The first selective one-pot synthesis of 1,3-dicarbonyl adamantanes from adamantane and 1,3-dimethyladamantane

Article abstract of DOI:10.1016/j.tetlet.2012.04.125

A new approach to a simple one-pot functionalization of adamantane and 1,3-dimethyladamantane with CO and various nucleophiles in the presence of the superelectrophilic complex, CBr₄·2AlBr₃ provides access to important 1,3-dicarbonyl adamantanes with two new functional groups at the bridge-head positions.

Full text of DOI:10.1016/j.tetlet.2012.04.125

Tetrahedron Letters 53 (2012) 3493–3496
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The first selective one-pot synthesis of 1,3-dicarbonyl adamantanes
from adamantane and 1,3-dimethyladamantane
⇑
Irena S. Akhrem , Dzhul’etta V. Avetisyan, Luidmila V. Afanas’eva
A.N. Nesmeyanov Institute of Organoelement Compounds Russian Academy of Sciences, 28 Vavilov Street, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to a simple one-pot functionalization of adamantane and 1,3-dimethyladamantane with
CO and various nucleophiles in the presence of the superelectrophilic complex, CBr4Á2AlBr3 provides
access to important 1,3-dicarbonyl adamantanes with two new functional groups at the bridge-head
positions.
Received 8 February 2012
Revised 9 April 2012
Accepted 27 April 2012
Available online 2 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
One-pot synthesis
sp3 C–H bifunctionalization of adamantanes
Superelectrophiles
1,3-Dicarbonyl adamantanes
, 2) YH
1) CO
+
-
1,3-Dicarbonyl adamantanes are promising for the synthesis of
biologically active compounds,1 thermally and chemically stable
polymers,2 novel crown ethers, peptide ionophores,3 and other
important chemicals.4 The methods commonly used for their prep-
aration are based on 1,3-adamantanecarboxylic acid as the starting
material.5 The disadvantages of these methods include the limited
availability of the diacid, the necessity to use strong protic acids,
oleum, and a multistep procedure. In some cases, these reaction se-
quences result in poor selectivities and low yields.5e
We have elaborated two new one-pot methods for the prepara-
tion of 1,3-dicarbonyl adamantanes containing different or the
same carbonyl groups. The first method involves the functionaliza-
tion of amides and the methyl ester of 1-adamantanecarboxylic
acid by CO and nucleophiles.6 The second consists of the one-pot
bifunctionalization of bromoadamantanes.7 In both cases, the po-
tent superelectrophile, CBr4ÁAlBr3 was used as the initiating agent.8
Here, we report the first one-pot synthesis of 1,3-dicarbonyl
adamantanes from adamantane and 1,3-dimethyladamantane.
Readily available adamantanes are the most promising starting
compounds for the direct synthesis of 1,3-dicarbonyl adaman-
tanes. However, reaction (3) which involves the cleavage of two
C–H bonds was expected to be more difficult than reactions (1)
and (2), wherein, only one C–H bond is cleaved (Scheme 1).
At 0 °C under a CO atmosphere, adamantane was converted
quantitatively over 3 h, in the presence of 50% excess of the
superelectrophile CBr4Á2AlBr3 (E). However, after quenching the
.
Al2Br7
CBr3
1) AdX
2) AdBr
+
XAd' (CO)Y
,
,
Al2Br6
CBr3H HBr
1) 2 CO,2) 2 YH
+
-
]
Ad' [(CO)
Y
Al2Br7
CBr3
2
+
,
,
CBr3H
2HBr Al2Br6
,
2) 2 YH
1) 2 CO
CBr + Al2Br7
-
]
Y
Ad' [(CO)
2
2
AdH
3)
+
3
,
2CBr3H 2HBr, 2Al2Br6
;
= CONH , CONEt , COOMe Ad
=
2
;
X
adamantyl Ad' disubstituted adamantane
=
YH nucle2ophile
=
Scheme 1. One-pot synthesis of 1,3-dicarbonyl adamantanes from AdH and its
derivatives.
carbonylation product with iPrOH, the yield of 1,3-Ad(COOPri)2
was only 48%. The yield of Ad(COOPri)2 was found to depend
strongly on the molar ratio, n = [E]:[AdH], that is, 93–100%
(n = 2), <86% (n = 1.7), <53% (n = 1.6), <48% (n = 1.5).
Functionalization of adamantane (1) and 1,3-dimethyladaman-
tane (2) occurred efficiently and selectively under conditions simi-
lar to those described for our functionalization of bromoadaman
tanes,7 but with a somewhat larger excess of CBr4Á2AlBr3. Under
optimal conditions (0 °C, 2.5–3 h, at CO, [E]:[1 or 2] = 1.7–2), a range
of 1,3-dicarbonyl adamantanes were prepared in high yield using
water or alcohols as nucleophiles (Scheme 2).
The use of amines and aromatic compounds as nucleophiles al-
lowed the one-pot preparation of adamantane-1,3-dicarboxamides
and 1,3-diacyladamantanes from 1 and 2. The yields of the target
⇑
Corresponding author. Tel.: +7 499 135 9329; fax: +7 499 135 5085.
E-mail address: cmoc@ineos.ac.ru (I.S. Akhrem).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.125

