The first one-pot 'alkane-like' reactions of carbonyl-containing adamantanes

Article abstract of DOI:10.1016/j.tetlet.2009.12.022

A novel 'alkane-like' methodology for the direct and very simple one-pot functionalization of amides and an ester of 1-adamantanecarboxylic acid provides access to new and synthetically challenging 1,3-dicarbonyl-containing adamantanoid compounds with the same or different functional groups.

Full text of DOI:10.1016/j.tetlet.2009.12.022

Tetrahedron Letters 51 (2010) 907–911
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first one-pot ‘alkane-like’ reactions of carbonyl-containing adamantanes
*
Irena Akhrem , Dzhul’etta Avetisyan, Lyudmila Afanas’eva, Nikolai Kagramanov, Pavel Petrovskii,
Alexander Orlinkov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow 119991, Russian Federation
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
Revised 26 November 2009
Accepted 4 December 2009
Available online 11 December 2009
A novel ‘alkane-like’ methodology for the direct and very simple one-pot functionalization of amides and
an ester of 1-adamantanecarboxylic acid provides access to new and synthetically challenging 1,3-dicar-
bonyl-containing adamantanoid compounds with the same or different functional groups.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
‘Alkane-like’ reactions
Synthesis
1,3-Dicarbonyl-containing adamantane
Superelectrophiles
1. Introduction
Herein we report a novel method for the introduction of a car-
bonyl-containing functional group, via C–H activation, into the sat-
Selective, one-pot C–H functionalization of monofunctional or-
ganic molecules is a promising method for the synthesis of bifunc-
tional compounds with desired properties. However, finding
reagents and conditions for such transformations represents a con-
siderable challenge, as most functional groups have low tolerance
to the highly reactive species and catalysts that are able to cleave
non-activated sp3 C–H bonds.
Examples of the one-pot C–H selective functionalization of
monofunctional organic compounds are very rare.1,2 The reactions
of aliphatic alcohols, ketones, and aldehydes with ozone and magic
acid in SO2ClF or FSO3H solvent have been reported.1 Tertiary or
urated hydrocarbon moiety of monofunctionalized adamantanoid
compounds. Remarkably, the initial functional group remains in-
tact during the reaction which occurs in a highly selective manner
under very mild conditions.
Our strategy for the one-pot functionalization of alkanes was
based on the use of the superelectrophiles CX4ꢁ2AlBr3 (X = Cl,
Br),4,5 which, as we have found, can easily generate R+ carbocations
from RH even below room temperature. In the presence of CO, R+ is
transformed into the much more stable acyl cation RCO+. The latter,
in turn, can be converted into carbonyl-containing functionalized
hydrocarbons RCOY upon addition of HY nucleophiles. In this man-
ner, we have obtained a variety of carbonyl-containing compounds
directly from saturated hydrocarbons RH, CO, and YH (alcohols;
aliphatic, cyclic, heterocyclic and aromatic amines; tetraorganosil-
anes; aromatics; heteroaromatics; tetrahydrofuran; etc.) in the
presence of CX4ꢁ2AlBr3 in a one-pot procedure (Scheme 1).5
The obtained results5 prompted us to propose that the same
strategy based on electrophilic C–H activation might be suitable
for the synthesis of bifunctional products from hydrocarbons al-
ready bearing one functional group. However, further functionaliza-
tion of an already monosubstituted hydrocarbon seemed to be a
more challenging task for the following two reasons. First, the pres-
ence of an electron-withdrawing group on the substrate is expected
to destabilize the generated carbocation. Second, lone electron pairs
on the already present functional group were expected to interact
with the superelectrophile, resulting in diminished reactivity.
