Superelectrophilic sp3 C-H carbonylation of n-octyl acetate as a way to new bifunctional neo-octanes

Article abstract of DOI:10.1016/j.mencom.2011.11.010

Carbonylation of n-octyl acetate in the presence of CBr₄· 2AlBr₃ followed by treatment with nucleophiles such as alcohols, amines or (het)arenes affords 7-acetoxy-2,2-dimethylheptanoyl-containing products.

Full text of DOI:10.1016/j.mencom.2011.11.010

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 323–325
Superelectrophilic sp3 C–H carbonylation of
n-octyl acetate as a way to new bifunctional neo-octanes
Irena S. Akhrem,* Dzhul’etta V. Avetisyan, Lyudmila V. Afanas’eva,
Alexander V. Orlinkov, Nikolai D. Kagramanov and Pavel V. Petrovskii
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: cmoc@ineos.ac.ru
DOI: 10.1016/j.mencom.2011.11.010
Carbonylation of n-octyl acetate in the presence of CBr4∙2AlBr3 followed by treatment with nucleophiles such as alcohols, amines or
(het)arenes affords 7-acetoxy-2,2-dimethylheptanoyl-containing products.
Selective functionalization of sp3 C–H bonds of monofunctional
compounds has great synthetic potential, as it offers a solution to
the problem of converting monofunctional derivatives to bifunc-
tional compounds with distant functional groups. Finding initiating
systems for such transformations presents a considerable challenge as
the most functional groups have a low tolerance for highly reactive
agents which are capable of cleaving unactivated sp3 C–H bonds.
Investigations in this field started more than a century ago.1
Up to date, the sp3 C–H bond functionalization of monofunctional
compounds mediated by radical systems,2 compounds of tran-
sition or post transition metals,3 and strong electrophiles4 has
been reported.† Over the last decade, transition metal-mediated
sp3 C–H bond functionalization has been vigorously studied. In
contrast, similar reactions initiated by strong electrophiles are
rare.4 Carbonylaion of methyl isoalkyl ketones in excess HF–SbF5
was shown to proceed selectively at w – 1 position, however, con-
versions of ketones amounted to 16–66%; linear ketones reacted
with CO unselectively to produce desired products as minor
components, if at all.4(c)
bifunctional products of neo-structure with the acetate group
AcO(CH2)5C(Me)2COY (Y = OPri, NC4H8O, C6H4OMe) in high
yield.5 In the present work, we verified the scope of this reaction
by application of different nucleophiles, namely, alcohols, amines
and (het)arenes.
In fact, carbonylation of n-octyl acetate at –20°C under CO
atmosphere (1 bar) in the presence of 70% molar excess of super-
electrophilic complex CBr4∙2AlBr3 (E) for 3 h, followed by the
in situ treatment of the carbonylation product with alcohols such
as HOCH2CH(Et)Bu, CF3CH2OH, HO(CH2)3Br, HOCH2CºCH
led to the corresponding 7-acetoxy-2,2-dimethylheptanoic esters
in 63–78% yields (Scheme 1).‡
These products also had neo-structures, in which the new
functional groups were located at the quaternary C-atom being
maximum remote from the initial acetoxy group. The elabora-
tion of syntheses of bifunctional aliphatic compounds having
neo-structures is of special interest because they display valuable
CO, E+
Me
O
Me
O
C8H17
(CH2)5C(Me)2CO+
Recently, we have developed a new strategy for selective one-pot
C–H bond functionalizations of alkanes,5 including monofunc-
tional ones.6,7 The potent superelectrophilic complex CBr4∙2AlBr3
in organic medium allowed easy generation of carbocations XR+
(X is a functional group) from monofunctional compounds, XRH,
namely n-alkyl acetates5 and monofunctional adamantanes,6 to
occur. In the presence of CO, the XR+ cations are converted into
acylium cations XRCO+, which, in their turn, form bifunctional
products on final treatment with nucleophiles, the original func-
tional group remaining intact. In this approach, CO plays a crucial
role because it generates a synthon suitable for one-pot synthesis
of a broad variety of products depending on the nature of the
nucleophile.