3494
I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 3493–3496
i
COOH
COOMe
COOPr
i
R'
R'
R'
COOH
COOMe
5, 91%* (2)
COOPr
R'
R'
R'
6, 90% (1); 7, 70% (2)
3, 80%* (1); 4, 60%* (2)
H2O
i
PrOH
MeOH
H
R'
H
R'
R' = H (1); Me (2)
HOCH2CH(Et)Bu
HOCH2CF3
COOCH2CF3
COOCH2CH(Et)Bu
HOCH2CH(Me)CF3
COOCH2CH(Me)CF3
R'
COOCH2CH(Et)Bu
R'
COOCH2CF3
8, 90% (1)
R'
R'
10, 56% (1)
R'
COOCH2CH(Me)CF3
9, 95% (1)
R'
Scheme 2. One-pot selective synthesis of adamantane-1,3-diacids and adamantane-1,3-diesters from adamantanes 1 and 2. The yields of isolated products are indicated by
an asterisk.
O
N
N
R'
R'
O
11, 80%* (1)
N
H
O
NH
O
N
H
H2N
HNEt2
H
N
N
R'
R'
H
R'
R'
O
O
R'
R'
12, 71% (1); 13, 65%* (2)
R' = H (1); Me (2)
O
OMe 17, 71%* (1); 18, 58%* (2)
HN
O
OMe
O
N
O
O
N
O
O
OMe
O
R'
R'
R'
O
R'
O
O
R'
R'
O
14, 66%* (1)
19, 78%* (1); 20, 66%* (2)
15, 44% (1); 16, 40% (2)
Scheme 3. One-pot synthesis of diamides and diketones from adamantanes 1 and 2. The yields of isolated products are indicated by an asterisk.
products were 60–80%. In the case of furan, the reactions were
nonselective and the yields of the products were 40–44% only,
with the adamantane conversions being close to 100% (Scheme 3).
A possible mechanism for the one-pot conversion of 1 and 2
into the corresponding 1,3-dicarbonyl adamantanes (Scheme 4)
is similar to that proposed for bromoadamantanes7 differing only