Monofunctional adamantanes 1-AdCOX, where X = NH2 (I), NEt2
(II), or OMe (III), were chosen as substrates on the basis of the
secondary C–H bonds of primary alcohols located at the c-position,
or further removed from the functional group were shown to un-
dergo insertion reactions with protonated ozone to give oxidation
products in good yields. In contrast, secondary C–H bonds at the
c-position of aldehydes and ketones remained unreactive toward
ozone under similar conditions. Such reactions with protonated
ozone occurred only with higher ketone and aldehyde homo-
logues.1 Attempts to perform selective carbonylation of methyl
n-alkyl ketones with CO in the presence of excess HF-SbF5 were
unsuccessful.2 Under these conditions, only methyl n-alkyl ketones
MeCOCnH2nꢀ1 (n = 7–9) having tertiary C–H bonds were selectively
carbonylated with the conversions of the ketones being only 16–
66%.2 Initial attempts to react carbonyl-containing adamantanes
with CO or HCOOH in protic superacids were unsuccessful.3
* Corresponding author. Tel.: +7 499 135 9329.
E-mail address: cmoc@ineos.ac.ru (I. Akhrem).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.022

908
I. Akhrem et al. / Tetrahedron Letters 51 (2010) 907–911
ESTERS
AMIDES
+
CX3
CO
R+
RCO+
RH
ALKYL- and ARYL KETONES
HETEROARYL KETONES
C2H6, C3H8, n-C4H10, n-C5H12
,
R'
RH =
(R' = Me, Et)
Scheme 1. Examples of one-pot alkane functionalizations.
following considerations. First, 1-substituted adamantanes such as
amides and esters of 1-adamantanecarboxylic acid are commer-
cially available. Second, these molecules contain three relatively
reactive CH–bonds in the bridgehead positions. The projected
transformation would lead to 1,3-bifunctional adamantanes that
could be useful in the synthesis of new biologically active com-
pounds,6,7 thermal and chemical stable polymers,8 novel crown
ethers, peptide ionophores,9 and other valuable fine chemicals.6 Fi-
nally, the CONR2 and COOMe groups already present, and those to
be introduced, can be easily transformed into a broad range of
other functionalities, including COOH, CN, CH2NR2, COOR0, and
CON(OH)R0.6c
Thus the development of simple and efficient methods to syn-
thesize 1,3-dicarbonyl-containing adamantanes directly from
readily available monosubstituted starting materials is expected
to open new methods for the preparation of novel biologically ac-
tive compounds, polymers, and other valuable products.
In this work, we report that the use of the powerful superelec-
trophile CBr4ꢁ2AlBr3 in a 30–50% excess allows the effective car-
bonylation of monofunctional adamantanes 1-AdCOX (I, II, and
III), and as a result, the preparation of various 1,3-bifunctional ada-
mantanes in high yields and with good selectivity (Scheme 2).
The carbonyl group is clearly a much stronger nucleophile than
an sp3 C–H bond. However, while interactions of the superelectro-
phile with the carbonyl group are reversible, C–H bond cleavage
followed by acylium cation formation in the presence of CO is vir-
tually irreversible. As a result, the less nucleophilic center can still
react with the superelectrophile, even in the presence of much
stronger CO donors.
The carbonylation of I, II, and III under atmospheric CO pressure
in the presence of polyhalomethane superelectrophiles was studied
in detail in the temperature range 0 °C to ꢀ20 °C. The CX4ꢁnAlCl3
(X = Cl, Br, n = 1–2), CCl4ꢁnAlBr3 (n = 1–2), and CBr4ꢁnAlBr3 (n =
1–3) systems were tested as superelectrophiles (E) in CH2X2
(X = Br, Cl). The dependence of the results on the nature and molarity
of the superelectrophile, the temperature, and duration of the reac-
tion was studied. In situ treatment of the resultant carbonylated
product was carried out under the optimal conditions found,
namely, with 2–4 equiv of various HY nucleophiles with respect to
I, at ꢀ20 °C to 0 °C; 0.5 h (depending on the nature of the nucleo-
phile). The following nucleophilic substrates HY were used: alco-
hols, amines (diethylamine, pyrrolidine, piperidine, morpholine,
and aniline), aromatics, and aromatic heterocycles (anisole, pyrrole,
thiophene, and furan), and ethylene.
