 0.333
3.186 0.567
1.288 0.242
3.9
27.5
12.5
2.4
3
4
5
c
c
c
6
0.148
0.190
0.8
7
2a
2c
3
32.731 4.597
18.751 0.082
1.249 0.134
54.921 6.211
22.361 3.012
3.023 0.797
0.971 0.494
0.351 0.107
1.848 0.412
0.774 0.033
10.8
19.3
3.5
8
9
10
11
3a
3c
29.7
28.9
a
Specific D1 ligand [3H] SCH 23390, Specific D2 ligand [3H]
raclopride. Results expressed as mean SEM from three experiments.
b
c
From refs 23, 24. From refs 25, 26.
These results show structure−activity relationships (SARs),28
which clearly suggest that the para-fluoro substitution in these
antipsychotic drugs is, in principle, not a requisite for biological
activity and that the move of the fluorine atom or the
introduction of new halogen atoms across the ring improve the
selectivity of the drug for the D2 receptor. These are, to our
knowledge, the first SAR studies on fluoro-butyrophenones
varying the aromatic side, thus complementing those already
performed varying the amine24 or the ketone,29,30 and
expanding the possibilities for incorporating new fluorine
atoms on these drugs. The use of fluorine in medicinal
chemistry is well-recognized.31−33 Besides, this study adds
understanding to the biochemistry of the dopaminegic
receptors D1 and D2, which have not been isolated yet.34,35
To expand the synthetic results, we tested the Sonogashira-
hydration methodology for the preparation of regioisomers of
the well-known non-steroideal anti-inflammatory drug
(NSAID) ibuprofen 8, another core medicine in the WHO
Essential Medicines List, which is prepared by Friedel−Crafts
acylation of isobutylbenzene in industry. Figure 3 shows the
synthesis of meta-ibuprofen 8a and ortho-ibuprofen 8b from the
corresponding bromoarenes36 in four steps.37
Figure 3. Synthesis of meta-ibuprofen 8a and ortho-ibuprofen 8b
(top), isolated yields. Synthesis of alkyl aryl ketones obtained by the
Sonogashira-hydration reaction sequence (bottom), combined GC
yields after two steps.
completely Markovnikov, thus the use of triflimidic acid can
be avoided. Comparative studies about the hydration of aryl
alkynes with different metal and Brønsted catalysts can be
found elsewhere.14 The isobutyl chain is installed by palladium-
catalyzed Suzuki reaction, before or after the Sonogashira
coupling (see Supporting Information for details). Yields are
moderate to good for the meta isomer and lower for the ortho
isomer, probably due to the steric hindrance imparted by the
bulky alkyl substituent. In any case, the corresponding ketones
10a,b could be converted to meta- and ortho-ibuprofen 8a,b
after hydrocyanation followed by a one-pot hydrolysis−
dehydration process under reported conditions.37 With these
compounds in hand, the two regioisomers were submitted to
biological screening for cyclooxygenase activity (COX-1 and
COX-2). The results in Figure 4 show that the COX-1
inhibition observed for the two acids is very similar, which is
explained by the increasing steric hindrance around the acid
The results in Figure 3 show that meta- and ortho-ibuprofen
8a,b can be prepared by a palladium-catalyzed Sonogashira
reaction followed by TMS-deprotection and Markovnikov
hydration of the terminal alkyne at room temperature under
gold-catalyzed conditions.8,38−40 Notice that the regioselectivity
of hydration of terminal alkynes with gold catalysts is
Figure 2. Plot of binding−concentration for pipamperone 3 and the meta-chloro-substituted derivative 3c. The selectivity to D2 receptors increases
significantly for 3c while maintaining a similar activity to 3.
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Figure 4. Percent inhibition of COX-1 and COX-2 with the concentration of ibuprofen derivative.
function when compared to the para-substituted, as also
evidenced by the 1H NMR signals of compound 8b. This result
is consistent with the proposed mechanism of action of
ibuprofen 8 that consists in the interaction of the carboxylic
acid group with the COX-1 receptor within a narrow cone-like
cavity that has no room for bulky groups nearby and only
allows the entrance of linear para-substituted rings or, in
general, flat molecules.41 The COX-2 receptor has a cavity 17%
bigger than COX-1 and does not discriminate so strongly
depending on the steric hindrance that surrounds the carboxylic
group.42 Therefore, it could very well occur that the bioactivity
of the two isomers meta 8a and ortho 8b differs in the case of
COX-2. The results show that 8a inhibits the COX-2 receptor 5
times more efficiently than 8b. Although the overall activity of
the regioisomers 8a,b is lower than ibuprofen 8, the results
presented here show a possible way to enhance the selectivity
for COX-2 receptors, which is in turn one of the main current
challenges in medicinal chemistry.42
Finally, we used the Sonogashira-hydration synthetic route to
prepare other butyrophenones having functional groups
incompatible with the Friedel−Crafts reaction. Figure 3
shows that the acyl group can be readily furnished on phenols
and benzoic acids under these reaction conditions, to give
ketones 11 and 12 in good yields. These results confirm that
the methodology presented here opens a way to prepare
acylated substrates that can not be prepared by direct Friedel−
Crafts acylation.
unreported ortho-, meta-, and para-substituted analogues of the
widely used drugs melperone, haloperidol, pipamperone, and
ibuprofen. The catalytic sequence presented here opens a new
way to obtain substituted aryl alkyl ketones and to design new
retro-synthetic routes.
EXPERIMENTAL SECTION
■
Synthesis of 4-Chloro-1-butyne. 3-Butynol (3.02 mL, 40 mmol)
and pyridine (256 μL, 4 mmol) were placed in a 10 mL round-
bottomed flask, and the mixture was cooled in an ice bath. Then,
thionyl chloride (2.91 mL, 40 mmol) was added dropwise for 10 min.
The flask was shaken occasionally during the addition, and after the
thionyl chloride was added, the mixture was heated under reflux for 30
min. Fractional distillation of the products gave 4-chloro-1-butyne as a
yellow liquid (3.34 mL). Isolated yield: 95%. IR (ν, cm-1): 3335 (i,
Csp3-H), 3324 (i), 3005 (l, C−H), 2967 (l, C−H), 2924 (l, C−H),
2358 (l), 2339 (m), 1275 (i), 1260 (i), 764 (vi), 751 (vi), 645 (vi).
GC-MS (m/z, M+•
̇ 88), major peaks found: 88 (50%), 73 (1%), 62
(2%), 53 (100%), 39 (6%). 1H NMR (δ, ppm; J, Hz): 3.60 (CH2, t, J =
7.2), 2.66 (CH2, td, J = 7.2, 2.6), 2.08 (CH, t, J = 2.6). 13C NMR (δ,
ppm): 80.2 (C), 70.4 (CH), 41.9 (CH2−Cl), 22.8 (CH2).
Synthesis of Fluorinated Aminobutyrophenones from
Aromatic Halides, Alkynes, and Amines (Figure 1). Sonogashira
CONCLUSIONS
Coupling. PdCl2(PPh3)2 (88 mg, 1 mol %) and copper iodide (40 mg,
2 mol %) were placed in a 50 mL round-bottomed flask equipped with
a magnetic bar and then nondried 1,4-dioxane (10 mL), the
corresponding iodide (10 mmol), 4-chloro-1-butyne (1 mL, ∼12
mmol, 1.2 equiv), and triethylamine (345 μL, 2.5 mmol, 5 equiv) were
added. The flask was capped with a rubber septum, and the resulting
mixture was placed in a preheated oil bath at 50 °C and magnetically
stirred for 30 min. One aliquot was taken for GC analysis, and the rest
■
A Sonogashira coupling followed by hydration with triflimidic
acid gives susbtituted alkyl aryl ketones in good yields and
selectivity, giving access to bioactive compounds. The presence
of neighboring functional groups for anchimeric assistance in
the hydration step is not required and the applicability of the
method has been demonstrated by the synthesis of previously
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was diluted in diethyl ether (100 mL) after cooling (the ammonium
salt can be observed as crystals in some cases), removing the solids by
filtration. The resulting solution was purified by column chromatog-
raphy (n-hexane) to yield the corresponding alkyne product (see
below for details).