I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 3493–3496
3495
CO+
CO+
COBr
H
E
CO
Y
CO +
:
2HY
E, CO
E, CO
- 2 H+
CO
CO
Y
-
Br
-
E
Br
CO
CO+
EH
EH
E
E = CBr3+ Al2Br7
Scheme 4. Suggested pathway for the synthesis of bifunctional products from 1 or 2.
in the initial step. Both involve the formation of AdCO+- and then
1,3-Ad(CO)2+-like species serving as the precursor (P) which after
quenching with a nucleophile gives the 1,3-dicarbonyl product
Ad(COY)2 (Scheme 4).
equimolar amount of AlCl3 and AlBr3 under the conditions shown
in Table 1 were as follows:
Me2Ad(COOPri
80%
Ad(COC H OMe)
,
Ad(CONEt ) , Ad(CONC H O)
)
,
6
4
2
2 2
4
%
8
2
2
At room temperature under CO, 1 was consumed quantitatively
over one hour in the presence of CBr4Á2AlBr3, CBr4ÁAlBr3, or
CBr4Á2AlCl3. However, the yields of Ad(COOPri)2 differed considerably
in these three reactions. They amounted to ꢀ100%, 58%, and 21%,
respectively. Ad(COOPri)2 was also obtained, when 1,3-Ad(COCl)2
was treated with AlBr3 or with CBr4Á2AlBr3 prior to the addition of
iPrOH. If the precursor P was kept at room temperature under a CO
atmosphere, both the yield of 1,3-Ad(COOPri)2 and selectivity of its
formation changed only to a small degree. For example, under these
conditions after 20 h, P was converted on treatment with iPrOH into
a complex mixture of products including Ad(COOPri)2 (74%), 1,3-
BrAdCOOPri (13%), 1,3-Br2AdCOOPri (7%), AdBr (3%), AdBr2 (2%), and
Br2AdCOOPri (1%). Importantly, 1,3-Ad(COOPri)2 remained the major
product when P was treated with iPrOH after storage for one month at
room temperature in an NMR tube under CO. However, the situation
changed dramatically when P was generated in the presence of a lar-
ger excess of CBr4Á2AlBr3 and was stored at room temperature in the
absence of CO. In fact, the generation of P at a molar ratio of
[CBr4Á2AlBr3]:[AdH] = 3, followed by storage for 20 h in the absence
56%
55
37% (isolated)
It is likely, that the activating effect of AlCl3 consisted in break-
ing some of the Br bridges in Al2Br6. As a result, mixed Al2BrnCl6-n
dimers were formed to generate more active coordinatively unsat-
urated complexes with one Br bridge, or even monomeric AlBr3.9
Mixed CBr4Á2AlX3 systems are now under investigation.
The structures of the products are consistent with 1H, 13C, 19F
NMR and mass spectra, and elemental analyses. Typical experi-
mental procedures are presented.10
In conclusion, the first one-pot method for the synthesis of 1,3-
dicarbonyl adamantanes from readily available adamantanes has
been elaborated. The method developed should be applicable to
the preparation of various 1,3-dicarbonyl adamantanes using
nucleophiles which are not extremely active toward superelectro-
philes. In the case of very active nucleophiles, the corresponding
1,3-dicarbonyl adamantanes can be prepared by known multistep
reactions starting from adamantanedicarboxylic acids, which can
be obtained by our method using water as the nucleophile.
i
of CO and then quenching with PrOH led to a mixture of products
with 1,3-Ad(COOPri)2 as a minor component, while Br2AdCOOPri
(50% yield) was the major product under these conditions. Spectral
and theoretical studies of precursor (P) are now in progress.
With the aim of using, at least partially, cheaper AlCl3 instead of
AlBr3, we studied the activities of mixed systems CBr4Á2AlX3
(where 2AlX3 = mAlCl3 + (2–mAlBr3), where m is the number of moles
of AlX3) in the one-pot preparation of 1,3-Ad(COOPri)2.
Acknowledgements
We thank the Russian Foundation for Basic Research (Project N
09-03-00110) and the RAS Presidium Fund (Program 7P) for finan-
cial support.
Supplementary data
Table 1 shows that the system containing an equimolar amount
of AlCl3 and AlBr3 displayed high activity. Even the system contain-
ing a twofold molar excess of AlCl3 relative to AlBr3 turned out to
be rather active. With [AlCl3]:[AlBr3] = 3, the CBr4Á2AlX3 system
showed moderate activity, however its activity exceeded twice
that of the CBr4Á2AlCl3.system.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
04.125.
References and notes
The yields of other 1,3-dicarbonyl adamantanes prepared from
1 and 2 in the presence of the CBr4Á2AlX3 system containing an
1. (a) Fort, R. C. Adamantane. The Chemistry of Diamond Molecules; Marcel Dekker:
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Adamantany: Poluchenie, Svoistva, Primenenie (Adamantanes: Production,
Properties. Application); Nauka: Moscow, 1989 (in Russian).
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Chem., Int. Ed. 2010, 49, 1267; (b) Chen, S. H.; Mastrangelo, J. C.; Shi, H.; Bashir-
Hashemi, A.; Li, J.; Gelber, N. Macromolecules 1995, 28, 7775.
Table 1
Activities of superelectrophilic systems in the formation of 1,3-Ad(COOPri)2 from
AdHa
Entry
E = CBr4Á2AlX3
1,3-Ad(COOPri)2, yield (%)
AlBr3, moles
AlCl3, moles
1
2
3
4
5
2
1
0.66
0.50
0
1
1.33
1.50
2
95
78
61
37
0
16
E = CBr4ÁAlX3
1,3-Ad(COOPri)2, yield (%)
Entry
AlBr3, moles
AlCl3, moles
5. (a) Dohm, J.; Nieger, M.; Rissanen, K.; Vögtle, F. Chem. Ber. 1991, 124, 915; (b)
Butenko, L. N.; Protopopov, P. A.; Derbisher, V. E.; Khardin, A. P. Synth. Commun.
1984, 14, 113; (c) Stetter, H.; Wulff, C. Chem. Ber. Ger. 1960, 93, 1366; (d)
Moiseev, I. K.; Doroshenko, R. I. Zh. Org. Khim. 1983, 19, 1111 [J. Org. Chem. USSR
(Engl. Transl.), 1983, 19, 999]; (e) Yagrushkina, I. N.; Zemtzova, M. N.;
6
7
1
0.5
0
0.5
52
30
a
Carbonylation was carried out under a CO atmosphere in CH2Br2 at 20 °C for 1 h
at a molar ratio [E]:[AdH] = 2.