For the carbonylation of 1-AdCONH2 (I), the molar ratio [I]:[E],
the reaction time, and the molarity of E ranged from 1:1 to 1:3,
from 1 to 20 h, and from 0.38 to 1.17 M, respectively. Comparison
of the CBr4ꢁ2AlBr3 and CCl4ꢁ2AlCl3 systems under the same condi-
tions ([I]:[E] = 1, 0 °C, 4 h) showed that, in both cases, the same
products were formed and the conversions of I were very similar,
but the selectivities of these reactions were different. Indeed, the
yields of 1,3-Ad(CONH2)(COOPri) were 65% and 36%, and those of
the by-product 1,3-Ad(CONH2)Br amounted to 23% and 50%,
respectively. Using the CBr4ꢁ2AlBr3 system under different condi-
tions ([I]:[E] = 1:1; 10 °C; 3 h, treatment with pyrrole) resulted in
a 24% yield of the pyrrole acylation product and a 51% yield of
the 1,3-Ad(CONH2)Br by-product.
Thus, the selectivity of the formation of 1,3-bifunctional ada-
mantanes was not high in equimolar reactions at 0 °C to ꢀ20 °C
even with the most potent CBr4ꢁ2AlBr3 superelectrophile. However,
at 0 °C for 2.5–4 h in the presence of 30–50% excess of CBr4ꢁ2AlBr3,
the carbonylation of amide I became the main process. This en-
abled the preparation of acylation products in high yield, and as
a rule, with high selectivity. Two by-products were formed in small
amounts in these reactions: the bromide 1,3-Ad(CONH2)Br and
alkylation 1,3-Ad(CONH2)Y products. In most cases, their amounts
ranged from 0–6% and 0–15%, respectively.
The observed results are shown in Scheme 3.
The proposed mechanistic scheme includes the generation of
cation A from amide I coordinated with the superelectrophile. This
cation can either add Br- from the solvating Al2Br7 anion or a neu-
ꢀ
tral CO molecule. The addition of Brꢀ occurs more easily, as intra-
molecular transformations of cations proceed more readily than
intermolecular examples.10 Increasing the temperature favors
X
O
X
O
E
X
O
X
O
E
1) HY
E
CO
2) H2O
+
- EH
CO+
COY
-
Al2Br7
-
Al2Br7
E = CBr3+ Al2Br7
-
X = NH2 (I), NEt2 (II), OMe (III)
;
Scheme 2. One-pot synthesis of 1,3-bifunctional adamantanes.

I. Akhrem et al. / Tetrahedron Letters 51 (2010) 907–911
909
O
H2N
E
O
H2N
O
H2N
E
CO
E
+
- EH
-
CO+
Al2Br7
-
Al2Br7
I
(A)
(B)
-
E = CBr3+ Al2Br7
1) HY
1) HY
H2O
2) H2O
2) H2O
O
O
H2N
H2N
O
H2N
Y
COY
Br
Scheme 3. Reactions of 1-AdCONH2 (I) with CO and HY nucleophiles in the presence of CBr4ꢁ2AlBr3.
decarbonylation of the acyl salt and, consequently, the formation
of the above-mentioned by-products becomes more significant.
At 0 °C under CO and in the presence of excess superelectrophile,
the formation of bromide most probably represents a reversible
process. It is likely that acylium salt B is more stable at 0 °C under
the CO atmosphere, in comparison with AdCO+, because acceptor
groups in RCO+ stabilize the acylium salts against decarbonyla-
tion.11 Therefore, the bromide is a minor product under the opti-
mal conditions.
acylation products selectively and in high yields. These reactions
usually proceeded more selectively than those with I. In most
cases, the desired products were obtained in 81–96% yields, with
the conversions being almost 100%. No alkylation products were
produced in these reactions. It is worth noting that these 1,3-
bifunctional adamantanes can be prepared, as a rule, more easily
in an analytically pure state from II and III than from I. In most
cases, it was sufficient to just wash the crude products with
pentane.
