Self-acylation of 1-adamantylacetic acid in trifluoroacetic anhydride medium: A route to 2,4-bis(1-adamantyl)acetoacetic acid and its derivatives

Article abstract of DOI:10.1002/ejoc.201000312

The self-acylation of 1-adamantylaceti.c acid (1) in trifluoroacetic anhydride, catalyzed by triflic acid, proceeds through the formation of the mixed 2,4-bis(1-adamantyl)acetoacetictrifluoroacetic anhydride 2, and it was used as an efficient approach to previously unknown 2, 4-bis(1-adamantyl) acetoacetic acid. (3), its esters 4-6 and amides 7-11, and the sterically hindered 1-adamantyl(1-adamantylacetyl)ketene (12). The latter is stable in solution and can be isolated as a neat solid. Addition of methanol or primary amines to 12 gave the corresponding derivatives of acid 3. Acid 3 was decarboxylated to 1, 3-bis(1-adamantyl)acetone (22), whereas the heterocyclization of phenyl ester 6 with thiourea gave two isomeric adamantylated thiouracils 23 and 24. The structures of N-benzylamide 7 and thiouracil 23 were confirmed by single-crystal X-ray analysis. The utilization of the self-acylation method for the conversion of some other aliphatic acids is discussed and preliminarily tested.

Full text of DOI:10.1002/ejoc.201000312

FULL PAPER
DOI: 10.1002/ejoc.201000312
Self-Acylation of 1-Adamantylacetic Acid in Trifluoroacetic Anhydride
Medium: A Route to 2,4-Bis(1-adamantyl)acetoacetic Acid and Its Derivatives
Vladimir Kovalev,*[a] Elvira Shokova,[a] Alexander Shmailov,[a] Ivan Vatsouro,[a] and
Viktor Tafeenko[a]
Keywords: Acylation / Aldol reactions / Carboxylic acids / Perfluorinated solvents / Synthetic methods
The self-acylation of 1-adamantylacetic acid (1) in trifluoro-
acetic anhydride, catalyzed by triflic acid, proceeds through
the formation of the mixed 2,4-bis(1-adamantyl)acetoacetic–
trifluoroacetic anhydride 2, and it was used as an efficient
approach to previously unknown 2,4-bis(1-adamantyl)aceto-
acetic acid (3), its esters 4–6 and amides 7–11, and the steri-
cally hindered 1-adamantyl(1-adamantylacetyl)ketene (12).
The latter is stable in solution and can be isolated as a neat
solid. Addition of methanol or primary amines to 12 gave the
corresponding derivatives of acid 3. Acid 3 was decarboxyl-
ated to 1,3-bis(1-adamantyl)acetone (22), whereas the
heterocyclization of phenyl ester 6 with thiourea gave two
isomeric adamantylated thiouracils 23 and 24. The structures
of N-benzylamide 7 and thiouracil 23 were confirmed by sin-
gle-crystal X-ray analysis. The utilization of the self-acylation
method for the conversion of some other aliphatic acids is
discussed and preliminarily tested.
been reported.[5] Quite unexpectedly we have found no re-
ports on the activation of acids of the type RCH2CO2H
under acidic conditions to be used for the selective one-pot
self-acylation and preparative synthesis of β-keto acids or
their derivatives.