1.1), 86.3 (Calkyne, d, J5C−F = 1.7), 80.4 (Calkyne, dd, J4C−F = 2.7, J5
=
C−F
1.7), 41.9 (CH2), 23.6 (CH2). 19F NMR (δ, ppm; J, Hz): −136.30
(mult), −137.34 (mult). HRMS (ESI) m/z: [M+] calcd for C10H7ClF2,
200.0204; found, 200.0216.
Markovnikov Hydration. The purified alkyne (5 mmol) was treated
with a solution of HNTf2 (60−200 mol %) in 1,4-dioxane in a
Alkyne 6. The reaction crude was purified by column chromatog-
raphy using n-hexane as an eluent. Isolated yield: 1.27 g (70%). Rf (n-
hexane): 0.50. IR (ν, cm−1): 2959 (l, C−H), 2920 (l, C−H), 2000−
1600 (l, overtones), 1508 (vi, arC−C), 1232 (i, arC−F), 1157 (l), 834
(i), 533 (m). GC-MS (m/z, M+• 182), major peaks found: 182 (50%),
146 (25%), 133 (100%), 120 (12%), 107 (10%). 1H NMR (δ, ppm; J,
Hz): 7.42−7.35 (2C−H arom, mult), 7.03−6.94 (2C−H arom, mult),
3.67 (CH2, t, J = 7.2), 2.86 (CH2, t, J = 7.2). 13C NMR (δ, ppm; J,
preheated oil bath at 100 °C, under magnetic stirring, for 18−52 h,
and the corresponding ketone was purified by column chromatography
after cooling.
Hz): 162.3 (C, d, J1
= 248.6), 133.5 (2CH, d, J3
= 8.2), 118.2
C−F
C−F
(C, d, J4C−F = 3.8), 115.5 (2CH, d, J2C−F = 22.2), 85.3 (C), 81.4 (C),
42.1 (CH2), 27.3 (CH2).
Ketone 7. The reaction crude was purified by column
chromatography using 20% AcOEt in n-hexane as an eluent. Isolated
yield: 850 mg (85%). Rf (20% AcOEt in n-hexane): 0.66. GC-MS (m/
z, M+• 200), major peaks found: 200 (1%), 164 (1%), 138 (43%), 123
Alkyne 6a. The reaction crude was purified by column
chromatography using n-hexane as an eluent. Isolated yield: 1.51 g
(83%). Rf (n-hexane): 0.66. IR (ν, cm−1): 2965 (l, C−H), 1599 (m),
1515 (i, arC−C), 1419 (m, −CH2), 1302 (l), 1216 (m), 820 (m), 773
(m, alC-Cl). GC-MS (m/z, M+• 182), major peaks found: 182
(100%), 147 (80%), 133 (100%), 120 (26%), 107 (27%), 75 (27%),
49 (27%). 1H NMR (δ, ppm; J, Hz): 7.17−7.06 (2C−H arom, mult),
7.04−6.97 (C−H arom, mult), 6.92−6.86 (C−H arom, mult), 3.55
(CH2, t, J = 7.2), 2.75 (CH2, t, J = 7.2). 13C NMR (δ, ppm; J, Hz):
162.2 (C, d, J1C−F = 245.9), 129.7 (CH, d, J3C−F = 8.8), 127.5 (CH, d,
1
(100%), 107 (10%). H NMR (δ, ppm; J, Hz): 8.03−7.97 (2C−H
arom, mult), 7.17−7.09 (2C−H arom, mult), 3.68 (CH2, t, J = 6.2),
3.15 (CH2, t, J = 7.0), 2.22 (CH2, tt, J = 7.0, 6.2). 13C NMR (δ, ppm; J,
Hz): 197.3 (CO), 166.1 (C, d, J1C−F = 254.7), 133.2 (C, d, J4
= 22.2), 44.6
C−F
=
C−F
4.3), 130.6 (2CH, d, J3
= 9.3), 115.9 (2CH, d, J2
C−F
(CH2), 35.2 (CH2), 26.7 (CH2).
Ketone 7a. The reaction crude was purified by precipitation of the
catalyst and polimerization products with n-hexane. Isolated yield: 600
mg (60%). GC-MS (m/z, M+• 200), major peaks found: 200 (5%),
J4
= 3.3), 124.9 (C, d, J3
= 9.9), 118.4 (CH, d, J2
= 22.5),
C−F
C−F
C−F
115.3 (CH, d, J2C−F = 20.8), 86.8 (Calkyne), 81.2 (Calkyne, d, J4C−F = 3.3),
41.9 (CH2), 23.6 (CH2). HRMS (ESI) m/z: [M+] calcd for C10H8ClF,
182.0299; found, 182.0269.
1
164 (4%), 138 (40%), 123 (100%), 107 (15%). H NMR (δ, ppm; J,
Hz): 7.76 (C−H arom, dt, J = 7.7, 1.1), 7.68−7.62 (C−H arom, mult),
7.45 (C−H arom, td, J = 8.1, 5.6), 7.27 (C−H arom, tdd, J = 8.1, 2.6,
1.1), 3.67 (CH2, t, J = 6.2), 3.17 (CH2, t, J = 7.0), 2.23 (CH2, tt, J =
Alkyne 6b. The reaction crude was purified by column
chromatography using n-hexane as an eluent. Isolated yield: 1.36 g
(75%). Rf (n-hexane): 0.31. IR (ν, cm−1): 2964 (l, C−H), 2918 (l, C−
H), 2000−1600 (l, overtones), 1493 (vi, arC−C), 1448 (m), 1257 (i,
arC−F), 1217 (m), 1105 (m), 757 (vi, alC−Cl). GC-MS (m/z, M+•
182), major peaks found: 182 (40%), 146 (21%), 133 (100%), 120
7.0, 6.2). 13C NMR (δ, ppm; J, Hz): 197.8 (CO, d, J4
= 6.1), 130.3 (CH, d,
C−F
= 1.7),
C−F
162.9 (C, d, J1
= 248.1), 138.7 (C, d, J3
C−F
J3
= 7.1), 123.8 (CH, d, J4C−F = 3.3), 120.2 (CH, d, J2
= 21.4),
C−F
C−F
114.8 (CH, d, J2
= 22.5), 44.5 (CH2), 35.4 (CH2), 26.6 (CH2).
C−F
1
HRMS (ESI) m/z: [M+] calcd for C10H10ClFO, 200.0404; found,
200.0400.
(3%), 107 (2%). H NMR (δ, ppm; J, Hz): 7.36−7.30 (C−H arom,
mult), 7.23−7.15 (C−H arom, mult), 7.02−6.98 (C−H arom, mult),
6.97−6.92 (C−H arom, mult), 3.61 (CH2, t, J = 7.3), 2.84 (CH2, t, J =
Ketone 7b. The reaction crude was purified by column
chromatography using n-hexane as an eluent. Isolated yield: 630 mg
(63%). Rf (n-hexane): 0.38. IR (ν, cm−1): 2963 (l, C−H), 2925 (l, C−
H), 1686 (vi, CO), 1609 (i), 1480 (m, arC−C), 1453 (vi), 1272 (m,
arC−F), 1213 (m), 763 (vi, alC−Cl). GC-MS (m/z, M+• 200), major
peaks found: 200 (1%), 138 (39%), 123 (100%), 95 (3%), 75 (8%).
