Head-to-Tail Dimerization of 4-Fluoroacetophenone in the KOH/DMSO Superbase Suspension and Related SNAr Reaction

Article abstract of DOI:10.1002/ejoc.202000454

The head-to-tail autocondensation of 4-fluoroacetophenone in the KOH/DMSO superbase suspension stops on dimerization step affording 4-acetylbenzyl-4'-fluorophenylketone in 96 % yield. Further condensation of the diketone formed is prevented by a weaker electron-withdrawing effect of enolate spacer, –CH=C(OK)–. 2-Fluoro- and 3-fluoroacetophenones are inactive in this reaction. Other superbases of the type MOR/DMSO (M = Na, K; R = H, OBu^t) are inferior in promotion of this reaction providing 71–76 % yields of the dimeric ketone. Other weak acids like non-fluorinated acylbenzenes prove to be also capable of forming Csp²–Csp³ bond with 4-fluoroacetophenone under similar conditions. This new group of fluorine substitution (S_NAr) reaction opens a short and simple route to so far inaccessible aromatic diketones via the nucleophilic substitution of fluorine atom in 4-fluoroacetophenone by available acylbenzenes. The quantum-chemical rationale of the observed substitution process as competing with aldol condensation is suggested.

Full text of DOI:10.1002/ejoc.202000454

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Head-to-Tail Dimerization of 4-Fluoroacetophenone in the KOH/
DMSO Superbase Suspension and Related SNAr Reaction
Authors: Ivan A. Bidusenko, Elena Yu. Schmidt, Igor’ A. Ushakov,
Vladimir B. Orel, Damir Z. Absalyamov, Nadezhda M.
Vitkovskaya, and Boris A. Trofimov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000454
Link to VoR: https://doi.org/10.1002/ejoc.202000454
01/2020

10.1002/ejoc.202000454
European Journal of Organic Chemistry
FULL PAPER
Head-to-Tail Dimerization of 4-Fluoroacetophenone in the
KOH/DMSO Superbase Suspension and Related SNAr Reaction
Ivan A. Bidusenko,[a] Elena Yu. Schmidt,[a] Igor’ A. Ushakov,[a] Vladimir B. Orel,[b] Damir Z.
Absalyamov,[b] Nadezhda M. Vitkovskaya,[b] and Boris A. Trofimov*[a]
[a]
[b]
Dr. Ivan A. Bidusenko, Dr. Elena Yu. Schmidto, Dr. Igor’ A. Ushakov, Prof. Dr. Boris A. Trofimov
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences
1 Favorsky St., 664033 Irkutsk, Russian Federation
E-mail: boris_trofimov@irioch.irk.ru
Dr. Vladimir B. Orel, Damir Z. Absalyamov, Prof. Dr. Nadezhda M. Vitkovskaya
Laboratory of Quantum Chemistry
Irkutsk State University
1 K. Marks St., 664003 Irkutsk, Russian Federation
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
Abstract:
The
head-to-tail
autocondensation
of
4-
30)[8] consisting of alkaline metal hydroxide or alkoxide and
complexing strong polar solvents (DMSO, DMF, HMPA and the
like),[1] which separate the ion pairs thereby increasing
concentration and basicity of carbanions.
A promising contribution to SNAr reactions leading to new
Csp2-Csp3 bonds could be introducing in this area a group of
monofluorinated arenes containing weaker (compared to NO2)
activating groups such as acyl substituents, which might
simultaneously provide carbanionic centers in the superbase
media. These mutually inwardly activated species could
participate in the head-to-tail autocondensation to render the
synthesis of aromatic oligo (di-, tri- or higher) ketones with active
methylene carbonyl (enolate) spacer terminated by acyl and
fluorine substituents (Scheme 1).
fluoroacetophenone in the KOH/DMSO superbase suspension stops
on dimerization step affording 4-acetylbenzyl-4′-fluorophenylketone
in 96% yield. Further condensation of the diketone formed is
prevented by a weaker electron-withdrawing effect of enolate spacer,
–CH=C(OK)–. 2-Fluoro- and 3-fluoroacetophenones are inactive in
this reaction. Other superbases of the type MOR/DMSO (M = Na, K;
R = H, OBut) are inferior in promotion of this reaction providing 71-
76% yields of the dimeric ketone. Other weak acids like non-
fluorinated acylbenzenes prove to be also capable of forming Csp2–
Csp3 bond with 4-fluoroacetophenone under similar conditions. This
new group of fluorine substitution (SNAr) reaction opens a short and
simple route to so far inaccessible aromatic diketones via the
nucleophilic substitution of fluorine atom in 4-fluoroacetophenone by
available acylbenzenes. The quantum-chemical rationale of the
observed substitution process as competing with aldol condensation
is suggested.