Introduction
β-Keto esters and β-keto acids bearing several electro-
philic and nucleophilic centers are widely used in organic
synthesis as polyfunctional reagents. The most common
synthetic approaches to such compounds are self- and
cross-Claisen-type condensations.[1,2] Among the large
number of modifications of the Claisen reaction, the acid-
catalyzed self-acylation of acid chlorides or anhydrides con-
taining α-CH2 protons seems to be one of the most attract-
ive approaches to β-keto acids of the general formula
RCH2C(O)CH(R)CO2H. However, due to the low stability
of the latter, and difficulties with the selectivity of these
condensations, the published data on the successful applica-
tion of such reactions are limited. Already Meerwein has
found[3] that the self-acylation of acetic anhydride in the
presence of BF3 has led to acetylacetone, and the anhy-
drides of propionic or butyric acid have transformed into
the corresponding symmetrical dialkyl ketones; the initially
formed self-acylation products undergo decarboxylation
during the reaction treatment and hydrolysis. Later this
method was extended to other aliphatic ketones.[4] For the
aliphatic acid chlorides RCH2COCl (R ϶ H) the selective
cyclotrimerization in the presence of AlCl3 including, ac-
cording to the authors, the initial formation of the corre-
sponding β-keto acid chlorides as aluminum chelates has
In this paper, the possibility of the acid-catalyzed self-
acylation of 1-adamantylacetic acid (1) is investigated. In
the literature there are several examples of selective electro-
philic reactions that involve the methylene group of this
acid. Thus, it is known[6] that 1-adamantylacetic acid chlo-
ride can be easily and selectively halogenated at the α-meth-
ylene group by bromine or iodine. When treated with so-
dium nitrite in trifluoroacetic anhydride (TFAA)/trifluoro-
acetic acid (CF3CO2H) medium, 1 was converted into 1-
adamantylnitrile, probably through nitrosation of the α-
CH2 group, followed by decarboxylation and dehydration.[7]
This led us to explore the reactions of activated derivatives
of 1-adamantylacetic acid (1) in which the α-CH2 group
undergoes electrophilic acyl attack.
Results and Discussion
As a medium and a reagent for the activation of acid 1,
we chose TFAA because it is well known[8] that the mixed
anhydrides of aliphatic carboxylic acids and trifluoroacetic
acid are excellent acylating reagents. It was found that after
heating at reflux in TFAA, followed by distillation of the
solvent and quenching the reaction mixture with water, acid
1 returned unchanged. However, if the reaction was carried
out in the presence of a small amount of triflic acid, in
[a] Chemistry Department of Moscow State University,
Lenin’s Hills, Moscow 119991, Russia
E-mail: kovalev@petrol.chem.msu.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000312.
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2,4-Bis(1-adamantyl)acetoacetic Acid and Its Derivatives
Scheme 1. Preparation of 2 and its applications.
a few minutes the initially homogeneous reaction mixture exists exclusively in the enol form. On the other hand, the
started to become heterogeneous, and after 1–1.5 h a white 13C NMR spectrum contains the signal of the AdCH2C=O
solid formed. After 2–2.5 h TFAA was removed and the group at δ = 205.83 ppm, suggesting the structure of mono-
residue was thoroughly dried and then carefully treated trifluoroacetoxylated 1-adamantyl-1-(1-adamantylacetyl)-
with cold water or, after dissolution in dichloromethane, ketene 2b, but not enol 2c. Treatment of the dichlorometh-
with different OH or NH nucleophiles (alcohols, benzyl- ane solution of 2 with a slight excess of triethylamine led
amine, hydrazine hydrate, phenylhydrazine, hydroxylamine, almost immediately and quantitatively to α-oxoketene 12,
and semicarbazide). As a result, 2,4-bis(1-adamantyl)aceto- as clearly evidenced by the changes in the 1H and 13C NMR
acetic acid (3) and its derivatives Ϫ esters 4–6, amide 7, spectra after addition of triethylamine into the solution of
hydrazides 8 and 9, hydroxamic acid 10, and semicarbazide 2 in CDCl3. In the 1H NMR spectrum of 12, in addition to
11 Ϫ were obtained in high yields (Scheme 1).
the signals of adamantane nuclei, there is only the singlet
We suppose that in mixed anhydride 1a, formed by the of the AdCH2 methylene groups at δ = 2.10 ppm, whereas
reaction of acid 1 with TFAA in the presence of triflic acid, the 13C NMR spectrum contains the signals of the carbonyl
enolization is easy and the acylating properties of the reac- group at δ = 197.10 ppm (AdCH2C=O), one from the cen-
tant are amplified. An aldol-type condensation of anhy- tral ketene carbon at δ = 193.21 ppm (C=C=O), and one
dride 1a and its enol results in the formation of the mixed from the sp2 carbon atom of the ketene at δ = 64.10 ppm
anhydride of 2,4-bis(1-adamantyl)acetoacetic and trifluoro- (C=C=O). For comparison, the essential 13C NMR spectro-
acetic acids 2, which, as we initially anticipated, exists in scopic data for 2b, α-oxoketene 12, and known sterically
keto form 2a, because 2,4-bis(1-adamantyl)acetoacetic acid hindered α-oxoketenes 13–15[9–11] are given in Scheme 2.
