Catalyst-free alkanoylation of aromatic rings via arylstannanes. Scope and limitations

Article abstract of DOI:10.1016/j.jorganchem.2009.07.019

The reaction of alkanoyl chlorides with arylstannanes in 1,2-dichlorobenzene (180 °C) is a simple and direct route for the catalyst-free and regioselective synthesis of tertiary alkyl aryl ketones in good to excellent isolated yields (55-77%). Nevertheles

Full text of DOI:10.1016/j.jorganchem.2009.07.019

Journal of Organometallic Chemistry 694 (2009) 3674–3678
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Journal of Organometallic Chemistry
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Note
Catalyst-free alkanoylation of aromatic rings via arylstannanes. Scope
and limitations
,1
*
*
Marcos J. Lo Fiego, María T. Lockhart , Alicia B. Chopa
INQUISUR, Departamento de Química, Universidad Nacional del Sur, Avenida Alem 1253, 8000 Bahía Blanca, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2009
Received in revised form 6 July 2009
Accepted 7 July 2009
Available online 12 July 2009
The reaction of alkanoyl chlorides with arylstannanes in 1,2-dichlorobenzene (180 °C) is a simple and
direct route for the catalyst-free and regioselective synthesis of tertiary alkyl aryl ketones in good to
excellent isolated yields (55–77%). Nevertheless, under similar conditions, reactions carried out with
alkanoyl chlorides bearing
a-hydrogens render only the product of protodestannylation.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Arylstannanes
Aromatic electrophilic acylation
Tertiary alkyl ketones
1. Introduction
as the special work-up carried out in order to recover the Bu3SnCl
generated.
Ketones are vital building blocks in organic synthesis as well as
an important functionality found in several natural products and in
various pharmaceutical compounds. Electrophilic aromatic substi-
tution (EAS) such as Friedel–Crafts (F–C) acylation [1] and cross-
coupling reactions of acyl chlorides with organometallic reagents
[2] are presumed to be the preferences for the synthesis of aro-
matic ketones. Although these reactions are efficient methods to
form ketones in good yields, there are some disadvantages related
with them. Thus, intrinsic limitations of F–C reactions are the sub-
stituent-directing effects, the reactivity substrate requirements
and the fact that recovery and recycling of the catalyst is seldom
possible after aqueous work-up and a large amount of toxic waste
is generated. On the other hand, although Pd-cross-coupling reac-
tions are effective, Pd-catalysts are expensive and it is usually nec-
essary to find the appropriate catalytic protocol for each pair of
reactants. Recently, based on the exceptional leaving group ability
of the trialkylstannyl group in electrophilic aromatic substitutions,
we have proposed efficient catalyst-free straightforward routes for
the mono-, bi- and triaroylation of aromatic rings, by the reaction
of mono-, bi- and tristannylarenes with different aroyl chlorides
[3].
2. Results and discussion
As electrophilic attack is accelerated by the presence of elec-
tron-donating groups on the arene system we started the study
of the reactivity of tributyl(4-methoxyphenyl)stannane (1) to-
wards different commercially available alkanoyl chlorides such as
acetyl and butyryl chloride under the best reaction conditions pre-
viously established for the synthesis of triaryl ketones, that is, in
1,2-dichlorobenzene as solvent, at 180 °C [3b]. Unfortunately, the
desired ketones were not detected, no starting material was recov-
ered and the reactions led only to the corresponding protodestan-
nylated product, i.e., anisole, indicative of the presence of
important amounts of HCl in the reaction mixture. Taking into ac-
count that we reduce to an extreme the presence of HCl in the
starting acylation agents, we considered that the HCl should be
generated under the reaction conditions, probably, by a b-elimina-
tion of the alkanoyl chloride [4]. In order to minimize this undesir-
able reaction we decided to work at lower temperature (130 °C,
[3a]). After longer reaction times (72 h) an important decrement
of the amount of protodestannylated product was observed but,
unfortunately, large amounts of starting substrate 1 was recovered
(ca. 80%) and only traces of the desired ketone were detected (GC/
MS). In order to prove our hypothesis, we decided to study the
reaction of 1 with 1-adamantylcarbonyl chloride (13a) which does
The results obtained encouraged us to explore its application to
the mono-, bi- and trialkanoylation of aromatic rings. Now, we re-
port the synthetic scope and limitations of these reactions as well
* Corresponding authors. Tel.: +54 291 4595100; fax: +54 291 4595187.