Introduction
The close attention of organic chemists to aromatic nucleophilic
substitution (SNAr reaction) is not faded over the years.[1] The
SNAr reactions are commonly recognized as central to organic
chemistry.[2] Most often, in these reactions, the leaving groups
are halogens, first of all, fluorine atom.[1,3] Such reactions are
known to proceed especially smoothly for perfluoroarenes and
aromatic compounds with strong electron-withdrawing
substituents such as NO2, CF3SO2. The activating effect of other
electron-accepting groups (like CN, CF3, COR, etc.) for
substitution of halogen in ArX is insufficient.[1] Despite the
outward simplicity, these reactions feature complex and
divergent mechanisms.
Of special synthetic and theoretical importance are SNAr
reactions leading to the formation of new Csp2–Csp3 bonds.
Among the known methods to bring about these types of SNAr
reactions are the metal-catalyzed/mediated C–F bond
activation,[4] and employment of organometallic reagents[5] as a
source of nucleophiles. Another approach represents base-
promoted reactions of fluoroarenes (mainly, polyfluoroarenes)[6]
having strong electron-accepting substituents like NO2 groups
(most often, several ones),[7] with C-H acids.[1] In the latter
reactions, a pivotal role belongs to the superbase media (pKa ~
Scheme 1. Head-to-tail autocondensation of 4-fluoroacetophenone 1a in the
KOH/DMSO system.
Results and Discussion
Our first trial of this assumption with 4-fluoroacetophenone 1a
(KOH/DMSO, 60 oC, 0.5 h) gave optimistic 36% yield of the
expected diketone 2a (Scheme 1). Encouraged by this result, we
have scrutinized the reaction to examine the effect of
temperature and time on the yield of diketone 2a (Table 1).
Finally, we managed to reach 96% yield of the target product
o
(KOH/DMSO, 80 C, 2 h, entry 6). Other superbase media such
as KOBut, NaOH, NaOBut also promote SNAr reaction, though
with somewhat less efficiency securing 71-76% yields of
diketone 2a (entries 7-9).
1
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10.1002/ejoc.202000454
European Journal of Organic Chemistry
FULL PAPER
diketone 2e, in 56% yield, that is expectedly lower than for the
corresponding fluorine analog (Scheme 4). Consequently, 4-
bromoacetophenone 1f was completely recovered from the
reaction mixture.
Table 1. Synthesis of diketone 2a by dimerization of 4-fluoroacetophenone 1a
in MOR/DMSO superbase media.[a]
Conversion
Yield of 2a
Entry
MOR
T (oC)
t (h)
of 1a (%)[b]
(%)[c]
1
2
3
4
5
6
7
8
9
KOH
KOH
40
60
80
100
80
80
80
80
80
0.5
0.5
0.5
0.5
1
3
traces
36
37
KOH
69
68
KOH
90
54
KOH
91
89
KOH
2
100
85
96
NaOH
NaOBut
KOBut
2
71
2
100
100
76
2
72
Scheme 4. Reactions of ketones 1e and 1f in the KOH/DMSO system.
[a] Reaction conditions: 1a (1 mmol, 138 mg), MOR (1 mmol), DMSO (4 mL).
[b] Conversion was determined by 1H NMR spectroscopy of the crude reaction
mixtures. [c] Isolated yield after column chromatography (SiO2, n-hexane/ethyl
acetate).
Next, the possibility of replacement of fluorine atom in 4-
fluroacetophenone 1a by non-fluorinated acylbenzenes as
sources of carbanions has been investigated. For the
optimization, the reaction of 1a with acetophenone 1g was
chosen. The reactant molar ratio (1a:1g), order of the reactant
mixing, and time were varied (Table 2).
In the case of 4-fluoropropiophenone 1b, the yield of the
corresponding diketone 2b was considerably lower (27%,
Scheme 2), likely due to a weaker CH acidity of the propionyl
substituent and steric hindrance to the substitution.
Table 2. Optimizing the conditions of the SNAr reaction of 4-fluroacetophenone
1a with acetophenone 1g.[a]
Scheme 2. Head-to-tail autocondensation of 4-fluoropropiophenone 1b in the
KOH/DMSO system.
2a:2g
Reaction
conditions
Yield of
Entry
1a:1g[b]
t (h)
Molar
2g (%)[c]
ratio[b]
1
2
3
4
5
6
7
8
A
A
A
A
B
B
B
B
1:1
1:2
2
2
2
2
2
4
6
2
52:48
33:67
29:71
68:32
40:60
26:74
28:72
22:78
36
47
48
18
54
50
42
67
Notably
that
2-fluoroacetophenone
1c
and
3-
fluoroacetophenone 1d turned out to be inactive relative to the
major reaction (no traces of the target products were detected).