1H NMR (δ, ppm; J, Hz): 7.87 (C−H arom, td, J = 7.4, 1.9), 7.56−
7.48 (C−H arom, mult), 7.23 (C−H arom, ddd, J = 7.9, 6.8, 1.1), 7.14
(C−H arom, ddd, J = 11.4, 8.3, 1.1), 3.66 (CH2, t, J = 6.3), 3.18 (CH2,
td, J = 7.0, 3.0), 2.22 (CH2, t, J = 6.3). 13C NMR (δ, ppm; J, Hz):
197.2 (CO, d, J3C−F = 3.8), 162.0 (C, d, J1C−F = 254.7), 134.6 (CH,
d, J3C−F = 9.3), 130.5 (CH, d, J4C−F = 2.7), 125.3 (CH), 124.4 (CH, d,
7.3). 13C NMR (δ, ppm; J, Hz): 162.8 (C, d, J1
= 250.8), 133.6
C−F
(CH, d, J4C−F = 1.1), 129.8 (CH, d, J3C−F = 8.3), 123.9 (CH, d, J4
=
C−F
3.8), 115.4 (CH, d, J2
= 20.9), 111.6 (C, d, J2
= 15.4), 91.0
C−F
C−F
(Calkyne, d, J3
= 3.3), 75.8 (Calkyne), 41.9 (CH2), 23.9 (CH2). 19F
C−F
NMR (δ, ppm; J, Hz): −110.60 (mult). HRMS (ESI) m/z: [M+] calcd
for C10H8ClF, 182.0299; found, 182.0271.
Alkyne 6c. The reaction crude was purified by column
chromatography using n-hexane as an eluent. Isolated yield: 1.58 g
(73%). Rf (n-hexane): 0.35. IR (ν, cm−1): 2964 (l, C−H), 2918 (l, C−
H), 2000−1600 (l, overtones), 1497 (vi, arC−C), 1265 (m, arC−F),
1062 (m, arC−Cl), 822 (m). GC-MS (m/z, M+• 217), major peaks
found: 216 (36%), 180 (7%), 167 (100%), 146 (36%), 132 (10%). 1H
NMR (δ, ppm; J, Hz): 7.37 (C−H arom, dd, J = 7.2, 2.0), 7.18 (C−H
arom, ddd, J = 8.7, 4.5, 2.0), 6.97 (C−H arom, t, J = 8.7), 3.58 (CH2, t,
J = 7.1), 2.78 (CH2, t, J = 7.1). 13C NMR (δ, ppm; J, Hz): 157.8 (C, d,
J1C−F = 251.4), 133.7 (CH), 131.5 (CH, d, J3C−F = 7.7), 116.5 (CH, d,
J3
= 3.3), 116.7 (CH, d, J2
= 23.6), 44.4 (CH2), 40.3 (CH2, d,
C−F
J4CC−−FF = 7.7), 26.6 (CH2, d, J5C−F = 1.6). HRMS (ESI) m/z: [M+] calcd
for C10H10ClFO, 200.0404; found, 200.0417.
Ketone 7c. The reaction crude was purified by column
chromatography using 10% AcOEt in n-hexane as an eluent. Isolated
yield: 725 mg (62%). Rf (10% AcOEt in n-hexane): 0.44. IR (ν, cm−1):
2964 (l, C−H), 2927 (l, C−H), 1689 (vi, CO), 1592 (i), 1496 (l,
arC−C), 1402 (m, −CH2), 1249 (vi, arC−F), 1059 (m, arC−Cl), 698
(m, alC−Cl). GC-MS (m/z, M+• 235), major peaks found: 234 (1%),
172 (41%), 157 (100%), 129 (29%), 109 (7%), 94 (6%). 1H NMR (δ,
ppm; J, Hz): 8.04 (C−H arom, dd, J = 7.2, 2.2), 7.88 (C−H arom,
ddd, J = 8.7, 4.5, 2.2), 7.23 (C−H arom, t, J = 8.7), 3.67 (CH2, t, J =
6.2), 3.14 (CH2, t, J = 7.0), 2.22 (CH2, tt, J = 7.0, 6.2). 13C NMR (δ,
ppm; J, Hz): 196.3 (CO), 161.1 (C, d, J1C−F = 257.4), 133.9 (C, d,
J2
= 21.4), 86.6 (Calkyne), 80.2 (Calkyne), 41.9 (CH2), 23.6 (CH2).
C−F
19F NMR (δ, ppm; J, Hz): −114.00 (mult.). HRMS (ESI) m/z: [M+]
calcd for C10H7Cl2F, 215.9909; found, 215.9893.
Alkyne 6d. The reaction crude was purified by column
chromatography using n-hexane as an eluent. Isolated yield: 1.6 g
(80%). Rf (n-hexane): 0.25. IR (ν, cm−1): 2965 (l, C−H), 1599 (m),
1515 (vi, arC−C), 1419 (m, −CH2), 1302 (m), 1216 (m, arC−F), 820
(m), 773 (m, alC−Cl). GC-MS (m/z, M+• 200), major peaks found:
1
200 (45%), 165 (17%), 151 (100%), 125 (5%), 101 (4%). H NMR
J4
= 3.8), 131.0 (CH), 128.4 (CH, d, J3
= 8.8), 121.9 (C, d,
C−F
(δ, ppm; J, Hz): 7.24−7.17 (C−H arom, mult), 7.16−7.10 (C−H
arom, mult), 7.09−7.02 (C−H arom, mult), 3.66 (CH2, t, J = 7.1),
J2C−F = 22.2), 116.8 (CH, d, J2
= 21.4), 44.4 (CH2), 35.2 (CH2),
C−F
C−F
2.86 (CH2, t, J = 7.1). 13C NMR (δ, ppm; J, Hz): 150.4 (C, dd, J1
=
26.5 (CH2). HRMS (ESI) m/z: [M+] calcd for C10H9Cl2FO,
234.0014; found, 234.0002.
C−F
250.8, J2C−F = 12.1), 149.8 (C, dd, J1C−F = 248.0, J2
= 12.6), 128.2
(CH, dd, J3C−F = 6.6, J4C−F = 3.8), 120.6 (CH, d, J2CC−−FF = 19.2), 119.9
Ketone 7d. The reaction crude was purified by column
chromatography using 10% AcOEt in n-hexane as an eluent. Isolated
(C, dd, J3C−F = 7.7, J4C−F = 4.4), 117.3 (CH, dd, J2C−F = 18.1, J3
=
C−F
726
dx.doi.org/10.1021/cs401075z | ACS Catal. 2014, 4, 722−731

ACS Catalysis
Research Article
yield: 710 mg (65%). Rf (10% AcOEt in n-hexane): 0.48. IR (ν, cm−1):
2924 (l, C−H), 2000−1700 (l, overtones), 1685 (vi, CO), 1276
(m), 1261 (m), 764 (vi, alC−Cl), 750 (vi). GC-MS (m/z, M+• 218),
major peaks found: 218 (1%), 182 (<1%), 156 (44%), 141 (100%),
mult), 2.26−2.02 (O−H + CH2, mult), 1.97−1.80 (CH2, mult), 1.47−
1.63 (CH2, mult). 13C NMR (δ, ppm): 207.2 (CO), 162.8 (C, d,
J1C−F = 247.5), 147.0 (C), 139.3 (C, d, J3C−F = 6.1), 132.5 (C), 130.2
(CH, d, J3C−F = 7.7), 128.2 (2 × CH), 126.1 (2 × CH), 123.8 (CH, d,
J4C−F = 3.3), 119.8 (CH, d, J2C−F = 21.4), 114.7 (CH, d, J2C−F = 22.0),
70.9 (C−OH), 57.6 (CH2−N), 49.2 (2CH2−N), 38.1 (2 × CH2),
36.3 (CH2), 21.8 (CH2). 19F NMR (δ, ppm; J, Hz): −111.91 (mult).
HRMS (ESI) m/z: [M+] calcd for C21H23ClFNO2, 376.1474; found,
376.1472.