(3) and its derivatives obtained from anhydride 2 do not
Direct structural approval for 12 comes also from the
tend to enolize in solutions, as shown by NMR spec- highly characteristic and strong ketene absorption band in
troscopy.
the IR spectrum at 2091 cm–1 (compare to dipivaloylketene,
Although hygroscopic, mixed anhydride 2 can be safely 2131 cm–1[10]), and one carbonyl absorption band at
exposed to air for a short time and its manipulation does 1654 cm–1. Obtained α-oxoketene 12 is stable on the labora-
not require any special precautions when carrying out fur- tory timescale, and it could be stored in isolated solutions
1
ther reactions. Thus, we were able to characterize it by H of dry dichloromethane or hexane for several days; it is
and 13C NMR spectroscopy in dry CDCl3. The H NMR stable against TLC on SiO2 with dry non-nucleophilic sol-
1
spectrum of this key intermediate does not contain the sig- vents. When kept in an unsealed vessel, solid 12 underwent
nal of the AdCH proton, suggesting that the compound slow decomposition to 1,3-bis(1-adamantyl)acetone.
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Scheme 2. Some 13C NMR spectroscopic data for 2b, 12, and known stable α-oxoketenes.
α-Oxoketenes are known to undergo reactions of two
main types: (i) addition of nucleophiles and (ii) cycload-
dition reactions.[12] Addition of nucleophiles to α-oxoket-
enes is a familiar process and in general leads to β-keto
acids derivatives. In our case, the interaction of α-oxoketene
12 with methanol, tryptamine, 2-amino-6-methylpyridine,
and p-toluidine resulted in corresponding ester 4 and
amides 16–18. At the same time, 12 did not undergo dimer-
ization in hexane, even when heated at reflux for 7 h, and it
also did not participate in various [2+4] hetero-Diels–Alder
cycloadditions with polarized multiple bond systems
(acetone, benzaldehyde, dicyclohexylcarbodiimide, benzyl-
ideneaniline),[13] which are common for α-oxoketenes (e.g.,
14[14] and 15[11]). It should be noted that known α-ada-
mantylated ketenes demonstrate quite different reactivities
depending on their structural features. For instance, the
parent 1-adamantylketene could not be isolated as a neat
compound, whereas it is stable in dilute ether solutions. It
also readily reacts with HO and NH nucleophiles to give 1-
adamantylacetic acid derivatives.[15] (1-Adamantyl)ethoxy-
carbonyl ketene available from ethyl 3-(1-adamantyl)-2-di-
azo-3-oxopropanoate both by thermal- or photodecompo-
sition can be stored in hexane under an inert atmosphere at
room temperature for several days and is a good precursor
of adamantane-substituted malonic acid derivatives.[16] At
the same time, both of the ketenes mentioned above are
poorly active in 1,2-cycloaddition with benzylideneaniline.
On the other hand, bis(1-adamantyl)ketene is extremely
stable as a monomer and reacts slowly, even with water,
leading to bis(1-adamantyl)acetic acid.[17]
Figure 1. Displacements ellipsoids plot of 7 are shown at the 50%
probability level. Hydrogen atoms are shown as spheres of arbitrary
radii. Hydrogen atoms of the adamantyl moieties and some atoms
labeling are omitted for clarity.
hexylamide led to 1,3-bis(1-adamantyl)acetone,[19] probably
due to the hydrolysis and decarboxylation of the initially
formed β-keto ester during the quenching of the reaction
mixture. As for adamantane-containing β-keto acids, these
compounds were synthesized in the form of the correspond-
ing esters 19–21 by the acylation of malonic ester with 1-
adamantanecarboxylic acid chloride[20] or 1-adamantyl-
acetic acid chloride[21] or by the adamantylation of β-keto
esters with 1-bromo-[22,23] or 1-hydroxyadamantanes.[24]
These adamantylated keto esters were used in the synthesis
of depsipeptides[25] and various heterocycles[21,22,24,26,27] in-
cluding biologically active ones.