Instead, with 3-fluoroacetophenone 1d, inseparable mixture of
products was formed. However, from the reaction mixture with
1c, two unexpected products 3 and 4 were isolated in 16 and
11% yields, respectively (Scheme 3). They are likely resulted
from aldol crotonic condensation, solvolysis and intramolecular
cyclization.
1:3
2:1
1:1
1:1
1:1
1:1.5
[a] Reaction conditions A: 1a (1 mmol, 138 mg), 1g (1 or
3 mmol),
KOH×0.5H2O (2 mmol, 130 mg), DMSO (8 mL), 80 oC, 2 h. Reaction
conditions B: 1a (1 mmol, 138 mg) in DMSO (1 mL) was added dropwise to a
mixture of 1g (1 or 1.5 mmol), KOH×0.5H2O (2 mmol, 130 mg) in DMSO (7
mL) at 80 oC. [b] Determined by 1H NMR spectroscopy of the crude reaction
mixtures. [c] Isolated yield after column chromatography (SiO2, n-hexane/ethyl
acetate).
o
For 1:1 molar ratio of 1a:1g (80 C, 2h), a 52:48 mixture of
diketones 2a and 2g was obtained (entry 1). The increasing
acetophenone 1g loading up to three-fold molar excess relative
to 1a (entry 3), and slow adding of 4-fluroacetophenone 1a to
the reaction mixture (entry 5), allowed shifting the ratio towards
diketone 2g up to 71 and 60%, after separation of the mixture,
the yield of pure 2g being 48 and 54%, respectively. The
increased loading (2-fold excess) of 4-fluroacetophenone 1a
expectedly reduces the yield of diketone 2g (18%, entry 4). The
best result (67% yield of 2g) was obtained using 1.5 eq. of
Scheme 3. Reactions of ketones 1c and 1d in the KOH/DMSO system
In accordance with commonly recognized reactivity profile of
aromatic nucleophilic substitution,[9] 4-chloroacetophenone 1e
delivered the corresponding head-to-tail autosubstitution product,
2
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10.1002/ejoc.202000454
European Journal of Organic Chemistry
FULL PAPER
acetophenone 1g and drop-wise adding of 4-fluroacetophenone
1a to the reaction mixture (entry 8).
Under these conditions, the substrate scope of
acylbenzenes 1 has been roughly estimated (Table 3).
From the mechanistic point of view, the synthesis studied is
a regular SNAr process (as it can be judged from normal halogen
substituent effect, F > Cl > Br), albeit with atypical substitution
patterns. Indeed, the key substrate 1a contains acetyl
substituent commonly considered as not strong enough to
promote substitution of a halogen in the aromatic ring.[1] Also,
monofluorinated aromatic compounds are usually not so active
substrates in SNAr reactions as polyfluorinated ones.[1] The
combination of these two different in electronic demand
substitution entities in a one molecule, a kind of chemical
centaur, provides a possibility for polycondensation of the head-
to-tail type. However, although this process did take place it is
selectively interrupted on the dimerization step indicating that
initial mutual inward activation of the acetyl substituent and
fluoro-substituted carbon center does not any longer work after
formation of dimer 2a. Apparently, such an unexpected behavior
takes place in enolization of -CH=C(OK)- spacer (Scheme 1),
which in its anionic form lacks its ability to activate the C-F bond
towards the nucleophilic attack. Another puzzle of this reaction is
why CH2 group of this spacer does not participate in further
nucleophilic substitutions being definitely more CH acidic than
the acetyl substituent. Most likely, this is a result of the steric
screening by hydrogen atom of neighboring phenyl substituents.
Table 3. Substrate scope for SNAr reaction of 4-fluroacetophenone 1a with
acetylaromatics 1.
Yield
Acetylaromatic 1
Product 2
2a:2[b]
of 2
(%)[c]
22:78
67
42
1g
1h
2g
2h
25:75
The
quantum-chemical
rationale
((B2PLYP/6-
311+G**//B3LYP/6-31+G*, see Supplementary Material for
computational details) allow understanding why the observed
SNAr reaction wins the competition with probable aldol
condensation.
From the energy profiles of SNAr and aldol reactions of 4-
fluroacetophenone 1a in KOH/DMSO medium (Figure 1), it
follows that while the aldol reaction of ketone requires a lower
activation energy (G‡ = 16.4 kcal/mol) than the SNAr reaction
(G‡ = 21.8 kcal/mol), the formation of diketone 2a is more
thermodynamically favorable (Table S1 in the Supplementary
Material). The reversibility of the aldol reaction is a cause of
almost quantitative conversion of ketone 1a into the target
diketone 2a. Notably, the subsequent substitution of the fluorine
atom in 2a by methylene carbanionic species B, generated from
the diketone 2a, requires a higher (by 4.2 kcal/mol) activation
energy than a similar substitution in the starting ketone 1a by
anion A. Thus, further SNAr reactions stop at the step of the
formation of diketone 2a and the subsequent chain growth does
not occur.