E-mail addresses: teresa.lockhart@uns.edu.ar (M.T. Lockhart), abchopa@uns.
edu.ar (A.B. Chopa).
not possess an
a-hydrogen. With pleasure we observed that, after
1 h, the desired ketone, i.e., 1-adamantyl-4-methoxyphenylmetha-
none (14a) was obtained in 76% yield (entry 1, Table 1).
1
Member of CIC.
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.07.019

M.J. Lo Fiego et al. / Journal of Organometallic Chemistry 694 (2009) 3674–3678
3675
Table 1
Reactions of arylstannanes with acyl chlorides in 1,2-dichlorobenzene.a
Table 1 (continued)
Entry
12
Stannane
RCOClb
Ketone
Time (h)
4
Yield (%)c
80(73)
Entry
1
Stannane
1
RCOClb
Ketone
Time (h)
1
Yield (%)c
76(68)
2
13b
O
13a
O
O
15b
13
14
3
6
13b
13b
5
70(62)
69(60)
14a
O
O
2
3
4
5
6
2
3
4
5
6
13a
13a
13a
13a
13a
3
75(66)
73(67)
60(58)
72(66)
62(55)
16b
16
15a
O
O
O
4
19b
16a
15
9
13b
3
81(70)
O
O
3
O
O
F
F
22b
17a
O
16
17
10
11
13b
13b
2
7
82(71)
79(68)
24
16
23b
18a
O
O
O
O
Cl
Cl
24b
19a
18
12
13b
6
75(66)
7
8
7
8
13a
13a
5
4
74(69)
36(30)
O
25b
20a
19d
11
3
13c
13c
O
F
48
48
0
0
O
F
O
22c
20d
O
21a
9
9
13a
2
72(68)
O
O
16c
All reactions were performed at 180 °C (oil bath).
RCOCl (1.2 equiv) were used unless otherwise stated.
Determined by GC.; isolated products between parentheses as an average of at
F
F
a
b
c
22a
O
10
11
10
11
13a
13a
1.5
84(77)
80(70)
least two independent runs.
d
RCOCl (2.4 equiv).
23a
6
O
In view of this result we synthesized a series of electronically
diverse starting tributylarylstannanes 1–12 (Fig. 1,) by reaction of
the corresponding aryl Grignard reagent with tributyltin chloride
[5], and we studied their reactivity towards commercially available
tertiary alkanoyl chlorides 13a–c (Fig. 1).
Cl
24a
The results obtained are summarized in Table 1.
It can be seen that the reactions of arylstannanes bearing either
electron-withdrawing or electron-releasing groups proceed in
good to high yields with both 13a and 13b. As it was predictable,

3676
M.J. Lo Fiego et al. / Journal of Organometallic Chemistry 694 (2009) 3674–3678
Fig. 1. Starting tributylarylstannanes and acid chlorides.
those arylstannanes carrying activating groups in meta- and para-
position (1–4) (entries 1–4, 12 and 13) react faster than those
carrying a deactivating group such as chlorine in the same posi-
tions (11 and 12) (entries 11, 17 and 18). The decreased reactivity
shown by substrates 5 and 6 (entries 5, 6 and 14) are, probably, due
to steric effects. Nevertheless, the results demonstrate that the
route proposed is effective for the synthesis of more crowded
ketones. On the other hand, the increased reactivity shown by
substrates 9 and 10 (entries 9, 10, 15 and 16), which support a fluo-
rine group, is in agreement with the ‘‘anomalous” reactivity of fluo-
robenzene in EAS [6]. Moreover, our results demonstrate that in
these reactions substrates 9 and 10 react faster even than sub-
strates bearing activating substituents such as 2, 3 and 4.