The structures of β-keto acid 3 and its derivatives 4–11
and 16–18 were confirmed by 1H and 13C NMR spec-
1
troscopy and mass spectrometry (ESI). The H NMR spec-
tra contain singlets at δ = 3.16–3.58 ppm assigned to α-
methine protons (AdCH). The signals at δ = 69.47–
70.31 ppm in the 13C NMR spectra of 4–11 and 16–18
correspond to tertiary carbon atoms of the keto forms. No
enol forms were detected in CDCl3 or [D6]DMSO in all
the cases. Obviously, the presence of the bulky adamantane
groups prevents enolization of these molecules. Similar ob-
We have studied some transformations of keto acid 3 and
servations have been made with some other sterically hin- its ester 6 (Scheme 3). As expected, heating of β-keto acid
dered β-keto acid derivatives.[11,18]
3 in a mixture of diluted acetic and sulfuric acids was easily
The structure of 7 was confirmed by X-ray analysis. A decarboxylated, giving 1,3-bis(1-adamantyl)acetone 22
displacement ellipsoids plot of 7 is shown in Figure 1. quantitatively. The same was obtained by heating mixed an-
It should be noted that 2,4-bis(1-adamantyl)acetoacetic hydride 2 under these conditions. It should be noted that
acid (3) could not be synthesized by the classic Claisen con- our method of synthesis of 1,3-bis(1-adamantyl)acetone is
densation. It is only known that the self-condensation of much more convenient and easier than those described ear-
ethyl 1-adamantylacetate in the presence of lithium dicyclo- lier.[19,28]
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2,4-Bis(1-adamantyl)acetoacetic Acid and Its Derivatives
carbonyl group in 1,3-bis(tert-butyl)acetone, which does not
form the semicarbazide, oxime, hydrazone, and 2,4-dini-
trophenylhydrazone under ordinary conditions.
In order to evaluate the applicability of the TFAA-medi-
ated self-acylation method as a common route to β-keto
acids, we checked it on a series of α-CH2 carboxylic acids:
acetic, propionic, isovaleric, tert-butylacetic, phenylacetic,
1-naphthylacetic, and phenoxyacetic acids. Among the ac-
ids tested, only tert-butylacetic and isovaleric acids 25 and
26 yielded the dimeric self-acylation products more or less
selectively, whereas the others gave polymeric adducts.
Moreover, in contrast to 1-adamantylacetic acid (1), which
gave TFAA-insoluble anhydride 2, mixed anhydrides
25·CF3CO2H and 26·CF3CO2H remained dissolved in the
reaction mixture, so they were not separated as pure com-
pounds, but reacted directly with HO and NH nucleophiles
(Scheme 4). As a result, 2,4-bis(tert-butyl)acetoacetic acid
(27),[31] its phenyl ester 28, and N-benzylamide 29, as well
as phenyl ester 30 were obtained in moderate to good yield.
In the case of β-keto acid 27, the sample obtained con-
tained up to 10% of 1,3-bis(tert-butyl)acetone (31), which
formed easily from 27 upon heating under acidic condi-
tions.
Scheme 3. Transformations of keto acid 3 and its ester 6.
The condensation of phenyl ester 6 with thiourea in eth-
anol in the presence of NaOEt gave expected thiouracil 24
along with isomeric pyrimidine derivative 23, having the
exocyclic double bond. These compounds were isolated in
51 and 25% yield, respectively, after column chromatog-
raphy on silica. The structure of 23 was confirmed by X-
ray analysis. Figure 2 shows the molecular structure and the
atom labeling scheme of 23.
Scheme 4. Self-acylation of acids 25 and 26.
Figure 2. The asymmetric unit of 23, showing the atom labeling
scheme; ellipsoids are shown at the 50% probability level. Hydro-
gen atoms are shown as spheres of arbitrary radii. Hydrogen atoms
of the adamantyl moiety are omitted for clarity.
Conclusions
In summary, we have found the previously unknown self-
Unexpectedly, β-keto esters 5 and 6 were not trans- acylation of 1-adamantylacetic acid (1) in TFAA in the
formed into heterocyclic compounds when reacted with hy- presence of CF3SO3H, yielding the versatile mixed 2,4-
drazine hydrate, phenylhydrazine, or cyanoacetamide. In the bis(1-adamantyl)acetoacetic–trifluoroacetic anhydride 2.