32:68
24:76
48
37
1i
1j
2i
2j
[a] Reaction conditions: 1a (1 mmol, 138 mg) in DMSO (1 mL) was added
dropwise to a mixture of 1 (1.5 mmol) and KOH×0.5H2O (2 mmol, 130 mg) in
DMSO (7 mL) at 80oC for 2 h. [b] Molar ratio. [c] Isolated yield after column
chromatography (SiO2, n-hexane/ethyl acetate, 9:1).
The pure target diketones 2g-j were obtained in 37-67%
isolated yield, along with fluoroterminated ketone 2a. In all the
cases, the mixtures were separated by the column
chromatography. As follows from Table 3 data, the reaction
tolerates different acetylated aromatic derivatives including
benzene, biphenyl, 1,4-diacetylbenzene and naphthalene. It is
understood that the real scope of the reaction is not exhausted
by the selected examples here presented. Certainly, for each
aromatic substrate a special finer optimization is required.
Essentially, the second component of the product mixtures, i.e.
diketone 2a, is also
a synthetically valuable compound.
Noteworthy, fluorobenzene, when reacted with acetophenone 1g
under the above standard conditions, did not form any
substitution products. In fact, we have developed an efficient
method (total yields of 2a + 2g-j are near to quantitative ones)
for simultaneous preparation of so far inaccessible, but highly
promising as building blocks for organic synthesis, aromatic
diketones.
Figure 1. Scheme of energy profiles of SNAr and aldol reactions of 4-
fluroacetophenone 1a
3
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10.1002/ejoc.202000454
European Journal of Organic Chemistry
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Next, we estimated the effect the fluorine atom in different
positions of the benzene ring on the activation energy of the
SNAr reaction. For 3-fluoroacetophenone 1d, the activation
energy is 28.0 kcal/mol that is considerably higher than for 4-
fluoro- (1a) and even 4-chloro (1e) derivatives (21.8 kcal/mol
and 24.2 kcal/mol, respectively). This explains the absence of
substitution products for substrate 1d.
Experimental Section
General information. 1Н (400.1 MHz) and 13С (100.6 MHz) NMR
spectra were recorded on a Bruker AV400 instrument in СDCl3. The 1H
and 13C chemical shifts (δ) were referenced to HMDS (0.05 ppm and 2.0
respectively). Coupling constants (J) in hertz (Hz) were measured from
one-dimensional spectra and multiplicities were abbreviated as following:
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). The chemical
shifts were recorded in ppm. IR spectra were taken with FT-IR. The MS
spectra were measured on a Shimadzu GCMS-QP5050A spectrometer.
Melting points (uncorrected) were measured on a Kofler micro hot-stage
apparatus. The microanalyses were performed on a Flash EA 1112
Series elemental analyzer. Thin layer chromatography was carried out on
Merck silica gel 60 F254 pre-coated aluminium foil sheets (eluent:
Et2O/hexane = 1 : 3) and were visualized using UV light (254 nm).
Column chromatography was carried out using slurry packed Sigma
Aldrich silica gel (SiO2), 70-230 mesh, pore size 60 Å (eluent: ethyl
acetate/hexane). Ketones and all other chemicals and solvents are
commercially available and were used without further purification.
Synthesis of diketones 2a,b,e: A mixture of ketone 1 (1.0 mmol) and
KOH×0.5H2O (1.0 mmol, 65 mg) in DMSO (4 mL) was stirred at 80°C for
2 h. The reaction mixture was diluted with water (10 mL) and extracted
with Et2O (1 mL × 7). The combined organic extracts were washed with
water (1 mL × 3) and dried over K2CO3 for 1 h. Et2O was evaporated
under reduced pressure, and the residue was purified by column
chromatography [SiO2, eluent: ethyl acetate/hexane = 1:9].