Also, a global evaluation of the results obtained indicates that
13b is less reactive than 13a, rendering similar yields but after
longer reaction times (compare entries 2/12, 3/13, 9/15, 10/16
and 11/17).
A series of competitive experiments were carried out to confirm
the relative reactivity observed in the previous reactions. For
example, a mixture of 9 and 10 in a 1:1 equivalent ratio was al-
lowed to react with 1 equivalent of 13a for 2 h and the products
were analyzed by GC/MS. The reaction led to a mixture of the
respective ketones, 22a and 23a, in 1:1.5 ratio (Eq. (1)). A similar
result was obtained when a mixture of 9 and 10 react with 13b
(1:1:1), rendering ketones 22b and 23b in 1:1.4 ratio (Eq. (2)).
These results confirm the observed higher reactivity of substrate
10 over substrate 9 towards these acylation reagents (compare en-
tries 9/10 and 15/16).
It should be mentioned that in all the experiments carried out,
small amounts (not quantified) of ipso-protodestannylation prod-
ucts were detected (CG/MS), which probably result from minor
HCl impurities in the acyl chloride. These protodestannylation
products are irrelevant compared with the yields of the corre-
sponding ketones obtained.
In view of our results we considered that the commercially
available acyl chloride 13c could be a good reagent for an efficient
acylation reaction in which two bonds could be formed in one step,
leading to the corresponding b-diketone. So, we carried out the
reaction of both substrates 9 and 3 with 13c (ratio 2.4/1). Unfortu-
nately, even after 48 h at 180 °C the corresponding b-diketones
were not detected and high amounts of starting substrates were
recovered (GC/MS) (entries 19 and 20).
With the results obtained in hand and based on our previous
experience [3b], with the main goal of introducing more than
one alkanoyl group in an aromatic ring, we decided to study the
reactivity of bistannylarenes towards 13a. First, we carried out
the reaction of 1,4-bis(trimethylstannyl)benzene with 13a (1/2.4,
2.5 h, 180 °C) and the crude product was analyzed by GC/MS. The
reaction led to a mixture of the monoalkanoyldestannylation prod-
uct, i.e., 1-adamantyl-4-trimethylstannylphenylmethanone (26)
and 1-adamantyl-phenylmethanone (20a) in an 8.5/1 ratio, accom-
panied by starting arylstannane and chloroadamantane. The de-
sired bisalkanoylation product was not detected (Eq. (6)).
9
þ
10
þ
13a
! 22a þ 23a
ð1 : 1:5Þ
ð1Þ
ð2Þ
ð1 equivÞ ð1 equivÞ ð1 equivÞ
ð6Þ
9
þ
10 13b
þ
! 22b þ 23b
ð1 equivÞ ð1 equivÞ ð1 equivÞ
An increment in the reaction time (5 h) led to a qualitatively anal-
ogous product distribution. Nevertheless, we observed that mean-
while the yield of compound 26 decreased with time, the yield of
compound 20a increased (26/20a, 1.8/1). It should be mentioned
that it was also detected larger amounts of chloroadamantane and
only traces of starting arylstannane. The results obtained showed
that it was not possible to introduce a second alkanoyl group under
these reaction conditions. Taking into account that the monoacylat-
ed product 26 should be an excellent intermediate for an asymmet-
ric bifunctionalization of the ring [7], we carried out a third reaction
using a defect of 13a (substrate/13a, 1/1.2, 5 h) in order to increase
the yield of 26. The GC/MS showed that 26 was the main product
and only traces of 20a were detected, but, unfortunately, large
amounts of starting arene were also present which made impossi-
ble the isolation of 26 from this mixture. It should be mentioned
that, under these conditions, chloroadamantane was not present
among the reaction products.