case of hydrazine, the starting esters returned unchanged, Upon treatment with water or various OH and NH nucleo-
although it is known[20–22,26] that adamantylated β-keto es- philes, this anhydride could be easily converted into 2,4-
ters 19 and 21 could be transformed into the corresponding bis(1-adamantyl)acetoacetic acid (3) and its esters, amides,
pyrazoles quite easily under these conditions. An attempt hydrazides, etc. Moreover, the reaction of anhydride 2 with
to obtain a pyridine structure according to the method pre- triethylamine led to stable α-oxoketene 12, which reacts
viously developed for ethyl acetoacetate[29] by boiling with methanol, tryptamine, 2-amino-6-methylpyridine, and
phenyl ester 6 with cyanoacetamide in methanol in the pres- p-toluidine to give the corresponding esters and amides of
ence of KOH resulted only in the formation of methyl ester 2,4-bis(1-adamantyl)acetoacetic acid. Acid 3 is easily decar-
4 by interesterification. We could also not get the oxime of boxylated to 1,3-bis(1-adamantyl)acetone (22), whereas the
22 by its reaction with hydroxylamine in the presence of reaction of its phenyl ester with thiourea gave isomeric di-
various bases (NEt3, pyridine). The latter result is consis- adamantylated thiouracil derivatives 23 and 24. As a pre-
tent with the known data[30] on the low reactivity of the liminary result, the TFAA-mediated self-acylation method
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28.52 (CHAd) ppm. MS (ESI): m/z (%) = 407.0 (100) [M + Na]+,
could also be applied for the synthesis of some selected β-
keto acids and their derivatives, whereas the detailed study
of the scope and limitations of the method is in progress.
384.9 (34) [M + H]+.
Ethyl 2,4-Bis(1-adamantyl)acetoacetate (5): Obtained from
1
(1 mmol), ethanol (3 mL), and triethylamine (0.28 mL, 2 mmol) as
described for 4. Yield: 90% (180 mg), colorless oil. C26H38O3
1
(398.58): calcd. C 78.35, H 9.61; found C 78.18, H 9.49. H NMR
Experimental Section
(400 MHz, CDCl3): δ = 4.11 (q, J = 7.2 Hz, 2 H, CH2CH3), 3.16
(s, 1 H, AdCH), 2.18 (s, 2 H, AdCH2), 1.92 (br. s, 3 H, CHAd),
1.89 (br. s, 3 H, CHAd), 1.74–1.58 (m, 24 H, CH2Ad), 1.21 (t, J =
7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
204.00 (C=O), 167.97 (CO2CH2), 70.32 (AdCH), 60.48 (OCH2),
57.89 (AdCH2), 42.08, 39.97 (CH2Ad), 37.07 (CAd), 36.71, 36.62
(CH2Ad), 33.63 (CAd), 28.49 (CHAd), 14.17 (CH3) ppm.
General Methods: 1H and 13C (APT) NMR spectra were measured
with a Bruker Avance 400 spectrometer with solvent signals as in-
ternal reference. ESI mass spectra were recorded with an Agilent
1100 LC/MS instrument. IR spectrum was recorded with a Thermo
Scientific Nicolet IR 200 FTIR spectrometer. X-ray measurements
were performed with an Enraf–Nonius CAD-4 diffractometer.
Chemicals were of commercial grade and used without further pu-
rification. Column chromatography was performed on silica
(Merck Kieselgel 60). Solvents were purified and dried according
to standard procedures. TFAA was freshly distilled from P2O5. 1-
Adamantylacetic acid (1) was prepared according to a published