Figure 2. Scheme of energy profiles of SNAr and aldol reactions for 2-
fluoroacetophenone 1c
2-(4-Acetylphenyl)-1-(4-fluorophenyl)ethan-1-one (2a) was prepared
from 1a (1.0 mmol, 138 mg). 2a was isolated as a colorless solid (0.48
mmol, 123 mg, 96%); m.p. 125-126°C. Elemental analysis calcd (%) for
C16H13FO2 (256.272): C, 74.99; H, 5.11; F, 7.41; found: C, 74.69; H, 5.05;
F, 7.50. IR (film): νmax 3107, 3066, 3051, 3020, 2965, 2920, 2890, 2852,
1688, 1679, 1650, 1599, 1573, 1508, 1438, 1424, 1411, 1362, 1339,
1311, 1299, 1268, 1238, 1216, 1201, 1184, 1157, 1110, 1097, 1076,
1020, 999, 960, 926, 871, 839, 816, 756, 696, 669, 637, 629, 607, 593,
565, 495, 486, 466. 1H NMR: δ 8.05–7.99 (m, 2H, Ho), 7.94–7.90 (m, 2H,
Hmʹ), 7.37–7.30 (m, 2H, Ho'), 7.16–7.10 (m, 2H, Hm), 4.31 (s, 2H, H2),
2.57 (s, 3H, Me). 13C NMR: δ 197.8 (C1'), 195.2 (C1), 165.9 (d, 1J =
The energy profile (Figure 2) for the aldol reaction of 2-
fluoroacetophenone 1c (as well as for 1a) shows a lower
activation energy than that for the corresponding head-to-tail
SNAr reaction (16.6 kcal/mol vs 23.7 kcal/mol). However, in the
aldol reaction, intramolecular cyclization of intermediate C (G‡
= 22.4 kcal/mol relative to starting 1c and its carbanion) leads to
thermodynamically stable products 3 (H = -34.9 kcal/mol) and 4
(H = -45.0 kcal/mol).
4
255.5 Hz, Cp), 139.9 (Ci'), 135.9 (Cp'), 132.8 (d, J = 2.5 Hz, Ci), 131.2
(d, 3J = 9.4 Hz, Co), 129.8 (Co'), 128.7 (Cm'), 115.9 (d, 2J = 21.9 Hz, Cm),
45.2 (C2), 26.6 (Me). MS (EI): m/z calcd for C16H13FO2: 256.09 [M]+•,
found 256.16.
Conclusion
In conclusion, we have found the head-to-tail nucleophilic
dimerization of 4-fluoroacetophenone in the KOH/DMSO
1-(4-Fluorophenyl)-2-(4-propionylphenyl)propan-1-one
(2b)
was
prepared from 1b (1.0 mmol, 152 mg). 2b was isolated as a colorless
solid (0.13 mmol, 38 mg, 27%), conversion of ketone 1b 29%; m.p. 93-
94°C. Elemental analysis calcd (%) for C18H17FO2 (284.325): C, 76.04, H,
6.03, F, 6.68; found: C, 74.40, H, 6.00, F, 2.33. IR (film) νmax 3069, 2979,
2935, 2880, 1683, 1600, 1505, 1454, 1412, 1347, 1226, 1184, 1158,
1094, 1066, 1009, 952, 851, 803. 1H NMR: δ 7.96–7.91 (m, 2H, Ho),
7.90–7.86 (m, 2H, Hm'), 7.37–7.32 (m, 2H, Ho'), 7.07–7.01 (m, 2H, Hm),
superbase
suspension
to
afford
4-acetylbenzyl-4’-
fluorophenylketone in 96% yield. This synthesis represents an
atypical case of aromatic nucleophilic substitution wherein the
substrate consists of two different in chemical nature
substituents. The mutual inward activation of these opposite
functionalities (nucleophilic and electrophilic) smooth this SNAr
process despite a weak acceptor effect of the acetyl group and
lower reactivity of the C-F bond in monofluorinated aromatic
compounds as compared to polyfluorinated ones. The above
substrate has been proved to be a universal basic starting
compound for the synthesis of aromatic diketones by its reaction
with various acyl aromatics. The preference of the observed
SNAr process over the competing aldol condensation has been
rationalized using quantum-chemical calculations (B2PLYP/6-
311+G**//B3LYP/6-31+G*).
3
4.68 (q, 3J = 6.8 Hz, 1H, H2), 2.93 (q, J = 7.2 Hz, 2H, H2'), 1.53 (d, 3J =
3
6.8 Hz, 3H, H3), 1.18 (t, J = 7.2 Hz, 3H, H3'). 13C NMR: δ 200.3 (C1'),
198.1 (C1), 165.7 (d, 1J = 255.2 Hz, Cp), 146.5 (Ci'), 135.9 (Cp'), 132.7
4
3
(d, J = 2.9 Hz, Ci), 131.5 (d, J = 9.3 Hz, Co), 128.9 (Cm'), 128.0 (Co'),
115.8 (d, 2J = 21.8 Hz, Cm), 47.9 (C2), 31.8 (C2'), 19.4 (C3), 8.3 (C3').
MS (EI): m/z calcd for C18H17FO2: 284.12 [M]+•, found 284.09.
2-(4-Acetylphenyl)-1-(4-chlorophenyl)ethan-1-one (2e) was prepared
from 1e (1.0 mmol, 155 mg). 2e was isolated as a colorless solid (0.28
mmol, 76 mg, 56%), conversion of ketone 1e 62%; m.p. 119-120°C.