1
113 (34%), 63 (7%). H NMR (δ, ppm; J, Hz): 7.83−7.73 (2C−H
arom, mult), 7.29−7.19 (C−H arom, mult), 3.67 (CH2, t, J = 6.1),
3.13 (CH2, t, J = 7.0), 2.21 (CH2, quint, J = 6.5). 13C NMR (δ, ppm; J,
Hz): 196.3 (CO, d, J4C−F = 1.6), 153.7 (C, dd, J1C−F = 247.5, J2
=
=
13.2), 150.3 (C, dd, J1
= 241.5, J2C−F = 12.6), 133.8 (C, d, J3C−F
C−F
4.4), 125.0 (CH, d, J2C−F = 7.1), 124.9 (CH, d, J2
= 7.7), 117.2
Butyrophenone 1c. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:0.5) as an
eluent. Isolated yield: 122 mg (60%). Rf (AcOEt/MeOH/NH4OH
95:5:0.5): 0.58. IR (ν, cm−1): 3137 (bs, OH), 2949 (m, C−H), 2938
(m, C−H), 2821 (m), 1685 (vi, CO), 1594 (m), 1493 (m, arC−C),
1400 (i, −CH2), 1251 (i, arC−F), 1080 (i, arC−Cl), 821 (i), 547 (l).
1H NMR (δ, ppm; J, Hz): 8.04 (C−H arom, dd, J = 7.0, 2.2), 7.89
(C−H arom, ddd, J = 8.5, 4.5, 2.2), 7.31 (2C−H arom, dt, J = 8.9, 2.2),
7.29 (2C−H arom, dt, J = 8.9, 2.2), 7.22 (C−H arom, t, J = 8.5), 2.96
(CH2, t, J = 7.0), 2.81−2.72 (CH2, mult), 2.49−2.37 (2CH2, mult),
2.04−1.89 (2CH2, mult), 1.86 (O−H, bs), 1.71−1.61 (CH2, mult).
13C NMR (δ, ppm): 197.2 (CO), 160.9 (C, d, J1C−F = 256.9), 146.7
C−F
C−F
(CH, dd, J2
= 18.1, J3
= 1.6), 44.4 (CH2), 35.2 (CH2), 26.5
C−F
C−F
(CH2). HRMS (ESI) m/z: [M+] calcd for C10H9ClF2O, 218.0310;
found, 218.0330.
Amine Nucleophilic Substitution. The purified ketone (0.5 mmol)
was placed in a vial equipped with a magnetic bar and potassium
(C), 134.5 (C, d, J4
= 3.8), 132.8 (C), 131.0 (CH, d, J3C−F = 1.1),
C−F
128.3 (CH, d, J3C−F = 8.2), 128.4 (2CH), 126.0 (2CH), 121.8 (C−Cl,
iodide (1−10 mol %), sodium bicarbonate (2 equiv), anhydrous
toluene (0.5 M), and the corresponding amine (1−2 equiv). The vial
was closed and heated in a preheated oil bath at 100 °C for 18−36 h
under magnetic stirring. The resulting mixture was purified by column
chromatography or preparative TLC on silica to obtain the final
aminobutyrophenones.
d, J2 = 18.1), 116.7 (CH, d, J2
= 21.4), 71.0 (C−OH), 57.6
C−F
C−F
(CH2−N), 49.2 (2CH2−N), 38.1 (2CH2), 36.2 (CH2), 21.8 (CH2).
HRMS (ESI) m/z: [M − H+] calcd for C21H21Cl2FNO2, 408.0933;
found, 408.0944.
Butyrophenone 1d. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:0.5) as an
eluent. Isolated yield: 107 mg (54%). Rf (AcOEt/MeOH/NH4OH
95:5:0.5): 0.34. IR (ν, cm−1): 3445 (bs, OH), 2948 (m, C−H), 2926
(l, C−H), 2822 (l), 1687 (i, CO), 1611 (m), 1514 (m, arC−C),
1427 (l, −CH2), 1283 (vi, arC−F), 1125 (l, arC−Cl), 826 (l), 537
Haloperidol 1. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 112 mg (60%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.60. GC-MS (m/z, M+• 375), major peaks found: 375 (1%), 237
1
(98%), 224 (100%), 206 (26%), 165 (8%), 123 (16%), 95 (7%). H
1
(m). H NMR (δ, ppm; J, Hz): 7.82−7.64 (2C−H arom, mult), 7.31
NMR (δ, ppm; J, Hz): 8.03−7.95 (2C−H arom, mult), 7.41−7.35
(2C−H arom, mult), 7.32−7.26 (2C−H arom, mult), 7.17−7.08
(2C−H arom, mult), 3.53 (O−H, bs), 3.01 (CH2, t, J = 6.8), 2.97−
2.88 (CH2, m), 2.67−2.55 (2CH2, m), 2.20−2.07 (CH2, m), 2.06−
1.98 (CH2, m), 1.77−1.67 (CH2, m). 13C NMR (δ, ppm): 198.0 (C
(2C−H arom, d, J = 8.9), 7.26−7.12 (3C−H arom, mult), 2.89 (CH2,
t, J = 7.0), 2.76−2.65 (CH2, mult), 2.45−2.30 (2CH2, mult), 1.99−
1.75 (O−H + 2CH2, mult), 1.60 (CH2, d, J = 8.9). 13C NMR (δ,
ppm): 197.3 (CO), 161.9 (C), 160.9 (C), 146.8 (C), 132.8 (C),
132.3 (C), 128.4 (2CH), 126.0 (2CH), 124.8 (C−H), 117.4 (CH, d,
O), 164.0 (C, d, J1
= 254.7), 146.4 (C), 133.4 (C, d, J4
= 2.7),
C−F
C−F
J2
= 18.0), 71.0 (C−OH), 57.6 (CH2−N), 49.3 (2CH2−N), 38.3
132.9 (C), 130.7 (2CH, d, J3
= 9.3), 128.4 (2CH), 126.1 (2CH),
C−F
C−F
(2CH2), 36.2 (CH2), 21.8 (CH2). 19F NMR (δ, ppm; J, Hz): −130.20
(mult), −136.12 (mult). HRMS (ESI) m/z: [M+] calcd for
C21H22ClF2NO2, 394.1380; found, 394.1371.
115.6 (2CH, d, J2
= 21.9), 70.6 (C−OH), 57.4 (CH2−N), 49.1
C−F
(2CH2−N), 37.6 (2CH2), 36.0 (CH2), 21.0 (CH2).
Butyrophenone 1a. The reaction crude was purified by column
chromatography using n-Hex/AcOEt (50:50) then AcOEt/MeOH/
NH4OH (70:30:1) as eluents. Isolated yield: 83.5 mg (44%). Rf
Melperone 2. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 113 mg (86%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.50. GC-MS (m/z, M+• 263), major peaks found: 263 (1%), 165
1
(AcOEt/MeOH/NH4OH 70:30:1): 0.10. H NMR (δ, ppm; J, Hz):
7.69 (C−H arom, dt, J = 7.7, 1.2), 7.60 (C−H arom, ddd, J = 9.6, 2.5,
1.7), 7.38 (C−H arom, td, J = 8.1, 5.6), 7.32−7.27 (C−H arom, mult),
7.23−7.15 (4C−H arom, mult), 5.64 (O−H, bs), 2.91 (CH2, t, J =
6.9), 2.74−2.65 (CH2, mult), 2.44−2.28 (2CH2, mult), 1.97−1.82
(2CH2, mult), 1.63−1.53 (CH2, mult). 13C NMR (δ, ppm): 198.6
1
(4%), 125 (54%), 112 (100%), 95 (9%), 70 (6%). H NMR (δ, ppm;
J, Hz): 8.00−7.94 (2C−H arom, mult), 7.13−7.05 (2C−H arom,
mult), 2.99−2.85 (2CH2, mult), 2.42 (CH2, t, J = 7.3), 2.02−1.88
(2CH2, mult), 1.64−1.53 (CH2, mult), 1.42−1.27 (C−H, m), 1.26−
1.13 (CH2, mult), 0.88 (CH3, d, J = 6.2). 13C NMR (δ, ppm): 198.3
(CO), 165.5 (C, d, J1C−F = 254.1), 133.5 (C, d, J4C−F = 3.3), 130.6
(CO, d, J4C−F = 2.2), 162.8 (C, d, J1
= 247.5), 147.0 (C), 139.3
C−F
(C, d, J3C−F = 6.1), 132.5 (C), 130.2 (CH, d, J3C−F = 7.7), 128.2 (2 ×
(2CH, d, J3
= 9.3), 115.5 (2CH, d, J2
= 21.9), 57.8 (CH2−N),
C−F
CH), 126.1 (2 × CH), 123.8 (CH, d, J4C−F = 3.3), 119.8 (CH, d, J2
C−F
C−F
= 21.4), 114.7 (CH, d, J2
= 22.0), 70.9 (C−OH), 57.6 (CH2−N),
53.6 (2CH2−N), 36.2 (CH2), 33.8 (2CH2), 30.6 (CH), 21.7 (CH3),
21.4 (CH2).