O
O
E
E
Me Me
Me
O
O
OR
ROH
O
R = CF3CH2 (75%),
BuCH(Et)CH2 (75%),
HCºCCH2 (78%),
Br(CH2)3 (63%)
Scheme 1
‡
Typical procedure. At –20°C, under a CO atmosphere (1 bar), n-octyl
acetate (1.9 mmol) was added to a stirred solution of CBr4∙2AlBr3, freshly
prepared from AlBr3 (6.50 mmol) and CBr4 (3.24 mmol) in anhydrous
CH2Br2 (2.5 ml) at room temperature. After stirring for 2.5–3 h at –20°C
under a CO atmosphere, a nucleophile was added to the in situ prepared
carbonylation intermediate strictly under CO. The mixture was stirred
additionally for 10–15 min at –20°C and then left to warm to 0°C over
20–30 min. Water (10 ml) and CHCl3 (30 ml) were carefully added with
stirring. The organic layer was separated and the remaining aqueous layer
was extracted with CHCl3. The combined organic extracts were dried over
Na2SO4. The structures of the products were established by 1H, 13C NMR
and GC-MS spectra; conversions and isomeric ratios of products were
determined by GC. To perform NMR measurements, all solvents and high
volatile compounds were removed under reduced pressure and finely at
50°C (1 Torr). In some cases, the products were purified by chromatography
on silica gel. The yields of the obtained compounds were determined by
1H NMR with mesitylene as an internal standard.
Functionalization of n-octyl acetate with CO and nucleophiles
(isopropanol, morpholine and anisole) was shown to afford the
†
There are considerable distinctions between the mechanisms and the
nature of products of sp3 C–H functionalization initiated by different class
systems. The radical reactions trend to occur at the weakest C–H bond.
Likewise, superelectrophiles favor the formation of the more branched
carbocation, even to a greater extent, thus the formation of functional
products with a functional group at quaternary or tertiary C atom. Low
valent transition metals, however, trend to insert into the least substituted
C–H bond to give an alkylmetal hydride; as a result, linear functional
products are often preferred. However, the dividing of initiating systems
into three above mentioned classes is not strict, since some radical com-
pounds act in the presence of strong acids, while some high-valent metal
complexes behave as superelectrophiles.
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 323–325
properties, such as enhanced thermal and chemical stabilities,
Me
O
Me
CBr4∙2AlBr3
–20 °C
low freezing points, etc.8 The products of neo-structure cannot
+ CO
Me
O
be prepared with transition metal-mediated systems.‡
The THF ring-opening product was formed, if AcOC8H17
carbonylation product reacted with THF at 20°C under CO
atmosphere (Scheme 2, for the mechanism, see ref. 9).
Me
O
Et2NH
O
CO
Me
O
Me
HO
Me
Me Me
CO+ Al2Br7
O
Me
O
O
O
NEt2
O
NEt2
O
O
Me Me
CO+O
Me Me
Me
Alk2NH
20 °C
Me
O
Al2Br7
CO+
O
O
Me Me
Me Me
O
Me
O
O
Alk2NH
Me
O
NAlk2
Br
– MeC(O)NAlk2
O
O
O
major for Alk = Bu
Scheme 2
Me Me
The reaction proceeded regioselectively to give more than
96% of the neo-isomer. The yield of the target product was 72%
after 20 h. Small amounts of other THF ring-opening products,
XO(CH2)4Y (X = H,Y = Br; X = HOC8H16CO,Y = Br; X =Y = Br)
were formed as by-products.
HO
NAlk2
O
major for Alk = Et
Alk = Et, Bu
In our experiments, the functionalization of n-octyl acetate
occurs with good chemo- and regioselectivity. Previously, under
the action of superacids, alkanes C6–C10 generated mostly the
products of their degradative carbonylation, resulting in com-
pounds with different number of C-atoms in the alkyl moiety.10
On contrast, the degradative carbonylation of alkanes C6–C10
did not occur in the reactions initiated by the polyhalomethane-
based superelectrophiles.11 In this case, even at –40°C, these
alkanes are converted exclusively into carbonyl-containing products
with neo-alkyl substituents being the two dominating isomers,
AlkC(Me)2COOR and AlkC(Me)(Et)COOR.11 Carbonylation of
octane at –20°C leads to the aforementioned isomers (Alk = C5H11)
in comparable amounts. Individual carbonyl-containing products
starting from C6–C10 alkanes were never obtained.
Scheme 3
Similar results were observed for n-octyl acetate and Et2NH or
Bu2NH, although in the latter reaction, HO(CH2)5C(Me)2CONBu2
was found in trace amounts only and AcO(CH2)5C(Me)2CONBu2
remained as a major product (Scheme 3).
Acid-catalyzed ester cleavage has been extensively studied,
and evidence has emerged suggesting that protosolvation (or
electrophilic solvation) can play a role in this chemistry.12 Thus,
methyl acetate is found to be completely protonated at the acyl
oxygen in superacidic FSO3H/SbF5/SO2 solution at low tem-
perature. However, even at –78°C, protonated methyl acetate
undergoes acyl-oxygen cleavage to give the acetyl cation and
protonated methanol.12(c)
The results of this work show that in the presence of the
acetoxy group, an individual carbocation is generated selecti-
vely in each case. Therefore, the corresponding acylium cation
accumulates in the reaction medium, leading finally to a single
product. We believe that the site for hydride abstraction from the
alkyl acetate molecule is dictated by two factors: (i) its remote-
ness from the existing functional group, and (ii) the stability of
the carbocation to be generated. For n-octyl acetate, these two
requirements lead to a compromise resulting in the formation
of the most stable tertiary cation separated from the functional
group by five CH2 units. The difference in the selectivities of
carbonylation of n-octane and n-octyl acetate stems from the fact
that the former gives two cations that are rather similar in
stability, whereas the latter is transformed into an intermediate
Me2C+(C5H11) bearing the cationic center in the position that is
the most remoted from the acetoxy group.
