Sp3 C-H bond functionalization of methyl n-alkyl ketones [MeCOCnH2n+1 (n = 6-8)] as a novel method for the one-pot regioselective synthesis of 'bifunctional alkanes' with remote functional groups

Article abstract of DOI:10.1016/j.tetlet.2012.05.164

Selective one-pot functionalization of methyl n-alkyl ketones, C _nH_2n+1COMe (n = 6-8) involving C-sp³-H bond cleavage with CO and various nucleophilic substrates [ⁱPrOH, BuCH(Et)CH₂OH, CF₃CH₂OH, (CF ₃)(Me)CHOH, H(CF₂)₂CH₂OH, HCCCH ₂OH, furan, thiophene, and anisole] in the presence of the superelectrophilic system CBr₄·2AlBr₃ has been performed for the first time.

Full text of DOI:10.1016/j.tetlet.2012.05.164

Tetrahedron Letters 53 (2012) 4221–4224
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
sp3 C–H bond functionalization of methyl n-alkyl ketones [MeCOCnH2n+1
(n = 6–8)] as a novel method for the one-pot regioselective synthesis
of ‘bifunctional alkanes’ with remote functional groups
⇑
Irena S. Akhrem , Lyudmila V. Afanas’eva, Nikolai D. Kagramanov, Pavel V. Petrovskii
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Selective one-pot functionalization of methyl n-alkyl ketones, CnH2n+1COMe (n = 6–8) involving C-sp3–H
bond cleavage with CO and various nucleophilic substrates [iPrOH, BuCH(Et)CH2OH, CF3CH2OH,
(CF3)(Me)CHOH, H(CF2)2CH2OH, HC„CCH2OH, furan, thiophene, and anisole] in the presence of the
superelectrophilic system CBr4Á2AlBr3 has been performed for the first time.
Article history:
Received 18 January 2012
Revised 11 May 2012
Accepted 31 May 2012
Available online 9 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
n-Alkyl methyl ketones
Functionalization
Superelectrophiles
Functionalized ketones
Ketones are a broad class of organic compounds, which are pro-
duced industrially as solvents, polymers, pharmaceutical precur-
sors, perfumes, etc.1 In methyl n-alkyl ketones, there are three
only with higher ketones and aldehydes.5 In the second case, car-
bonylation of methyl isoalkyl ketones in excess HF-SbF5 was
shown to occur selectively at the
x-1 position to produce the cor-
reaction centers, namely: CO and
a
- and b-C–H bonds. In contrast
responding acids after quenching of the carbonylation intermedi-
ate with water. However, the ketone conversions were in the
range of 16–66%. The attempts to perform selective carbonylation
of methyl n-alkyl ketones with CO in the presence of this proton
superacid were unsuccessful. The reactions of linear ketones either
did not occur at all or led to mixtures consisting predominantly of
degradative carbonylation products with smaller numbers of C
atoms in the alkyl group at the carbonyl than in the initial ketones,
while the desired products were formed in only small amounts, or
not at all.6
to - and b-C–H bonds, the other C–H bonds in ketones are inert to
a
both common nucleophiles and electrophiles (Scheme 1).
Transition metal complexes were shown to form chelates with
ketones with the participation of ketone
a
- or b-C–H bonds.2,3
While ketone sp3 C–H bond functionalization by transition metal
complexes results in chelate formation, functionalization by super-
electrophiles4 opens the unique possibility to introduce a novel
functional group into the most distant position from the existing
carbonyl group and to obtain regioselectively, bifunctional prod-
ucts of neo- or tertiary structures.5–9 Prior to our studies,7–9 only
two cases of one-pot, selective sp3 C–H bond intermolecular func-
tionalization of monofunctional linear aliphatic compounds by
superelectrophiles were reported.5,6 One of these involved in reac-
tions of aliphatic alcohols, ketones, and aldehydes with ozone in
magic acid in SO2ClF.5 Primary alcohols containing tertiary or sec-
We have found that the use of the potent superelectrophilic
complexes, CX4Á2AlX3 (X = Br or Cl) allows easy generation, not
only of carbocations R+ from alkanes RH,10 but also carbocations
Enolization
Halogenation
ondary C–H bonds at the c-position, or more remote from the oxo-
nium center, were shown to undergo insertion reactions with
Dehydrogenation
protonated ozone to give oxidation products in good yield. In con-
trast to primary alcohols, secondary C–H bonds at the c-position of
aldehydes and ketones remained unreactive toward ozone in
SO2ClF at À40 °C. Such reactions with protonated ozone occurred
CH3CCH2CH2(CH2)nH
O
Addition of nucleophiles
Coordination with strong electrophiles
⇑
Corresponding author. Tel.: +7 499 135 93 29; fax: +7 499 135 50 85.
E-mail address: cmoc@ineos.ac.ru (I.S. Akhrem).
Scheme 1. Reaction centers in ketones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.164