procedure.[32]
Phenyl 2,4-Bis(1-adamantyl)acetoacetate (6): Obtained from 1
(2 mmol), a solution of phenol (470 mg, 5 mmol), and triethyl-
amine (0.82 mL, 6 mmol) in dry CH2Cl2 (6 mL) as described for
4. Instead of crystallization, the product was purified by column
chromatography (CH2Cl2/hexane, 1:1). Yield: 87% (390 mg), white
solid, m.p. 121–122 °C. C30H38O3 (446.62): calcd. C 80.68, H 8.58;
1
Trifluoroacetic 2,4-Bis(1-adamantyl)acetoacetic Anhydride (2): A
solution of 1-adamantylacetic acid (1; 194 mg, 1 mmol) in a mix-
ture of TFAA/CF3SO3H (97.5:2.5, 2 mL) was kept at 60–65 °C for
2–2.5 h and cooled. The excess amount of the solvent mixture was
carefully decanted from the solid formed, and the residue was dried
under reduced pressure. Yield: 95–99% (221–231 mg), yellowish so-
lid, m.p. 88–90 °C. Freshly prepared anhydride 2 was used without
further purification. 1H NMR (400 MHz, CDCl3): δ = = 2.69 (s, 2
H, AdCH2), 2.13 (br. s, 3 H, CHAd), 2.08 (br. s, 3 H, CHAd), 2.03
(br. s, 6 H, CH2Ad), 1.78–1.65 (m, 18 H, CH2Ad) ppm. 13C NMR
(100 MHz, CDCl3): δ = = 205.84 (C=O), 172.75 (CO2COCF3),
157.99 (q, J = 41.9 Hz, COCF3), 119.34 (q, J = 317.0 Hz, COCF3),
76.82 [AdCO(Ad)C=C], 53.75 (AdCH2), 42.33, 40.56 (CH2Ad),
found C 80.83, H 8.35. H NMR (400 MHz, CDCl3): δ = 7.37 (m,
2 H, Ph), 7.24 (m, 1 H, Ph), 7.07 (m, 2 H, Ph), 3.47 (s, 1 H, AdCH),
2.39 (d, J = 16.6 Hz, 1 H, AdCH2), 2.35 (d, J = 16.6 Hz, 1 H,
AdCH2), 2.02 (br. s, 3 H, CHAd), 1.97 (br. s, 3 H, CHAd), 1.80–
1.60 (m, 24 H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3): δ =
203.50 (C=O), 166.59 (CO2Ph), 150.37 (CPh), 129.40, 125.92,
121.43 (CHPh), 70.16 (AdCH), 58.20 (AdCH2), 42.21, 40.93
(CH2Ad), 37.71 (CAd), 36.75, 36.63 (CH2Ad), 33.87 (CAd), 28.56,
28.54 (CHAd) ppm. MS (ESI): m/z (%) = 469.2 (68) [M + Na]+,
447.1 (100) [M + H]+.
2,4-Bis(1-adamantyl)-N-benzylacetoacetamide (7): Obtained from 1
(1 mmol), benzylamine (0.21 mL, 2 mmol), and triethylamine
(0.41 mL, 3 mmol) as described for 6. Yield: 65% (150 mg), white
solid, m.p. 213-215 °C. C31H41NO2 (459.67): calcd. C 81.00, H
37.78, 37.07 (CAd), 35.93, 35.72 (CH2Ad), 28.65, 28.46 (CHAd
ppm.[33]
)
1
8.99, N 3.05; found C 80.63, H 9.12, N 3.16. H NMR (400 MHz,
2,4-Bis(1-adamantyl)acetoacetic Acid (3): A sample of 2 obtained
from 1 (1 mmol) was carefully treated with cold water, and the pre-
cipitate formed was filtered, washed with water, and dried. Yield:
97% (180 mg), white solid, m.p. 190–195 °C (decomp.). C24H34O3
CDCl3): δ = 7.42 (t, J = 6.6 Hz, 1 H, NH), 7.24–7.30 (m, 5 H, Ph),
4.57 (dd, J = 14.8, 6.6 Hz, 1 H, PhCH2), 4.36 (dd, J = 14.8, 6.6 Hz,
1 H, PhCH2), 3.44 (s, 1 H, AdCH), 2.45 (d, J = 13.3 Hz, 1 H,
AdCH2), 2.07 (d, J = 13.3 Hz, 1 H, AdCH2), 1.98 (br. s, 3 H,
CHAd), 1.93 (br. s, 3 H, CHAd), 1.80–1.50 (m, 24 H, CH2Ad) ppm.
13C NMR (100 MHz, CDCl3): δ = 212.80 (C=O), 165.92 (CONH),
138.51 (CPh), 128.51, 127.69, 127.25 (CHPh), 72.13 (AdCH), 61.08
(AdCH2), 43.31 (PhCH2), 42.46, 40.54 (CH2Ad), 38.46 (CAd), 36.59,
36.46 (CH2Ad), 34.44 (CAd), 28.65, 28.48 (CHAd) ppm. MS (ESI):
m/z (%) = 498.3 (18) [M + K]+, 482.3 (45) [M + Na]+, 460.3 (100)
[M + H]+.