C−F
49.2 (2CH2−N), 38.1 (2 × CH2), 36.3 (CH2), 21.8 (CH2). 19F NMR
(δ, ppm; J, Hz): −111.91 (mult). HRMS (ESI) m/z: [M+] calcd for
C21H23ClFNO2, 376.1474; found, 376.1469.
Butyrophenone 2a. The reaction crude was purified by column
chromatography using AcOEt/MeOH (80:20) as an eluent. Isolated
1
yield: 60.5 mg (46%). Rf (AcOEt/MeOH 80:20): 0.8. H NMR (δ,
Butyrophenone 1b. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:0.5) as an
eluent. Isolated yield: 150 mg (80%). Rf (AcOEt/MeOH/NH4OH
95:5:0.5): 0.66. IR (ν, cm−1): 3435 (bs, OH), 2947 (l, C−H), 2921 (l,
C−H), 2831 (l), 1681 (l, CO), 1593 (l), 1486 (l, arC−C), 1383 (l,
−CH2), 1129 (l, N−alC), 1095 (l, arC−Cl), 912 (vi), 828 (l), 745
(vi). GC-MS (m/z, M+• 375), major peaks found: 375 (1%), 237
(44%), 224 (100%), 206 (26%), 172 (22%), 139 (27), 123 (30%), 77
ppm; J, Hz): 7.70 (C−H arom, dt, J = 7.7, 1.1), 7.55 (C−H arom, ddd,
J = 9.4, 2.6, 1.6), 7.40 (C−H arom, td, J = 8.1, 5.6), 7.21 (C−H arom,
tdd, J = 8.1, 2.6, 1.1), 3.52−3.40 (CH2, mult), 3.10−3.04 (2CH2,
mult), 2.89−2.77 (CH2, mult), 2.29−2.20 (CH2, mult), 1.88−1.78
(C−H, mult), 1.75−1.62 (CH2, mult), 0.95 (CH3, d, J = 6.0). 13C
NMR (δ, ppm): 197.2 (CO, d, J4
= 2.2), 162.6 (C, d, J1
=
C−F
C−F
248.1), 138.1 (C, d, J3
= 6.1), 130.3 (CH, d, J3
= 7.1), 123.8
C−F
C−F
(14%), 42 (14). H NMR (δ, ppm; J, Hz): 7.49−7.36 (4C−H arom,
(CH, d, J4C−F = 3.3), 120.3 (CH, d, J2C−F = 21.4), 114.5 (CH, d, J2
1
C−F
mult), 7.35−7.27 (2C−H arom, td, J = 8.7, 1.9), 7.17 (C−H arom, d, J
= 7.8), 7.06 (C−H arom, td, J = 7.4, 1.0), 3.26 (CH2, td, J = 12.0, 2.5),
3.14−3.05 (CH2, mult), 2.87−2.77 (CH2, mult), 2.54−2.40 (CH2,
= 22.5), 56.2 (CH2−N), 52.6 (2CH2−N), 30.6 (2 × CH2), 29.1
(CH2), 28.7 (CH), 20.7 (CH2), 18.4 (CH3). HRMS (ESI) m/z: [M+]
calcd for C16H22FNO, 264.1758; found, 264.1761.
727
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Butyrophenone 2b. The reaction crude was purified by column
chromatography using AcOEt/MeOH (95:5) as an eluent. Isolated
yield: 89.5 mg (72%). Rf (AcOEt/MeOH/NH4OH 95:5:0.5): 0.95. IR
(ν, cm−1): 2932 (l, C−H), 2848 (l, C−H), 2811 (l), 1671 (i, CO),
(100%), 292 (17%), 246 (19%), 220 (12%), 208 (12%), 194 (31%),
165 (76%), 138 (66%), 123 (57%), 110 (24%), 98 (14%). H NMR
1
(δ, ppm; J, Hz): 7.86 (C−H arom, td, J = 7.7, 2.0), 7.54−7.45 (C−H
arom, mult), 7.21 (C−H arom, ddd, J = 7.7, 7.0, 1.1), 7.11 (C−H
arom, ddd, J = 11.4, 8.3, 1.1), 6.70 (N−H, bs), 5.16 (N−H, bs), 2.98
(CH2, td, J = 7.0, 2.82), 2.91−2.81 (CH2, mult), 2.60−2.55 (4CH2,
mult), 2.00−1.69 (3CH2, mult), 1.58−1.49 (2CH2, mult), 1.58−1.38
(CH2, mult). 13C NMR (δ, ppm; J, Hz): 197.9 (CO), 178.6 (H2N−
CO), 163.5 (C, d, J1C−F = 254.7), 134.3 (CH, d, J3C−F = 9.3), 130.6
1
1611 (m), 1594 (l), 914 (vi, N−alC), 745 (vi). H NMR (δ, ppm; J,
Hz): 7.40−7.35 (C−H arom, mult), 7.34−7.29 (C−H arom, mult),
7.09−7.05 (C−H arom, mult), 7.04−6.98 (C−H arom, mult), 3.73−
3.66 (CH2, mult), 3.24−3.12 (2CH2, mult), 2.78−2.66 (CH2, mult),
1.97−1.87 (CH2, mult), 1.78−1.67 (CH2, mult), 1.49−1.23 (C−H +
CH2, mult), 0.98 (CH3, d, J = 6.3). 13C NMR (δ, ppm): 197.2 (CO,
(CH, d, J4C−F = 2.7), 125.8 (C, d, J2C−F = 20.0), 124.3 (CH, d, J4
=
C−F
d, J4
= 2.2), 162.6 (C, d, J1
= 248.1), 138.1 (C, d, J3
= 6.1),
3.3), 116.6 (CH, d, J2
= 23.6), 64.5 (C−N), 57.3 (CH2−N), 50.2
C−F
C−F
C−F
C−F
130.3 (CH, d, J3C−F = 7.1), 123.8 (CH, d, J4C−F = 3.3), 120.3 (CH, d,
(2CH2−N), 47.5 (2CH2−N), 41.1 (CH2, d, J4
= 7.1), 28.7 (2 ×
C−F
J2 = 21.4), 114.5 (CH, d, J2
= 22.5), 56.2 (CH2−N), 52.6
C−F
CH2), 27.0 (2 × CH2), 24.9 (CH2), 21.3 (CH2). 19F NMR (δ, ppm; J,
Hz): −108.78 (mult). HRMS (ESI) m/z: [M+] calcd for
C21H30FN3O2, 376.2395; found, 376.2391.
C−F
(2CH2−N), 30.6 (2 × CH2), 29.1 (CH2), 28.7 (CH), 20.7 (CH2),
18.4 (CH3). HRMS (ESI) m/z: [M − H+] calcd for C16H21FNO,
262.1607; found, 262.1605.
Butyrophenone 3c. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 102 mg (50%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.35. GC-MS (m/z, M+• 410), major peaks found: 391 (1%), 365
(100%), 326 (17%), 280 (14%), 254 (7%), 242 (10%), 228 (24%),
199 (65%), 157 (46%), 138 (79%), 110 (30%), 98 (14%), 84 (12%).