While the functionalization of n-hexyl and n-octyl acetates
with CO and morpholine occurred effectively to afford the cor-
responding bifunctional product in 80–85% yield,6 the treatment
of their carbonylation product with Et2NH was accompanied with
the Ac–O bond cleavage in the initially formed amides to give
AcNEt2 and HOCnH2nCONEt2 (n = 6 or 8). In the case of n-hexyl
acetate, the use of three-fold excess of Et2NH relative to E led
to a mixture of AcOC6H12CONEt2 and HOC6H12CONEt2 in a
molar ratio 4:1 (total yield 65%), while this reaction with a larger
excess of Et2NH gave rise to HOC6H12CONEt2 as the only product.
The treatment of the carbonylation product with toluene led
to a mixture of toluene alkylation products (A) with AcOC8H1+6
cations, which were in equilibrium with the corresponding acylium
ions (Scheme 4). Alkylation of toluene, which is less nucleophilic
than anisole, occurs faster than acylation. Therefore, in spite of a
shift of equilibrium a under CO to the right, the only alkylation
is realized. Small amount of dialkylated toluenes with M+ 372 (B)
was formed as by-products. The latters are the AcOC8H16C6H4Me
E+
CO
Me
O
Me
O
Me
O
C8H17
C8H16
C8H16CO+
a
O
O
O
toluene
Me
Me
C8H16
Me
O
(CH2)5C
O
Me
A
main isomers
O
Me
C8H15
Me
O
Me
O
O
(CH2)8
(CH2)8
Me
O
B
small amount
Scheme 4
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Mendeleev Commun., 2011, 21, 323–325
alkylation products with unsaturated hydrocarbons C8H16. We did
Online Supplementary Materials
observed the formation of traces of C8H14 hydrocarbons (M = 110)
among the n-octyl acetate decomposition products. A molar ratio
of [A]:[B] was ~10:1, with the conversion of AcOC8H17 being
92%. Thus, sp3 C–H bond in n-octyl acetate transforms to C–C
bond via alkylation of toluene.
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.11.010.
References
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was probably a tertiary isomer.
Similar to the reported reaction with CO and anisole,5 the
processing of octyl acetate with CO and furan or thiophene occurs
chemo- and regioselectively, in each case to give practically
individual acylation products of neo-structure (Scheme 5).
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Me
(CH2)5CCO+
Me
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Me
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CO, E
C8H17
O
O
Me
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O
S
Me
(CH2)5C
Me
Me
(CH2)5C
Me
O
S
Me
O
O
Me
O
O
O
O
74%
76%
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Scheme 5
The possibility to involve in this functionalization five-mem-
beredheteroaromatics,whichareveryactivetowardelectrophiles,
is of interest. Thiophenes and furans are important structural
fragments in many pharmaceuticals.13 Therefore, a simple method
for preparation of their new derivatives may be promising for
synthesis of biologically active heteoaromatic compounds.
In summary, an ‘alkane-like’ strategy has been successfully
used for the direct and simple one-pot functionalization of n-octyl
acetate. This approach has provided access to new bifunctional
aliphatic compounds with an acetate group, which are of interest
for the synthesis of biologically active compounds and materials
for industrial use.
11 I. S. Akhrem, L. V. Afanas’eva, S. V. Vitt and P. V. Petrovskii, Mendeleev
Commun., 2002, 180.
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and D. A. Klumpp, Acc. Chem. Res., 2004, 37, 211; (c) G. A. Olah,
N. Hartz, G. Rasul, A. Burrichter and G. K. S. Prakash, J. Am. Chem.
Soc., 1995, 117, 6421.
All products obtained are novel and their structures were con-
firmed by 1H and 13C NMR spectroscopy and mass spectrometry
(see Online Supplementary Materials).
13 F. C. Meotte, D. O. Silva, A. R.S. dos Santos, G. Zeni, J. Batista, T. Rocha
and C. W. Nogueira, Environ. Toxicol. Pharmacol., 2003, 37, 37.
This work was supported by the Russian Foundation for Basic
Research (project no. 09-03-00110) and the RAS Presidium Fund
(Program 7P).
Received: 20th May 2011; Com. 11/3732
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