1
(370.53): calcd. C 77.80, H 9.25; found C 77.95, H 9.37. H NMR
(400 MHz, CDCl3, CF3CO2D): δ = 3.58 (s, 1 H, AdCH), 2.52 (d,
J = 13.5 Hz, 1 H, AdCH2), 2.25 (d, J = 13.5 Hz, 1 H, AdCH2),
2.05 (br. s, 3 H, CHAd), 1.98 (br. s, 3 H, CHAd), 1.80–1.55 (m, 24
H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3, CF3CO2D): δ =
213.93 (C=O), 172.76 (CO2H), 69.47 (AdCH), 60.04 (AdCH2),
42.48, 40.43 (CH2Ad), 40.05 (CAd), 36.41, 36.06 (CH2Ad), 35.14
(CAd), 28.63, 28.49 (CHAd) ppm. MS (ESI): m/z (%) = 409.1 (70)
[M + K]+, 393.2 (100) [M + Na]+, 371.1 (71) [M + H]+.
2,4-Bis(1-adamantyl)acetoacetylhydrazide (8): To a stirred mixture
of hydrazine hydrate (0.4 mL, 6 mmol) and CH2Cl2 (2 mL) was
added a solution of 2 (obtained from 1 mmol of 1) in dry CH2Cl2
(6 mL). The stirring was continued for 6 h at room temperature,
and the solvent was evaporated to dryness. The solid formed upon
addition of water was filtered, washed with water, and dried. Yield:
98% (190 mg), white solid, m.p. 320–325 °C (decomp.).
C24H36N2O2 (384.56): calcd. C 74.96, H 9.44, N 7.28; found C
Methyl 2,4-Bis(1-adamantyl)acetoacetate (4): Dry methanol (3 mL)
and triethylamine (0.28 mL, 2 mmol) were added to a stirred and
cooled (0–5 °C) solution of 2 (obtained from 1 mmol of 1) in dry
CH2Cl2 (4 mL). Stirring was continued for 6 h at room tempera-
ture, and the solvent was then evaporated to dryness. The residue
was redissolved in CH2Cl2, washed with 1  HCl and water, and
dried with MgSO4. The residue, after removal of the solvent, was
crystallized from methanol. Yield: 81% (155 mg), white solid, m.p.
101–102 °C. C25H36O3 (384.55): calcd. C 78.08, H 9.44; found C
78.31, H 9.31. 1H NMR (400 MHz, CDCl3): δ = 3.65 (s, 3 H,
1
75.11, H 9.27, N 7.04. H NMR (400 MHz, CDCl3): δ = 8.09 (br.
s, 1 H, NH), 4.05 (br. s, 2 H, NH2), 3.44 (s, 1 H, AdCH), 2.37 (d,
J = 13.8 Hz, 1 H, AdCH2), 2.07 (d, J = 13.8 Hz, 1 H, AdCH2),
1.94 (br. s, 3 H, CHAd), 1.90 (br. s, 3 H, CHAd), 1.75–1.45 (m, 24
OCH3), 3.19 (s, 1 H, AdCH), 2.19 (s, 2 H, AdCH2), 1.94 (br. s, 3 H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3): δ = 211.27 (C=O),
Ad
H, CHAd), 1.90 (br. s, 3 H, CHAd), 1.75–1.55 (m, 24 H, CH2
)
166.74 (CONH), 71.03 (AdCH), 60.61 (AdCH2), 42.32, 40.43
ppm. 13C NMR (100 MHz, CDCl3): δ = 203.94 (C=O), 168.56
(CH2Ad), 38.26 (CAd), 36.73, 36.34 (CH2Ad), 34.20 (CAd), 28.55,
(CO2CH3), 70.30 (AdCH), 57.88 (AdCH2), 51.62 (OCH3), 42.09, 28.41 (CHAd) ppm. MS (ESI): m/z (%) = 407.9 (43) [M + Na]+,
40.03 (CH2Ad), 37.18 (CAd), 36.74, 36.62 (CH2Ad), 33.65 (CAd),
385.0 (100) [M]+.
3758
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3754–3761

2,4-Bis(1-adamantyl)acetoacetic Acid and Its Derivatives
2,4-Bis(1-adamantyl)-NЈ-phenylacetoacetylhydrazide (9): Obtained
from 1 (1 mmol), phenylhydrazine (0.10 mL, 1 mmol), and triethyl-
amine (0.2 mL, 1.5 mmol) as described for 8. The product was puri-
fied by column chromatography (CH2Cl2). Yield: 39% (90 mg),
pale-brown solid, m.p. 221–225 °C. C30H40N2O2 (460.65): calcd. C
C34H44N2O2 (512.73): calcd. C 79.65, H 8.65, N 5.46; found C
79.38, H 8.72, N 5.71. H NMR (400 MHz, CDCl3): δ = 8.36 (br.