1H NMR (δ, ppm; J, Hz): 8.04 (C−H arom, dd, J = 7.2, 2.2), 7.87
(C−H arom, ddd, J = 8.5, 4.6, 2.2), 7.21 (C−H arom, t, J = 8.5), 6.74
(N−H, bs), 5.19 (N−H, bs), 2.94 (CH2, t, J = 7.0), 2.89−2.80 (CH2,
mult), 2.60−2.40 (4CH2, mult), 2.00−1.95 (CH2, mult), 1.69−1.89
(2CH2, mult), 1.58−1.49 (2CH2, mult), 1.46−1.38 (CH2, mult). 13C
NMR (δ, ppm): 197.0 (CO), 178.6 (H2N−CO), 161.6 (C−F),
Butyrophenone 2c. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:0.5) as an
eluent. Isolated yield: 112 mg (75%). Rf (AcOEt/MeOH/NH4OH
95:5:0.5): 0.55. IR (ν, cm−1): 2949 (i, C−H), 2925 (i, C−H), 2804
(m), 2767 (m), 1688 (vi, CO), 1592 (i), 1492 (i, arC−C), 1457 (m,
−CH2), 1399 (m, −CH3), 1260 (vi), 1247 (vi, arC−F), 1126 (m, N−
1
alC), 1061 (m, arC−Cl), 818 (m). H NMR (δ, ppm; J, Hz): 8.04
(C−H arom, dd, J = 7.2, 2.2), 7.88 (C−H arom, ddd, J = 8.5, 4.5, 2.2),
7.20 (C−H arom, t, J = 8.6), 2.93 (CH2, t, J = 7.1), 2.88−2.79 (CH2,
mult), 2.37 (CH2, t, J = 7.1), 1.98−1.85 (2CH2, mult), 1.62−1.52
(CH2, mult), 1.22−1.06 (CH2, mult), 1.38−1.25 (C−H, mult), 0.89
(CH3, d, J = 6.4). 13C NMR (δ, ppm): 197.5 (CO), 161.1 (C, d,
134.4 (C), 131.0 (CH), 128.4 (CH, d, J3
= 8.2), 121.6 (C−Cl),
C−F
J1
C−F
= 257.4), 134.4 (C, d, J4
= 3.8), 131.0 (CH), 128.4 (CH, d,
C−F
116.5 (CH, d, J2
= 22.0), 64.5 (C−N), 57.1 (CH2−N), 50.2
J3C−F = 8.8), 121.6 (C, d, J2
= 22.2), 116.7 (CH, d, J2
= 21.4),
C−F
(2CH2−N), 47.5 (2CH2−N), 36.1 (CH2), 28.6 (2 × CH2), 27.0 (2 ×
CH2), 24.9 (CH2), 21.5 (CH2). 19F NMR (δ, ppm; J, Hz): −108.17
(mult). HRMS (ESI) m/z: [M − 3H+] calcd for C21H26ClFN3O2,
406.1698; found, 406.1694.
C−F
C−F
57.8 (CH2−N), 53.8 (2CH2−N), 36.3 (CH2), 34.1 (2CH2), 30.8
(CH), 21.8 (CH3), 21.7 (CH2). 19F NMR (δ, ppm; J, Hz): −108.27
(mult). HRMS (ESI) m/z: [M+] calcd for C16H21ClFNO, 298.1368;
found, 298.1364.
Synthesis of the Regioisomers of Ibuprofen (Figure 3, Top).
meta-Ibuprofen 8a. Synthesis of Alkyne 9a. Palladium acetate (40
Pipamperone 3. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 85.0 mg (46%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.33. GC-MS (m/z, M+• 375), major peaks found: 375 (1%), 357
(1%), 331 (100%), 292 (20%), 246 (16%), 220 (7%), 208 (7%), 194
1
(33%), 165 (79%), 138 (64%), 123 (50%), 110 (21%), 95 (9%). H
NMR (δ, ppm; J, Hz): 7.95−7.88 (2C−H arom, mult), 7.05 (2C−H
arom, d, J = 8.7), 6.58 (N−H, bs), 5.82 (N−H, bs), 2.86 (CH2, t, J =
7.2), 2.71−2.61 (CH2, mult), 2.44−2.22 (4CH2, mult), 1.85 (CH2,
quint, J = 7.2), 1.74−1.64 (2CH2, mult), 1.51−1.40 (2CH2, mult),
1.39−1.29 (CH2, mult). 13C NMR (δ, ppm): 198.3 (CO), 178.4
(H2N−CO), 165.4 (C, d, J1C−F = 254.1), 133.5 (C, d, J4C−F = 3.3),
130.5 (2 × CH, d, J3C−F = 8.8), 115.3 (2 × CH, d, J2C−F = 22.0), 64.5
(C−N), 57.4 (CH2−N), 50.3 (2CH2−N), 47.3 (2CH2−N), 36.2
mg, 2 mol %) and SPhos (187 mg, 4.0 mol %) were placed in a 25 mL
round-bottomed flask and anhydrous toluene (10 mL) was added. The
mixture was magnetically stirred at room temperature for 10 min.
Then, the orange solution was added over a mixture of meta-
bromophenyltrimethylsilylacetylene (1.9 mL, 8.8 mmol), isobutylbor-
onic acid (1.08 g, 10.6 mmol, 1.2 equiv), and cesium carbonate (4.3 g,
1.5 equiv) in anhydrous toluene (8 mL), previously weighed in a 50
mL round-bottomed flask, and the final mixture was placed in a
preheated oil bath at 90 °C and magnetically stirred for 18 h. After
cooling, DCM (50 mL) was added, and the mixture was filtered.
Volatiles in the filtrates were removed under reduced pressure, the
resulting crude was redissolved in MeOH (15 mL), and potassium
carbonate was added (7 g, 5 equiv). The mixture was magnetically
stirred at room temperature for 5 h. DCM (20 mL) was added and the
mixture was filtrated and concentrated under reduced pressure.
Purification by column chromatography (hexane) yields the terminal
alkyne 9a. The reaction crude was purified by column chromatography
using n-hexane as eluent. Isolated yield: 736 mg (53%). Rf (n-hexane):
(CH2), 29.1 (2 × CH2), 26.9 (2 × CH2), 24.7 (CH2), 21.9 (CH2). 19
F
NMR (δ, ppm; J, Hz): −105.89 (mult). HRMS (ESI) m/z: [M+] calcd
for C21H30FN3O2, 375.2395; found, 375.2383.
Butyrophenone 3a. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 84.5 mg (45%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.30. 1H NMR (δ, ppm; J, Hz): 7.65 (C−H arom, dt, J = 7.9, 1.1), 7.55
(C−H arom, ddd, J = 9.6, 2.6, 1.7), 7.38 (C−H arom, td, J = 7.9, 5.6),
7.16 (C−H arom, tdd, J = 8.3, 2.6, 1.0), 6.60 (N−H, bs), 5.12 (N−H,
bs), 2.85 (CH2, t, J = 7.1), 2.66−2.54 (CH2, mult), 2.4−2.2 (4CH2,
mult), 1.70−1.57 (2CH2, mult), 1.48−1.25 (4CH2, mult). 13C NMR
(δ, ppm): 198.7 (CO), 178.5 (H2N−CO), 162.6 (C, d, J1
= 7.7), 123.6
C−F
=
C−F
247.5), 139.2 (C, d, J3
= 6.0), 130.0 (CH, d, J3
C−F
(CH, d, J4C−F = 3.3), 119.5 (CH, d, J2C−F = 21.4), 114.5 (CH, d, J2
C−F
= 22.5), 64.3 (C−N), 57.2 (CH2−N), 50.2 (2CH2−N), 47.2 (2CH2−
N), 36.3 (CH2), 29.0 (2 × CH2), 26.8 (2 × CH2), 24.7 (CH2), 21.9
(CH2). 19F NMR (δ, ppm; J, Hz): −112.12 (mult). HRMS (ESI) m/z:
[M+] calcd for C21H30FN3O2, 375.2395; found, 375.2401.
Butyrophenone 3b. The reaction crude was purified by column
chromatography using AcOEt/MeOH/NH4OH (95:5:1) as an eluent.