Elemental analysis calcd (%) for C16H13ClO2 (272.726): C, 70.46; H, 4.80;
Cl, 13.00; found: C, 70.61; H, 4.72; Cl, 13.11. IR (film): νmax 3086, 3070,
3053, 3041, 3007, 2965, 2940, 2920, 2875, 2850, 1689, 1678, 1650,
1605, 1589, 1571, 1488, 1423, 1398, 1361, 1342, 1309, 1267, 1216,
1198, 1181, 1099, 1076, 1014, 997, 958, 926, 872, 856, 829, 798, 756,
718, 704, 683, 668, 635, 627, 593582, 564, 530, 486, 471, 459. 1H NMR:
4
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10.1002/ejoc.202000454
European Journal of Organic Chemistry
FULL PAPER
3
δ 7.93–7.91 (m, 2H, Hm'), 7.91–7.88 (m, 2H, Ho), 7.45–7.38 (m, 2H, Hm),
7.35–7.29 (m, 2H, Ho'), 4.30 (s, 2H, H2), 2.56 (s, 3H, Me). 13C NMR: δ
197.8 (C1'), 195.6 (C1), 140.0 (Cp), 139.7 (Ci'), 136.0 (Cp'), 134.7 (Ci),
130.0 (Co), 129.9 (Co'), 129.2 (Cm), 128.8 (Cm'), 45.4 (C2), 26.7 (Me).
MS (EI): m/z calcd for C16H13ClO2: 272.06 [M]+•, found 272.03.
7.96 (d, J = 8.3 Hz, 1H, H4a), 7.94–7.85, 7.63–7.58, 7.58–7.53 (m, 6H,
Hm, HNaphth), 7.42–7.38 (m, 2H, Ho), 4.47 (s, 2H, H2), 2.57 (s, 3H, Me).
13C NMR: δ 197.8 (C1'), 196.8 (C1), 140.3 (Ci), 136.03 (C2''), 135.8,
133.9, 132.6 (C2'',9'',10''), 130.0 (Co), 128.8 (Cm), 130.5, 129.8, 128.9,
128.8, 128.0, 127.1, 124.2 (7C, CNaphth), 45.5 (C2), 26.7 (Me). MS (EI):
m/z calcd for C20H16O2: 288.12 [M]+•, found 288.13.
Synthesis of diketones 2g-j: 1a (1.0 mmol, 138 mg) in DMSO (1 mL)
was added dropwise to a mixture of 1 (1.5 mmol) and KOH×0.5H2O (2
mmol, 130 mg) in DMSO (8 mL) at 80°C for 2 h. The reaction mixture
was diluted with water (20 mL) and extracted with Et2O (2 mL × 7). The
combined organic extracts were washed with water (2 mL × 3) and dried
over K2CO3 for 1 h. Et2O was evaporated under reduced pressure, and
the residue was purified by column chromatography [SiO2, eluent: ethyl
acetate/hexane = 1:9].
2-(2-Fluorophenyl)-2-methylchroman-4-one
fluorophenyl)-1-(2-hydroxyphenyl)but-2-en-1-one (4)
(3)
and
A
(E)-3-(2-
mixture of
ketone 1d (1.0 mmol, 138 mg) and KOH×0.5H2O (1.0 mmol, 65 mg) in
DMSO (4 mL) was stirred at 80°C for 2 h. The reaction mixture was
diluted with water (10 mL) and extracted with Et2O (1 mL × 7). The
combined organic extracts were washed with water (1 mL × 3) and dried
over K2CO3 for 1 h. Et2O was evaporated under reduced pressure, and
the residue was purified by column chromatography [SiO2, eluent: ethyl
acetate/hexane = 1:9].
2-(4-Acetylphenyl)-1-phenylethan-1-one (2g) was prepared from 1a
(1.0 mmol, 138 mg) and 1g (1.5 mmol, 180 mg). 2g was isolated as a
colorless solid (0.67 mmol, 160 mg, 67%); m.p. 152-153°C. Elemental
analysis calcd (%) for C16H14O2 (238.281): C, 80.65; H, 5.92; found: C,
80.51; H, 5.72. IR (film): νmax 3065, 3029, 2960, 2936, 2922, 2894, 2851,
1682, 1607, 1597, 1580, 1449, 1422, 1408, 1363, 1336, 1312, 1302,
1270, 1221, 1202, 1159, 1143, 1116, 1107, 1098, 1076, 1022, 998, 962,
948, 912, 871, 839, 828, 815, 794, 762, 727, 699, 690, 650, 635, 608,
596, 579, 570, 488, 470, 450. 1H NMR: δ 8.01–7.97 (m, 2H, Ho), 7.93–
7.90 (m, 2H, Hm'), 7.59–7.54 (m, 1H, Hp), 7.49–7.44 (m, 2H, Hm), 7.37–
7.33 (m, 2H, Ho'), 4.34 (s, 2H, H2), 2.57 (s, 3H, Me). 13C NMR: δ 197.8
(C1'), 196.9 (C1), 140.2 (Ci'), 136.5 (Ci), 136.0 (Cp'), 133.6 (Cp), 130.0
(Co'), 128.9 (Cm), 128.8 (Cm'), 128.7 (Co), 45.5 (C2), 26.7 (Me). MS
(EI): m/z calcd for C16H14O2: 238.10 [M]+•, found 238.07.