Although both carbonylation and the subsequent reactions with
nucleophiles were carried out under a strict CO atmosphere, 1,3-
Ad(CONH2)Y alkylation products were still formed in some cases.
Their formation indicates the existence of an equilibrium between
A and B even at 0 °C in the presence of CO. Although this equilib-
rium is shifted toward B, and cation A is probably present in the
solution in only a small amount, the alkylation proceeds faster than
the acylation. Contrary to bromide formation, the processes yield-
ing the 1,3-Ad(CONH2)Y alkylation products are irreversible.
Functionalization of I with CO and piperidine proceeded less
selectively than with other nucleophiles, producing noticeable
amounts of the alkylation product 1,3-Ad(CONH2)(C5H10N).
We showed that in the presence of CBr4ꢁ2AlBr3, the alkylation of
I with a nucleophile could be carried out in moderate yield if the
nucleophile was added to the reaction mixture in the absence of
CO. Indeed, when thiophene was added to I at ꢀ30 °C in the pres-
ence of CBr4ꢁ2AlBr3, an exothermic reaction was observed giving
1,3-Ad(CONH2)Y and 1,3-Ad(CONH2)Br in 47% and 18% yields,
respectively, with full conversion of I in 1 h (Scheme 4).
The reactions of ethylene with the acyl salts generated in situ
from II and III were nonselective. At ꢀ40 °C, after 1 h, the reaction
of ethylene (1 atm) with 1,3-Ad(CONEt2)CO+ generated in situ from
II (0 °C, 4 h) produced 1,3-Ad(CONEt2)COCH@CH2 (30%) together
with 1,3-Ad(CONEt2)COCH2CH2Br (10%) and 1,3-Ad(CONEt2)CO-
CH2CH2OH (9%). At ꢀ20 °C, this reaction yielded 1,3-Ad(CONEt2)-
COCH@CH2 (67%) and 1,3-Ad(CONEt2)COCH2CH2Br (10%). By con-
trast, at ꢀ20 °C or at 0 °C, the reaction of the acyl salt generated from
III with ethylene led to alkylation products with Ad(COOMe)-
CH2CH2Br as the main product.
The previously described methods for the preparation of 1,3-
dicarbonyl-containing adamantanes are based on 1,3-adaman-
tane-dicarboxylic acid as the starting material.6–9,12,13 The disad-
vantages of these methods include the limited availability of the
diacid, the necessity to use strong protic acids such as oleum,
and a multistep synthesis involving carbonylation of adamantane
or its derivatives (1-AdCOOH or 1-AdBr) into 1,3-Ad(COOH)2,12 fol-
lowed by conversion into 1,3- Ad(COCl)2 and transformation into
the desired final product. In some cases, this reaction sequence re-
sulted in poor selectivities and low yields (often below 30% even
for the final step).13 Furthermore, these methods are not simple
routes for synthesizing adamantanes with two different functional
groups. By contrast, our new method offers a number of advanta-
ges, including simplicity (one-pot procedure), high selectivities,
and good yields of a wide range of products bearing identical or
different substituents at the 1 and 3 positions.
Under the optimal conditions, the yields of the desired 1,3-
bifunctional products were 67–90% with conversions of I being
close to 100%.
Under the above conditions (0 °C, 2.5–4 h), amide 1-AdCONEt2
(II) and methyl 1-adamantanecarboxylate 1-AdCOOMe (III) also re-
acted readily with CO at atmospheric pressure in the presence of
30–50% excess of the CBr4ꢁ2AlBr3 superelectrophile to form the
CONH2
CONH2
CONH2
CBr4 2AlBr3
+
+
- 30 oC, 1 h
S
Br
S
I
47%
18%
Scheme 4. The alkylation and bromination of I in the absence of CO.