Isolated yield: 113 mg (60%). Rf (AcOEt/MeOH/NH4OH 95:5:1):
0.50. GC-MS (m/z, M+• 375), major peaks found: 357 (1%), 331
1
0.45. H NMR (δ, ppm; J, Hz): 7.28 (C−H arom, ddd, J = 3.0, 3.1,
9.0), 7.24 (C−H arom, m), 7.16 (C−H arom, dd, J = 3.0, 6.1), 7.65
(C−H arom, ddd, J = 3.1, 6.1, 6.1), 2.98 (CH, s), 2.39 (CH2, d, J =
9.0), 1.80 (CH, m, J = 7.0), 0.84 (CH3, d, J = 6.0). 13C NMR (δ, ppm):
142.0 (C), 132.9 (CH), 129.9 (CH), 129.6 (CH), 128.2 (CH), 121.9
(C), 84.1 (C), 76.8 (CH), 45.2 (CH2), 30.2 (CH), 22.4 (CH3).
HRMS (ESI) m/z: [M+] calcd for C12H14, 158.1096; found, 158.1100.
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Research Article
Synthesis of Ketone 10a. AuSPhosNTf2 (47.6 mg, 2 mol %) was
placed in a 25 mL round-bottomed flask and methanol (5 mL) was
added. Then, the terminal alkyne 9a (420 mg, 2.7 mmol) and water
(140 μL, 3 equiv) were added and the mixture was magnetically stirred
at room temperature overnight. Direct purification by column
chromatography (3−5% AcOEt in hexane) yields the corresponding
ketone 10a. The reaction crude was purified by column chromatog-
raphy using as eluent 3−5% AcOEt in n-hexane. Isolated yield: 451 mg
1
(95%). Rf (5% AcOEt in n-hexane): 0.38. H NMR (δ, ppm; J, Hz):
7.87 (C−H arom, m), 7.84 (C−H arom, mult), 7.45 (C−H arom, dd,
J = 6, 1), 7.43 (C−H arom, m), 2.68 (CH3, s), 2.625 (CH2, d, J = 3),
1.98 (CH, m, J = 6.1), 1.00 (CH3, 1.00, J = 6). 13C NMR (δ, ppm):
198.3 (CO), 142.2 (C), 137.1 (C), 134.012 (CH), 128.7 (CH),
128.3 (CH), 125.9 (CH), 45.2 (CH2), 30.2 (CH), 22.3 (CH3). HRMS
(ESI) m/z: [M+] calcd for C12H16O, 176.1201; found, 176.1213.
Synthesis of Carboxylic Acid 8a. TiCl4 (439 μL) was dissolved in
anhydrous DCM (40 mL). A part of this solution (4.5 mL, 40 mol %)
was added over a preformed solution of the ketone 10a (250 mg, 1.4
mmol) in anhydrous DCM (3 mL) after adding TMSCN (211 μL, 1.2
equiv). The mixture was magnetically stirred at room temperature for
24 h. After the solvent was removed under reduced pressure, the
mixture was redissolved in a 1:1 (v/v) solution of HCl (3 M) and
acetonitrile (7 mL) and stirred for 1 h. Then, the mixture was
concentrated under reduced pressure, diluted with water (15 mL), and
extracted with AcOEt (3 × 25 mL). The combined organic phases
were washed with brine (15 mL), dried over MgSO4, filtrated, and
evaporation of the solvent gave an inseparable mixture (same Rf
values) of the cyanohydrin product and minor amounts of the starting
toluene (5 mL). Then, the above alkyne mixture, isobutylboronic acid
(1.2 g, 12 mmol), cesium carbonate (3.9 g, 1.5 equiv), and anhydrous
toluene (25 mL) were added, and the final mixture was placed in a
preheated oil bath at 90 °C and magnetically stirred for 18 h under
nitrogen atmosphere. After the sample was cooled, DCM (50 mL) was
added, and the mixture was filtered. Volatiles in the filtrates were
removed under reduced pressure, the resulting crude was redissolved
in MeOH (15 mL), and potassium carbonate was added (7 g). The
mixture was magnetically stirred at room temperature for 5 h. DCM
(20 mL) was added, and the mixture was filtrated and concentrated
under reduced pressure. The reaction crude was purified by column
chromatography using as eluent 3−5% n-hexane. Isolated yield: 461
mg (37%). Rf (n-hexane): 0.26. 1H NMR (δ, ppm; J, Hz): 7.58 (C−H
arom, dt, J = 1.2, 7.4), 7.34 (C−H arom, m), 7.24 (C−H arom, m),
3.31 (C−H, s), 2.79 (CH2, d, J = 7.25), 2.11 (CH, m), 1.04 (CH3, d, J
= 6.8). HRMS (ESI) m/z: [M+] calcd for C12H14, 158.1096; found,
158.1088.
1
ketone. H NMR (δ, ppm; J, Hz): 7.26 (C−H arom, m), 7.06 (C−H
arom, dt, J = 7.5, 1.4), 3.65 (OH, bs), 2.42 (CH2, d, J = 7.2), 1.78 (CH,
m), 1.78 (CH3, s), 0.81 (CH3, d, J = 6.6). 13C NMR (δ, ppm): 142.7
(C), 140.7 (C), 137.1 (C), 129.9 (CH), 128.7 (CH), 125.2, 121.9 (C),
121.8 (CH), 70.8 (C), 45.4 (CH2), 30.3 (CH), 22.3 (CH3), 22.4
(CH3). Aqueous HI (57 wt %, 400 μL) was added to the mixture (40
mg, 0.2 mmol) in a sealable vial, and the mixture was magnetically
stirred in a preheated oil bath at 100 °C for 4 h. Alternatively,
potassium iodide (333 mg, 2 mmol) and H3PO4 (85 wt % in water,
205 μL, 3 mmol) can be used instead of HI, at 135 °C reaction
temperature. After they were cooled, organics were extracted with
DCM (5 × 4 mL), and the combined organic phases were washed with
NaHCO3 saturated aqueous solution (20 mL), water (20 mL), and
brine (20 mL). After the samples were dried over MgSO4, filtrated,
and the solvent was evaporated, purification on preparative TLC (20%
AcOEt in hexane) gave the meta-ibuprofen derivative 8a. Rf (75%
AcOEt in hexane) = 0.75. The reaction crude was purified by column
chromatography using 75% AcOEt in n-hexane as eluent. Isolated yield
over two steps: 24.0 mg (58%). Rf (75% AcOEt in n-hexane) = 0.75.
1H NMR (δ, ppm; J, Hz): 7.16 (C−H arom, t, J = 7.5), 7.06 (C−H
arom, dt, J = 7.22, J = 1.55), 6.99 (C−H arom, m), 3.64 (CH, c, J =
7.15), 2.39 (CH2, d, J = 7.14), 1.78 (CH, m), 1.44 (CH3, d, J = 7.17),
0.82 (CH3, d, J = 6.6). 13C NMR (δ, ppm; J, Hz): 199.6 (C−OOH),
142.3 (C), 139.7 (C), 128.5 (CH), 128.6 (CH), 128.3 (CH), 124.9
(CH), 45.5 (CH2), 45.3 (CH), 30.3 (CH), 22.5 (CH3), 18.3 (CH3).
HRMS (ESI) m/z: [M+] calcd for C13H18O2, 206.1307; found,
206.1319.
Synthesis of Ketone 10b. AuSPhosNTf2 (57.1 mg, 4 mol %) was
placed in a 25 mL round-bottomed flask, and methanol (5 mL) was
added. Then, the terminal alkyne 9b (288 mg, 1.6 mmol) and water
(84 μL, 3 equiv) were added, and the mixture was magnetically stirred
at room temperature overnight. The reaction crude was purified by
column chromatography using as eluent 3−5% AcOEt in n-hexane.
Isolated yield: 194 mg (69%). Rf (n-hexane): 0.40. GC-MS (m/z, M+•
176), major peaks found: 176 (100%), 161 (100%), 133 (90%), 119
1
(32%), 91 (56%), 43 (75%). H NMR (δ, ppm; J, Hz): 7.58 (C−H
arom, dd, J = 1.5, 7.7), 7.32 (C−H arom, td, J = 1.5, 7.7), 7.32 (C−H
arom, dd, J = 1.5, 7.7), 2.73 (CH2, d, J = 7.1), 2.52 (CH3, s), 1.79
(CH2, m), 0.86 (CH3, d, J = 6.7). 13C NMR (δ, ppm): 202.4 (CO),
141.46 (C), 138.5 (C), 132.0 (CH), 130.9 (CH), 128.9 (CH), 125.7
(CH), 42.7 (CH2), 30.3 (CH), 30.1 (CH3), 22.5 (CH3). HRMS (ESI)
m/z: [M+] calcd for C12H16O, 176.1201; found, 176.1225.