3 was isolated as a light yellow oil (0.08 mmol, 21 mg, 16%). Elemental
analysis calcd (%) for C16H13FO2 (256.272): C, 74.99; H, 5.11; F, 7.41;
found: C, 74.72; H, 5.18; F, 7.35. IR (film): νmax 3369, 3073, 3043, 2983,
2933, 2901, 1693, 1608, 1582, 1478, 1459, 1414, 1377, 1318, 1285,
1230, 1169, 1158, 1119, 1074, 1043, 953, 899, 865, 825, 762, 735. 1H
NMR: δ 7.80–7.73 (m, 1H), 7.53–7.47 (m, 1H), 7.45–7.38 (m, 1H), 7.25–
7.18 (m, 1H), 7.12–7.07 (m, 1H), 7.05–6.93 (m, 3H) [HAr], 3.38 (d, 2J =
16.6 Hz, 1H), 3.16 (d, 2J = 16.6 Hz, 1H) [H3], 1.83 (s, 3H, 2-Me). 13C
NMR: δ 191.5 (C4), 159.8 (d, 1J = 247.5 Hz), 159.7 (C8a), 136.4 (C7),
3
129.8 (d, 2J = 12.2 Hz, C1'), 129.7 (d, J = 8.8 Hz, C4'), 127.5 (d, J = 3.7
Hz, CAr), 126.7 (C5), 124.3 (d, J = 3.4 Hz, CAr), 121.4 (CAr), 121.0 (C4a),
118.3 (CAr), 116.8 (d, 2J = 23.4 Hz, C3'), 81.5 (d, 3J = 3.9 Hz, C2), 47.7 (d,
3J = 5.7 Hz, C3), 27.3 (d, 4J = 3.0 Hz, 2-Me). MS (EI): m/z calcd for
C16H13FO2: 256.09 [M]+•, found 256.14.
1-([1,1'-Biphenyl]-4-yl)-2-(4-acetylphenyl)ethan-1-one
(2h)
was
prepared from 1a (1.0 mmol, 138 mg) and 1h (1.5 mmol, 294 mg). 2h
was isolated as a colorless solid (0.42 mmol, 132 mg, 42%); m.p. 199-
201°C. Elemental analysis calcd (%) for C22H18O2 (314.377): C, 84.05; H,
5.77; found: C, 83.34; H, 6.03. IR (film): νmax 3078, 3059, 3032, 2956,
2922, 2851, 1677, 1602, 1507, 1486, 1450, 1416, 1406, 1363, 1331,
1315, 1301, 1268, 1233, 1201, 1181, 1156, 1143, 1118, 1076, 1006, 965,
909, 870, 838, 816, 794, 764, 753, 733, 719, 688, 669, 635, 597, 584,
572, 531, 477. 1H NMR: δ 8.09–8.04 (m, 2H, Hm), 7.95–7.90 (m, 2H,
Hm'), 7.70–7.66 (m, 2H), 7.62–7.58 (m, 2H), 7.48–7.43 (m, 2H) (HAr),
7.41–7.36 (m, 2H, Ho',p''), 4.37 (s, 2H, H2), 2.57 (s, 3H, Me). 13C NMR: δ
197.8 (C1'), 196.5 (C1), 146.3 (Ci), 140.2 (Ci'), 139.9 (Ci''), 136.1 (Cp'),
135.2 (Cp), 130.0 (Co'), 129.3 (Cm), 129.1 (Co), 128.9 (Cm'), 128.5 (Cp''),
127.5, 127.4 (4C, Cm'',o''), 45.6 (C2), 26.7 (Me). MS (EI): m/z calcd for
C22H18O2: 314.13 [M]+•, found 314.10.