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I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 4221–4224
XR1 (X is a functional group) from n-alkyl acetates8,9 and mono-
functional adamantanes.7 In the presence of CO, cations R+ and
XR1+ convert spontaneously into the acyl cations RCO+ and XR1CO+,
respectively. In turn, the acyl cations RCO+ and XR1CO+, under the
action of nucleophilic substrates, produced monofunctional and
bifunctional products, respectively, in which the initially present
functional group remained intact.
located at the quaternary C atom, being the most distant from
the parent carbonyl group (Scheme 4).
+
In this case, the new functional group was separated from the
initial carbonyl by five carbon atoms. A similar tendency was ob-
served for n-alkyl acetates.7,8 The easier formation of the neo-prod-
ucts from methyl n-heptyl ketone with a longer alkyl chain showed
that isomerization of the long-chain cation MeCOC7H15+ proceeded
more rapidly than isomerization of its shorter homologs.
The synthesis of bifunctional aliphatic compounds with neo
structures is of special interest because they display valuable prop-
erties, such as enhanced thermal and chemical stabilities, low
freezing points, etc.12 The content of these neo products was no
less than ꢀ90% in the corresponding isomeric mixtures; in some
cases, other isomers were totally absent. The yields of the products
with alcohols, such as iPrOH, CF3CH2OH, CF3(Me)CHOH,
H(CF2)2CH2OH, ranged from 68% to 99%, while the yields of dike-
tones from anisole and thiophene, and an ester from BuCH(Et)CH2-
OH were approximately 50%. Alongside the diketone, the alkylation
product, MeCOC7H14C6H4OMe was formed in a small amount in
the reaction with anisole.
In this Letter, we report the first case of sp3 C–H bond function-
alization of methyl n-alkyl ketones resulting in bifunctional prod-
ucts with remote functional groups. We found that at À20 °C
under atmospheric CO pressure and in the presence of 50% molar
excess of the superelectrophilic complex CBr4Á2AlBr3, carbonyl-
ation of methyl n-alkyl ketones [CnH2n+1COMe (n = 6–8)] followed
by treatment of the carbonylation products with nucleophilic
agents led to the corresponding bifunctional products in good or
moderate yields. No products of destructive functionalization, in
which the number of carbon atoms in the alkyl group differed from
that in the initial ketones, were observed (Scheme 2).
The carbonyl group is clearly a much stronger nucleophile than
an sp3 C–H bond. However, while the interaction of the superelec-
trophile with a carbonyl group is reversible, C–H bond cleavage fol-
lowed by acylium cation formation in the presence of CO is virtually
irreversible. As a result, the less nucleophilic center can still react
with the superelectrophile, even in the presence of the much stron-
ger CO donors. Undoubtedly, the bonding of the carbonyl group to
the superelectrophile not only hinders the generation of the cation,
but also reduces the superelectrophilicity of the media.
The functionalization of methyl n-octyl ketone by CO with
iPrOH, thiophene, and anisole also occurred effectively, resulting
almost exclusively in the bifunctional products of neo structure
in good yield (Scheme 5).
It is important to note that furan (Scheme 4) and thiophene