Synthesis of Carboxylic Acid 8b. TiCl4 (439 μL) was dissolved in
anhydrous DCM (40 mL). A part of this solution (6.4 mL, 80 mol %)
was added over a preformed solution of the ketone 10b (198 mg, 1
mmol) in anhydrous DCM (2 mL) after adding TMSCN (151 μL, 1.2
equiv). The mixture was magnetically stirred at room temperature for
24 h. After the solvent was removed under reduced pressure, the
mixture was redissolved in a 1:1 (v/v) solution of HCl (3 M) and
acetonitrile (5 mL) and stirred for 1 h. Then, the mixture was
concentrated under reduced pressure, diluted with water (10 mL), and
extracted with AcOEt (3 × 20 mL). The combined organic phases
were washed with brine (10 mL), dried over MgSO4, filtrated, and
evaporation of the solvent gave an inseparable mixture (same Rf
values) of the cyanohydrin product and minor amounts of the starting
ortho-Ibuprofen 8b. Synthesis of Alkyne 9b. PdCl2(PPh3)2 (745
mg, 5 mol %) and copper iodide (405 mg, 10 mol %) were placed in a
100 mL round-bottomed flask equipped with a magnetic bar and then
anhydrous THF (13 mL), the dibromide (2.7 mL, 21.3 mmol),
trimethylsilylacetylene (3.24 mL, 21.3 mmol), and triethylamine (13.5
mL) were added. The flask was capped with a rubber septum, and the
resulting mixture was placed in a preheated oil bath at 60 °C and
magnetically stirred overnight. One aliquot was taken for GC analysis,
and the rest was diluted in diethyl ether (100 mL) after cooling. The
solids were removed by filtration, and the resulting solution was
purified by column chromatography to yield 2.0 g of the alkyne
product (37%) with minor amounts of the corresponding bis-alkyne.
Then, palladium acetate (66 mg, 5 mol %) and SPhos (246 mg, 10 mol
%) were placed in a 25 mL round-bottomed flask and magnetically
stirred at room temperature for 10 min after addition of anhydrous
1
ketone. H NMR (δ, ppm; J, Hz): 7.44 (C−H arom, m), 7.28 (C−H
arom, m), 7.18 (C−H arom, m), 7.10 (C−H arom, m), 2.88 (CH2, dd,
J = 7.4, 8.5), 2.31 (CH3, s), 2.13 (CH, m), 0.93 (CH3, dd, J = 6.6,
10.9). 13C NMR (δ, ppm): 142.7 (C), 140.7 (C), 137.1 (C), 129.9
(CH), 128.7 (CH), 125.2, 121.9 (C), 121.8 (CH), 70.8 (C), 45.4
(CH2), 30.3 (CH), 22.3 (CH3), 22.4 (CH3). Aqueous HI (57 wt %,
200 μL) was added to the mixture (20 mg, 0.1 mmol) in a sealable vial,
and the mixture was magnetically stirred in a preheated oil bath at 100
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ACS Catalysis
Research Article
°C for 2−4 h. After the samples were cooled, organics were extracted
with DCM (5 × 4 mL), and the combined organic phases were washed
with NaHCO3 saturated aqueous solution (10 mL), water (10 mL),
and brine (10 mL). Alternatively, solid NaHCO3 (67 mg) can be
added before extracting. After the samples were dried over MgSO4,
they were filtrated, and the solvent was evaporated. Purification on
preparative TLC (20% AcOEt in n-hexane) gives a two-step combined
yield of 47% (9.7 mg) of the ortho-ibuprofen derivative 8b. Rf (25%
AcOEt in n-hexane): 0.32. GC-MS (m/z, M+• 206), major peaks
found: 206 (43%), 164 (14%), 133 (28%), 117 (100%), 105 (18%), 91
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Severo Ochoa program and
Consolider-Ingenio 2010 (proyecto MULTICAT) from
MCIINN is acknowledged, and also to the King Saud
University. A.L.-P. thanks ITQ for a contract. J.R. C.-A. and
P.R.M. thank MCIINN for the concession of a FPU contract.
1
(31%). H NMR (δ, ppm; J, Hz): 7.24 (C−H arom, m), 7.11 (C−H
arom, dt, J = 8.1, 1.2), 7.09 (C−H arom, d, J = 14.1), 7.05 (C−H
arom, m), 3.94 (CH, d, J = 7.1), 2.49 (CH2, m), 1.79 (CH2, m), 1.39
(CH3), 0.86 (CH3, d, J = 6.7). 13C NMR (δ, ppm): 180.3 (COOH),
139.2 (C), 138.4 (C), 133.8 (CH), 126.8 (CH), 126.8 (CH), 126.5
(CH), 42.3 (CH2), 40.3 (CH), 29.9 (CH), 22.6 (CH3), 18.6 (CH3).
HRMS (ESI) m/z: [M+] calcd for C13H18O2, 206.1307; found,
206.1328.
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■
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1
(17%), 28 (25%). H NMR (δ, ppm, acetone-d6; J, Hz): 7.78 (C−H
arom, dd, J = 7.4, 2.2), 7.28 (C−H arom, ddd, J = 8.5, 4.5, 2.2), 6.89
(C−H arom, dd, J = 10.7, 8.5), 4.02 (CO2H, bs), 2.22 (CH2, t, J =
6.8), 1.43−1.24 (2 CH2, m), 1.31 (CH3, t, J = 7.2). 13C NMR (δ, ppm,
acetone-d6): 171.9 (CO2H), 162.6 (C, d, J1C−F = 256.3), 143.0 (CH),
137.3 (CH, d, J3C−F = 10.9), 125.4 (C−CO2H, d, J2C−F = 10.9), 121.5
(C, d, J4
= 3.8), 118.3 (CH, d, J2
= 24.2), 91.7 (Calkyne), 80.8
C−F
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C−F
(Calkyne), 32.4 (CH2), 23.5 (CH2), 20.2 (CH2), 14.8 (CH3). 19F NMR
(δ, ppm; J, Hz): 65.12 (s). This internal alkyne was then submitted to
hydration conditions by heating a solution in 1,4-dioxane with HNTf2
in a preheated oil bath at 100 °C, under magnetic stirring for 18−52 h
and following the formation of ketone 12 by GC and GC-MS, using
dodecane as an external standard. GC-MS (m/z, M+• 238), major
peaks found: 238 (2%), 195 (4%), 182 (89%), 167 (100%), 139
1
(13%), 83 (13%). H NMR (δ, ppm, acetone-d6; J, Hz): 8.48−8.32
(C−H arom, mult), 8.15−8.07 (C−H arom, mult), 7.28−7.17 (C−H
arom, mult), 4.74 (CO2H, bs), 2.92 (CH2, t, J = 7.2), 1.66−1.55 (CH2,
mult), 1.33−1.18 (2 CH2, mult), 0.83 (CH3, t, J = 7.0). 19F NMR (δ,
ppm; J, Hz): −82.15 (s). HRMS (ESI) m/z: [M+] calcd for
C13H15FO3, 238.1005; found, 238.1001.
́
ez, A.; Corma, A. Chem.
ASSOCIATED CONTENT
* Supporting Information
■
S
General and experimental procedures, compound character-
ization, binding assays, and copies of the NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Smith-Torhan, A.; Fawzi, A.; Lachowicz, J. Bioorg. Med. Chem. Lett.
2006, 16, 4548−4553.
AUTHOR INFORMATION
Corresponding Author
*E-mail: anleyva@itq.upv.es (A.L.-P.), acorma@itq.upv.es
(A.C.). Fax: +349638 77809. Tel.: +34963877800.
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
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