910
I. Akhrem et al. / Tetrahedron Letters 51 (2010) 907–911
COX
COX
COCH=CH2
67%
CO
COX
NH
COX
II
I
68%
COOiPr
CONEt2
88-95%
N
CH2=CH2
N
H
COX
84-95% (80-87%, I , III)
HNEt2
ROH
COX
COX
CO
HN
NH2
67-95% (53%, I; 85%, II, III)
CONHC6H5
COX
HN
O
III
(73%)
OMe
CO
N
O
COX
S
O
NH
77-94% (70-85%)
COX
OMe
CO
COX
COX
III
S
CO
94% (85%)
NH
O
CO
CO
75-80% (75%, II)
I
78%
77-95% (60-70%, II, III)
X = NH2 (I), NEt2 (II), OMe (III)
Scheme 5. The starting adamantanes I–III were used to generate all the products with the exception of those cases specifically marked (for example, III means that only
compound III was used in that particular reaction). The yields were determined by GC and NMR-methods, the yields of isolated products are given in brackets.
The products obtained are presented in Scheme 5.
rated and the aqueous solution was extracted again with CHCl3
(10 mL). The combined CHCl3 extracts were washed with H2O
and dried over MgSO4. After removing the solvent under reduced
pressure, the product was precipitated from minimal amounts of
toluene (benzene, ether, dioxane, and acetone) with pentane or
hexane, or washed with pentane or hexane. The product of reaction
III, CO and anisole was purified by crystallization from petroleum.
Conversions of I, II, or III were determined by GC, yields of prod-
ucts were measured by GC or NMR (with 1,3,5-tribromobenzene
as an internal standard). If the elemental analysis of a product
was not satisfactory, the above-mentioned procedure for the puri-
fication was repeated.
The structures of the products were proved from elemental
analysis, 1H and 13C NMR and mass spectroscopy. The products
of the in situ treatment of the carbonylation products II and III
with ethylene were characterized by GC–MS only.
Almost all the products obtained are new compounds. Their
melting points, elemental analyses, mass spectra, and 1H and 13C
NMR spectra are provided as Supplementary data. The assignment
of the chemical shifts was made mostly on the basis of calculated
values obtained with the Program ACD/HCNMR DB.
In summary, an ‘alkane-like’ strategy has been successfully dem-
onstrated for the selective one-pot synthesis of novel 1,3-bifunc-
tional adamantanes with the same or different functional groups,
from readily available derivatives of 1-adamantanecarboxylic acid,
CO, and various nucleophiles. We believe that this approach can be
extended to the preparation of other 1,3-disubstituted adamantanes
bearing desired functional groups. We are currently working on the
application of this concept to the synthesis of bifunctionalized
hydrocarbons from monofunctionalized alkanes.
Acknowledgments
We thank the Russian Foundation for Basic Research (Project N
09-03-00110) and the RAS Presidium Fund (Program 18P) for
financial support.
Supplementary data
2. Typical experimental procedure
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.022.
At 0 °C under atmospheric CO pressure, I, II, or III was added
with stirring to freshly prepared CBr4ꢁ2AlBr3 (E) in anhydrous
CH2Br2 at room temperature. Molar ratio [I] (II or III):E = 1:(1.3–
1.5); [E] ꢂ 1 M). The mixture was stirred for 2.5–4 h. The reaction
mixture was cooled to ꢀ20 °C and the nucleophilic substrate (2–
4 equiv with respect to I, II, or III) was added under atmospheric
CO. The mixture was allowed to warm to 0 °C and then cold CHCl3
(ꢂ10 mL per 0.2 g of the starting adamantane) and H2O (20 mL)
were carefully added under cooling. The organic extract was sepa-
References and notes
1. Olah, G. A.; Yoneda, N.; Ohnishi, R. J. Am. Chem. Soc. 1976, 98, 7341.
2. Yoneda, N.; Sato, H.; Fukuhara, T.; Takahashi, Y.; Suzuki, A. Chem. Lett. 1983, 19.
3. Kontonassios, D.; Sandris, C.; Tsatsas, G.; Casadio, S.; lumachi, B.; Turba, C. J.
Med. Chem. 1969, 12, 170.