3496
I. S. Akhrem et al. / Tetrahedron Letters 53 (2012) 3493–3496
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10. Typical procedures: Synthesis of 3. At room temperature, CBr4Á2AlBr3 was
prepared by stirring CBr4 with AlBr3 in a molar ratio of 1–2 in anhydrous
CH2Br2. Next, at 0 °C under atmospheric CO pressure, AdH (1) (1.43 mmol) was
added to the freshly prepared CBr4Á2AlBr3 (2.87 mmol) in CH2Br2 (3 mL). The
mixture was stirred for 3 h. Then at atmospheric CO pressure, H2O (15 mL) was
added carefully with cooling. The reaction mixture was kept for 1–2 d until the
precipitation of 1,3-Ad(COOH)2 was complete. The Ad(COOH)2 was filtered,
washed with H2O, dried, and crystallized from AcOH. The yield of analytically
pure compound was 80% with respect to 1. Mp 285–286 °C. Calcd. for C12H16O4,
(%): C, 64.27; H, 7.19. Found (%): C, 64.21; H, 7.24. Compounds 5–20. At 0 °C
under atmospheric CO pressure, AdH (1) or Me2Ad (2) was added to a stirred
solution of freshly prepared CBr4Á2AlBr3 (E) in anhydrous CH2Br2. After stirring
for 3 h at 0 °C under atmospheric CO pressure, the nucleophile was added to
the in situ prepared carbonylation intermediate under CO. The mixture was
warmed to room temperature over 20–30 min. After this, 10 mL of H2O and
20 mL of CHCl3 were carefully added with stirring. The organic layer was
separated and the remaining aqueous layer extracted twice with 20 mL of
CHCl3. The combined organic extracts were dried over Na2SO4. The structures
of the products were established by 1H, 13C, and 19F NMR spectroscopy, and
from GC-MS and elemental analyses. Conversions were determined by GC. To
perform NMR measurements, all solvents and higher volatile compounds were
removed under reduced pressure. In some cases, the product was recrystallized
or was simply washed with a suitable solvent and dried under vacuum. The
yields of the products were determined by 1H NMR spectroscopy with
mesitylene as an internal standard.