ð1 : 1:4Þ
On the other hand, we carried outanother competitive reaction of
3 and 10 (1:1) towards 13b (Eq. (3)). The result obtained (16b:23b,
1:1.3) corroborate the higher reactivity of substrates containing
fluorine over substrates carrying common activating groups.
3
þ
10
þ
13b
! 16b þ 23b
ð1 : 1:3Þ
ð3Þ
ð1 equivÞ ð1 equivÞ ð1 equivÞ
Finally, the higher reactivity of stannylarenes towards 13a over
13b was corroborated by the competitive reactions resumed in
Eqs. (4) and (5).
13a
þ
13b
þ
3
! 16a þ 16b
ð2:3 : 1Þ
ð4Þ
ð5Þ
ð1 equivÞ ð1 equivÞ ð1 equivÞ
13a 13b 11
þ
þ
! 24a þ 24b
ð1 equivÞ ð1 equivÞ ð1 equivÞ
ð2 : 1Þ

M.J. Lo Fiego et al. / Journal of Organometallic Chemistry 694 (2009) 3674–3678
3677
Furthermore, the reaction of 1,3-bis(trimethylstannyl)benzene
4. Experimental
with 13a (1/2.4, 2.5 h) led to a mixture of 20a and chloroadaman-
tane; no monoalkanoyldestannylation product, i.e., 1-adamantyl-
3-trimethylstannylphenylmethanone (27), was detected. When
we used a defect of 13a (substrate/13a, 1/1.2, 2.5 h) compound
27 was obtained together with 20a in a 1/1.8 ratio and chloroada-
mantane was not present. No starting substrate was detected un-
der both reaction conditions. We were not able to isolate
compound 27 from the mixture obtained.
The results indicate that when there is an excess of 13a in the
reaction media (substrate/13a, 1/2.4), compound 20a increased
in time at expense of compounds 26 or 27. Moreover, the substan-
tial amount of chloroadamantane found under these conditions
could be explained as a result of decarbonylation of the unreactive
excess of 13a2. It should be mentioned that no alkylation products
were detected in agreement with results reported by Neumann [8].
Aryltins were prepared according to literature methods [5].
4.1. Representative procedure for alkanoyldestannylation. Preparation
of 1-adamantyl-4-methoxyphenylmethanone (14a; Table 1, entry 1)
In an oven-dried 25 mL heavy walled Schlenk tube fitted with a
teflon plug valve, 0.240 g (1.2 mmol) of 1-adamantylcarbonylchlo-
ride (13a) were added to a stirred solution of tributyl(4-methoxy-
phenyl)stannane (1, 0.398 g, 1.0 mmol) in 1,2-dichlorobenzene
(1 mL) under a nitrogen atmosphere. The system was purged with
nitrogen by means of three vac-refill cycles and the reaction mix-
ture was heated at 180 °C (oil bath) for 1 h (monitoring the disap-
pearance of 1 by TLC). After addition of 10% (m/v) solution of NaOH
(2 mL), the mixture was stirred at room temperature for 15 min
and then diluted with ether (5 mL). The organic phase was succes-
sively washed with water and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatography
on silica gel doped with 10% of KF16 (hexane/CH2Cl2 = 60:40) gave
14a as a white solid (0.184 g, 68%); mp = 64–66 °C; Rf = 0.33 (hex-
3. Conclusions
The present results show that the protocol presents some limi-
tations in the alkanoylation of an aromatic ring. Thus, acyl chlo-
ane/EtOAc = 9:1); 1H NMR (300 MHz, CDCl3)