(Scheme 5), which are very active toward electrophiles, can be suc-
cessfully involved in the functionalization reactions.
We do not think that the coordination of a CO molecule to the
superelectrophile in the presence of the much stronger donor car-
bonyl group takes place. In fact, our calculations of the mechanism
of methane carbonylation with CO in the presence of superelectr-
ophilic complexes CX4Á2AlX3 have shown that CO forms only very
weak solvates with superelectrophiles, in which the bond lengths
and charges are practically the same as in the free CO molecule.11
At À20 °C, the functionalization of methyl n-hexyl ketone oc-
curred regioselectively to form products with the tertiary struc-
tures in moderate yields (Scheme 3).
This study demonstrates that in the presence of a carbonyl
group, a single carbocation is generated selectively in all of the
above reactions. Therefore, the corresponding acylium cation accu-
mulates in the reaction medium, allowing for regioselective func-
tionalization of the ketone. We believe that the site for hydride
abstraction from the methyl n-alkyl ketone molecule is determined
by two factors, namely: (1) its remoteness from the already exist-
ing carbonyl group, and (2) the stability of the carbocation gener-
ated. For ketone MeCOCnH2n+1 (n = 6), the remoteness from the
carbonyl is the decisive factor leading to an isocation with a non-
isomerized alkyl segment, while for ketones MeCOCnH2n+1 (P7),
the two factors work together to produce the most stable tertiary
cation separated from the parent carbonyl group by four or more
methylenes. The functional groups are remote from the original
carbonyl by 5 (n = 6 or 7) and 6 (n = 8) carbon atoms. We believe
that the different locations of the functional groups in these prod-
ucts are mainly due to repulsion between the carbonyl group coor-
dinated to the electrophile and the generated carbocation, rather
than to the higher stabilities of tertiary cations C(O)C+(Me)2 com-
pared with those of C(CO)C+(Me)(Alkyl) (where alkyl = Et, Pr, etc.).
All the products obtained in this study are new. Their structures
were established from 1H, 13C, and 19F NMR spectra, and mass
spectrometry. A typical procedure is presented.13
Functionalizations of methyl n-heptyl ketone by CO in the pres-
ence of the superelectrophilic system CBr4Á2AlBr3 (E) followed by
i
treatment of the carbonylation product with PrOH were shown
to proceed effectively both at À20 and at À10 °C, and at molar ra-
tios [E]:[ketone] of 1.5:1 and 1.3:1, respectively. At À20 °C for 2 h,
the conversion of ketone was close to 100% and a single neo-prod-
uct MeCOC7H14COOPri was formed. At À10 °C, the conversion and
selectivity were somewhat lower.
At À20 °C, functionalizations of methyl n-heptyl ketone,
[CnH2n+1COMe (n = 7)] by CO and various nucleophiles (iPrOH,
BuCH(Et)CH2OH, CF3CH2OH, CF3(Me)CHOH, H(CF2)2CH2OH, C6H5
OMe, and thiophene) resulted almost exclusively in bifunctional
products of the neo-structure, in which the functional group was
n = 6
Nu
O
O
+
+
CnH2n
CnH2nCO
+
CO
1. HNu:
2. H2O
CnH2n+1
CBr3
O
O
-HCBr3
O
E
E
n = 7, 8
E = CBr4. 2AlBr3
n = 6 - 8
HNu: = alcohol, arene, heteroarene
Nu
m
O
O
m = 1, 2
Scheme 2. One-pot functionalization of methyl n-alkyl ketones by CBr4Á2AlBr3.