4. Akhrem, I. S.; Orlinkov, A. V.; Vol’pin, M. E. J. Chem. Soc., Chem. Commun. 1993,
671.

I. Akhrem et al. / Tetrahedron Letters 51 (2010) 907–911
911
5. Akhrem, I. S.; Orlinkov, A. V. Chem. Rev. 2007, 107, 2037. and references cited
therein.
92078.; (d) Thompson, R. M. US Patent 3832332, 1974; Chem. Abstr. 1975, 82,
17791.
6. (a) Fort, R. C. Adamantane: The Chemistry of Diamond Molecules; Marcel Dekker:
New York, 1976; (b) Kurisaki, K. Chem. Econ. Eng. Rev. 1976, 8, 12; (c) Bagrii, E. I.
Adamantanes: Production, Properties, Application; Nauka: Moscow, 1989 (in
Russian); (d) Kovtun, V. Yu.; Plakhotnic, V. M. Zh Khim. Farmi. 1987, 28, 931 (in
Russian), and patents cited therein; (e) Shvekhgeimer, M.-G. A. Uspekhi Khim.
1996, 65, 603 (in Russian).
7. The incorporation of the adamantane cage into pharmaceuticals and other
biologically active compounds is reported Ref. 6d and in: (a) Tsuzuki, N.; Hama,
T.; Kawada, M.; Hasui, A.; Konishi, R.; Shiwa, S.; Ochi, Y.; Futaki, S.; Kitagawa, K.
J. Pharm. Sci. 1994, 83, 481; (b) Tsuzuki, N.; Hama, T.; Hibi, T.; Konishi, R.;
Futaki, S.; Kitagawa, K. Biochem. Pharmacol. 1991, 41, R5; (c) Wishnok, J. S. J.
Chem. Educ. 1973, 50, 780.
9. (a) Chaikovskaya, A. A.; Kudrya, T. N.; Pinchuk, A. M. Zh. Org. Khim. 1989, 25,
2000 (in Russian); (b) Yurchenko, A. G.; Likhotvoric, I. P.; Melnik, N. N. Zh. Org.
Khim. 1990, 26, 1808 (in Russian); (c) Kobiro, K.; Takada, S.; Odavia, J.;
Kawasaki, Y. Bull. Chem. Soc. Jpn. 1985, 88, 3635; (d) Ranganathan, D.; Haridas,
V.; Madhusudanan, K. P.; Roy, R.; Nagaraj, R.; John, G. B. J. Am. Chem. Soc. 1997,
119, 11578; (e) Ranganathan, D.; Haridas, V.; Madhusudanan, K. P.; Roy, R.;
Nagaraj, R.; John, G. B.; Sukhaswami, M. B. Angew. Chem., Int. Ed. 1996, 35, 1105;
(f) Mlinaric–Majerski, K.; Kragol, G. Kem. Ind. 2000, 49, 239.
10. Hogeveen, H.. In Advances in Physical Organic Chemistry; Gold, V., Ed.; Academic
Press: London, 1973; Vol. 10, p 29.
11. Orlinkov, A. V.; Akhrem, I. S.; Vol’pin, M. E. Russ. Chem. Rev. 1991, 60, 524.
12. Butenko, L. N.; Derbisher, V. E.; Khardin, A. P.; Shreibert, A. I. Zh. Org. Khim.
1973, 9, 728 (in Russian).
8. (a) Khardin, A. P.; Radchenko, S. S. Uspekhi Khim. 1982, 51, 480 (in Russian); (b)
Novakov, I. A.; Orlinson, B. S. Vysokomolecularnye soedineniya 2005, 47, 1302 (in
Russian); (c) Driscoll, G. L. US Patent 3464957, 1967; Chem. Abstr. 1969, 71,
13. Yagrushkina, N.; Zemtzova, M. N.; Klimochkin, Yu. N.; Moiseev, I. K. Zh. Org.
Khim. 1994, 30, 842 (in Russian).