4 was isolated as a light yellow oil (0.05 mmol, 14 mg, 11%). Elemental
analysis calcd (%) for C16H13FO2 (256.272): C, 74.99; H, 5.11; F, 7.41;
found: C, 74.64; H, 5.23; F, 7.32. IR (film): νmax 3157, 3057, 2960, 2923,
2854, 2750, 2627, 1632, 1582, 1487, 1445, 1354, 1299, 1245, 1206,
1158, 1038, 956, 872, 818, 756. 1H NMR: δ 12.64 (s, 1H, OH), 7.83–7.76
(m, 1H), 7.49–7.42 (m, 1H), 7.41–7.29 (m, 2H), 7.21–7.15 (m, 1H), 7.15–
7.09 (m, 1H), 7.08–7.05 (m, 1H), 7.01–6.97 (m, 1H), 6.90–6.83 (m, 1H)
[HAr, H2], 2.52 (s, 3H, 3-Me). 13C NMR: δ 196.5 (C1), 163.2 (CAr2'), 159.6
(d, J = 249.6 Hz, CAr2''), 151.2 (d, J = 1.1 Hz, C3), 136.2 (CAr4'), 131.0
(d, 2J = 13.1 Hz, CAr1''), 130.3 (d, 3J = 8.5 Hz, CAr4''), 130.1 (CAr6'), 129.3
(d, 3J = 3.3 Hz, CAr6''), 124.3 (d, 2J = 3.8 Hz, CAr1''), 124.3 (d, 4J = 3.9 Hz,
CAr5''), 124.3 (C2), 120.8 (CAr1'), 118.8, 118.5 (CAr3',5'), 116.3 (d, 2J =
22.7 Hz, CAr3''), 20.3 (d, 4J = 3.1 Hz, 3-Me). MS (EI): m/z calcd. for
C16H13FO2: 256.09 [M]+•, found 256.21.
1
3
1,2-Bis(4-acetylphenyl)ethanone (2i) was prepared from 1a (1.0 mmol,
138 mg) and 1i (1.5 mmol, 243 mg). 2i was isolated as a yellow solid
(0.48 mmol, 135 mg, 48%); m.p. 159-162°C. Elemental analysis calcd
(%) for C18H16O3 (280.318): C, 77.12; H, 5.75; found: C, 76.81; H, 5.67.
IR (film) νmax 2922, 2863, 1680, 1602, 1568, 1506, 1420, 1401, 1354,
Acknowledgements
1
The spectral data were obtained using the equipment of Baikal
Analytical Center for collective use of Siberian Branch of the
Russian Academy of Sciences. V.O., D.A., N.V. acknowledge
Grant No. FZZE-2020-0025 from the Ministry of Education and
Science of the Russian Federation.
1302, 1261, 1105, 1075, 1018, 957, 913, 863, 827, 732, 591. H NMR: δ
8.09–7.99 (m, 4H, Ho,m), 7.95–7.86 (m, 2H, Hm'), 7.38–7.31 (m, 2H,
Ho'), 4.37 (s, 2H, H2), 2.63 (s, 3H, H2'), 2.58 (s, 3H, H2"). 13C NMR: δ
197.7 (C1"), 197.4 (C1'), 196.3 (C1), 140.5 (Ci), 139.6 (Ci'), 139.5 (Cp),
136.1 (Cp'), 129.9 (Co'), 128.8 (Cm'), 128.8 (Cm), 128.7 (Co), 45.8 (C2),
26.9 (C2'), 26.7 (C2"). MS (EI): m/z calcd for C18H16O3: 280.11 [M]+•,
found 280.23.
Keywords: 4-Fluoroacetophenone • Acylaromatic • Superbase •
SNAr reaction • Csp2–Csp3 bond formation
2-(4-Acetylphenyl)-1-(naphth-2-yl)ethan-1-one (2j). was prepared from
1a (1.0 mmol, 138 mg) and 1j (1.5 mmol, 255 mg). 2j was isolated as a
colorless solid (0.37 mmol, 107 mg, 37%); m.p. 161°C. Elemental
analysis calcd (%) for C20H16O2 (288.340): C, 83.31%; H, 5.58%; found:
C, 83.59%; H, 5.76%. IR (film): νmax 3064, 3036, 2962, 2920, 2852, 1675,
1626, 1607, 1597, 1574, 1506, 1413, 1359, 1324, 1271, 1201, 1181,
1174, 1157, 1125, 1108, 1075, 1023, 995, 967, 959, 907, 876, 864, 838,
826, 817, 775, 752, 732, 647, 630, 599, 591, 568, 483. 1H NMR: δ 8.52
(d, 4J = 1.5 Hz, 1H, H1''), 8.04 (dd, 3J = 8.3 Hz, 4J = 1.5 Hz, 1H, H3''),
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European Journal of Organic Chemistry
FULL PAPER
Head-to-Tail Dimerization of 4-Fluoroacetophenone in the KOH/DMSO Superbase Suspension
and Related SNAr Reaction
Key Topic: Nucleophilic Aromatic Substitution
The head-to-tail autocondensation of 4-fluoroacetophenone in the KOH/DMSO superbase suspension stops on dimerization step
affording 4-acetylbenzyl-4′-fluorophenylketone. This new fluorine substitution (SNAr) reaction opens short and simple route to so far
inaccessible aromatic diketones via the nucleophilic substitution of fluorine atom in 4-fluoroacetophenone by available acylbenzenes.
7
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