d 7.74 (d, 2H,
rides bearing
a-hydrogens lead only to protodestannylated
J = 8.9 Hz), 6.88 (d, 2H, J = 8.8 Hz), 3.82 (s, 3H), 2.05 (br, 9H), 1.76
(br, 6H); 13C NMR (75.5 MHz, CDCl3) d 206.8 (CO), 161.4 (C),
131.0 (C), 130.0 (CH), 113.0 (CH), 55.1 (CH3), 46.6 (C), 39.3 (CH2),
36.5 (CH2), 28.6 (CH); EIMS m/z (rel intensity) 270 (M+, 10), 135
(100), 107 (12). Anal. Calcd for C18H22O2 (270.37): C, 79.96; H,
8.20. Found: C, 81.16; H, 8.43%.
products, and it is not possible to introduce a second alkanoyl
group, in contrast to the bisaroylation reactions [3b]. Nevertheless,
the reaction provides a new simple and direct route for the selec-
tive synthesis of tertiary alkyl aryl ketones in good to high yields.
Due to the high ipso-directing force of the tributylstannyl group
[9], all the reactions studied were regioselective and they went,
exclusively, through an ipso-acyldestannylation independently
whether the directing influences of the aryl substituents and the
tributylstannyl group are either matched (compounds 1, 2, 5, 9
and 11) or mismatched (compounds 3, 4, 10 and 12), taking place
even with substrates bearing deactivating groups. Thus, this ap-
proach overcomes the limited substrate scope and reduced regio-
control of traditional Friedel–Crafts acylation methods.
It should be mentioned that, in the last years, different strate-
gies have been developed which could be applied to the synthesis
of these bulky ketones, for example, F–C reactions catalyzed by In
[10], BiCl3 [11] or silica [12]; cross-coupling reactions with organo-
boron reagents [13]; the reaction of acyl chlorides and Grignard re-
agents catalyzed by metal halides [14] and the Pd-mediated cross-
4.2. Recovering method for tributyltin chloride
After flash chromatographic procedure (10.0 g of 40–63 lm sil-
ica gel for 1.00-mmol scale reaction) the column was eluted with
100 mL of THF. The silica was dried using compressed air and
poured into a 100-mL round-bottomed flask fitted with a condenser
and a nitrogen T-joint. Sodium chloride (293 mg, 5.00 mmol) and
50 mL of dry THF were added and the mixture was heated at reflux
with stirring for 4 days. It is then allowed to cool and poured into a
chromatography column plugged with a small piece of cotton wool.
All of the THF was drained with air pressure and then the column
was eluted with ether (2 ꢀ 50 mL). The combined ethers were con-
centrated in vacuo giving tributyltin chloride in ca. 80% with re-
spect to the starting aryltributylstannane.
coupling of
a-oxocarboxylic acids and aryl bromides [15]. The
method here proposed enables the high regioselective formation
of bulky ketones without employing a catalyst, that is, a more eco-
friendly acylation of aromatic rings.
Acknowledgment
However, one disadvantage is the generation of tributyltin chlo-
ride as secondary product. Because of the environmental problems
caused by the well-known toxicity of triorganotin residues, we
considered really important to trap the Bu3SnCl generated. With
this aim, product purification was carried out by chromatography
on a silica gel column doped with KF [16]. Thus, organotin residues
were totally removed from final products, trapped as Bu3SnF. Final-
ly, based on results reported by Mitchell [17], Bu3SnCl was recu-
perated (c.a. 80%) by treating the silica gel with an excess of NaCl
in THF (see Section 4).
In order to decrease the level of pollution, we have started the
study of an alternative route to obtain aryl ketones using poly-
mer-supported organotin reagents as key intermediates. This strat-
egy should combine the advantages of the method described in this
paper with those expected from polymer-supported tin reagents.
This work is in progress.
This work was partially supported by CONICET, CIC, ANPCYT
and the Universidad Nacional del Sur, Bahía Blanca, Argentina.
CONICET is thanked for a research fellowship to M.J.L F.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jorganchem.2009.07.019.
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2
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13a in 1,2-dichlorobenzene.

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