I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 4221–4224
4223
+
CO
.
CBr4 2AlBr3
CO
+
-20 oC
O
O
i PrOH
HOCH2C CH
anisole
O
i Pr
O
O
O
OCH2C CH
O
O
O
O
1 (53%)
2 (43%)
3 (40%)
Scheme 3. One-pot functionalization of methyl n-hexyl ketone.
O
O
CH(Me)CF3
O
OCH2CH(Et)Bu
OMe
O
O
O
7 (99%)
O
O
O
8 (52%)
9 (53%)
HOCH(Me)CF3
HOCH2CH(Et)Bu
+
O
O
CO
10 (45%)
O
O
OMe
O
HOCH2CF3
O
i PrOH
HOCH2(CF2)2H
O
O
i Pr
CH2(CF2)2H
CH2CF3
O
6 (68%)
O
O
O
O
5 (88%)
O
4 (78%)
Scheme 4. Products of the one-pot functionalization of methyl n-heptyl ketone.
O
O
+
CO
i PrOH
S
OMe
OMe
O
O
O
O
i Pr
S
O
O
O
13 (70%)
12 (55%)
11 (78%)
Scheme 5. Products of the one-pot functionalization of methyl n-octyl ketone.

4224
I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 4221–4224
3. Barrio, P.; Castarlenas, R.; Esteruelas, M. A.; Onate, E. Organometallics 2001, 20,
In summary, a new approach for the one-pot sp3 C–H function-
2635.
alization of methyl n-alkyl ketones has been demonstrated. The
use of a powerful superelectrophilic complex, CBr4Á2AlBr3 makes
possible the regioselective synthesis of ketones with remote func-
tional groups. A major benefit of this approach consists of the gen-
eration, under a CO atmosphere, of an acylium cation which serves
as a synthon for the one-pot synthesis of a broad series of bifunc-
tional products from each ketone.
4. Olah, G. A.; Surya Prakash, G. K.; Molnar, A.; Sommer, J. Superacid Chemistry;
John Wiley & Sons: New Jersey, 2009.
5. Olah, G. A.; Yoneda, N.; Ohnishi, R. J. Am. Chem. Soc. 1976, 98, 7341.
6. Yoneda, N.; Sato, H.; Fukuhara, T.; Takahash, Y.; Suzuki, A. Chem. Lett. 1983, 19.
7. Akhrem, I. S.; Avetisyan, D. V.; Afanas’eva, L. V.; Kagramanov, N. D.; Petrovskii,
P. V.; Orlinkov, A. V. Tetrahedron Lett. 2010, 51, 907.
8. Orlinkov, A. V.; Kagramanov, N. D.; Petrovskii, P. V.; Akhrem, I. S. Tetrahedron
Lett. 2010, 51, 259.
9. Akhrem, I. S.; Avetisyan, D. V.; Afanas’eva, L. V.; Orlinkov, A. V.; Kagramanov, N.
D.; Petrovskii, P. V. Mendeleev Commun. 2011, 6, 323.
Acknowledgements
10. (a) Akhrem, I. S.; Orlinkov, A. V.; Vol’pin, M. E. J. Chem. Soc. Chem. Commun.
1993, 671; (b) Akhrem, I. S.; Orlinkov, A. V. Chem. Rev. 2007, 107, 2037 and
references therein.
11. Chistyakov, A. L.; Stankevich, I. V.; Gambaryan, N. P.; Akhrem, I. S. Dokl. Akad.
Nauk 2006, 408, 780.
We thank the Russian Foundation for Basic Research (Project N
09-03-00110) and the Russian Academy of Sciences Presidium
Fund (Program 7P) for financial support.
12. Fatty Acids in Industry; Johnson, R. W., Fritz, E., Eds.; Marcel Dekker: New York,
Basel, 1989. Chapter 11, p. 233.
13. Typical procedure: At -20 °C, under atmospheric CO pressure, methyl n-alkyl
ketone (0.8–2.0 mmol) was added to a stirred solution of CBr4Á2AlBr3 (1.20–
3.0 mmol, respectively), freshly prepared from AlBr3 and CBr4 in the molar
ratio 2:1 in anhydrous CH2Br2 (1–2 mL) at room temperature. After stirring for
2–3 h at À20 °C under a CO atmosphere, a nucleophile was added to the in situ
prepared carbonylation intermediate strictly under CO. The mixture was
stirred for 10–15 min at À20 °C and then left to warm to 0 oC over 20–30 min.
Next, H2O (10 mL) and CHCl3 (30 mL) were carefully added to the mixture. The
organic layer was separated and the remaining aqueous layer was extracted
with CHCl3 (10 mL). The combined organic phase was dried over Na2SO4. The
structures of the products were established by 1H, 13C, and 19F NMR, and from
GC–MS spectra; conversions and isomeric ratios were determined by GC. To
perform NMR measurements, all solvents and highly volatile compounds were
removed under reduced pressure. In some cases, to remove by-products, the
product was washed with a suitable solvent and repeatedly dried in vacuum.
The yields of the products obtained were determined by 1H NMR spectroscopy
with mesitylene as an internal standard.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
164. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. Organic Chemistry; Morrison, R. T., Boyd, R. N., Eds., second ed.; Allyn and Bacon,
Inc.: Boston, 1970. Chapter 19, Aldehydes and ketones.
2. Feller, M.; Karton, A.; Leitus, G.; Martin, J. M.; Milstein, D. J. Am. Chem. Soc. 2006,
128, 12400.