1
s, 1 H, NH), 7.63 (d, J = 7.9 Hz, 1 H, Ind), 7.35 (d, J = 8.1 Hz, 1
H, Ind), 7.20–7.09 (m, 2 H, Ind, NH), 7.06 (d, J = 2.2 Hz, 1 H,
Ind), 3.63 (m, 2 H, NHCH2CH2), 3.36 (s, 1 H, AdCH), 2.98 (m, 2
78.22, H 8.75, N 6.08; found C 78.35, H 8.60, N 6.35. 1H NMR H, NHCH2CH2), 2.39 (d, J = 13.6 Hz, 1 H, AdCH2), 2.06 (d, J =
(400 MHz, CDCl3): δ = 8.72 (s, 1 H, NH), 7.21 (m, 2 H, Ph), 6.89
(m, 1 H, Ph), 6.83 (m, 2 H, Ph), 3.51 (s, 1 H, AdCH), 2.49 (d, J =
13.2 Hz, 1 H, AdCH2), 2.14 (d, J = 13.2 Hz, 1 H, AdCH2), 2.03
(br. s, 3 H, CHAd), 1.97 (br. s, 3 H, CHAd), 1.80–1.58 (m, 24 H,
CH2Ad) ppm. 13C NMR (100 MHz, CDCl3): δ = 211.65 (C=O),
13.6 Hz, 1 H, AdCH2), 1.92 (br. s, 6 H, CHAd), 1.72–1.50 (m, 24
H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3): δ = 212.63 (C=O),
165.93 (CONH), 136.39, 127.20 (CInd), 121.98, 121.94, 119.22
(CHInd), 112.74 (CInd), 111.10 (CHInd), 72.08 (AdCH), 60.93
(AdCH2), 42.36, 40.41 (CH2Ad), 39.49 (NHCH2CH2), 38.18 (CAd),
166.05 (CONH), 148.16 (CPh), 129.02, 121.14, 113.90 (CHPh), 71.66 36.58, 36.39 (CH2Ad), 34.18 (CAd), 28.44, 28.43 (CHAd), 25.43
(AdCH), 60.85 (AdCH2), 42.52, 40.56 (CH2Ad), 38.56 (CAd), 36.57,
36.38 (CH2Ad), 34.59 (CAd), 28.63, 28.48 (CHAd) ppm. MS (ESI):
m/z (%) = 460.3 (100) [M]+.
(NHCH2CH2) ppm. MS (ESI): m/z (%) = 512.6 (100) [M]+.
2,4-Bis(1-adamantyl)-N-(6-methylpyridin-2-yl)acetoacetamide (17):
Obtained from 1 (1 mmol) and 2-amino-6-methylpyridine (108 mg,
1 mmol) as described for 16 with the reaction time increased to
24 h. Yield: 61% (2 steps, 140 mg), white solid, m.p. 90–92 °C.
C30H40N2O2 (460.65): calcd. C 78.22, H 8.75, N 6.08; found C
2,4-Bis(1-adamantyl)-N-hydroxyacetoacetamide (10): Obtained
from
1
(1 mmol), hydroxylamine hydrochloride (104 mg,
1.5 mmol), and triethylamine (0.48 mL, 3.5 mmol) as described for
8. The product was purified by column chromatography (CH2Cl2/
MeOH, 99:1). Yield: 52% (100 mg), white solid, m.p. 150–152 °C.
C24H35NO3 (385.54): calcd. C 74.77, H 9.15, N 3.63; found C
74.98, H 9.01, N 3.38. 1H NMR (400 MHz, [D6]DMSO): δ = 10.55
(s, 1 H, OH), 8.94 (s, 1 H, NH), 2.80 (s, 1 H, AdCH), 2.28 (d, J =
15.1 Hz, 1 H, AdCH2), 2.00 (d, J = 15.1 Hz, 1 H, AdCH2), 1.89
(br. s, 6 H, CHAd), 1.74–1.51 (m, 24 H, CH2Ad) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 204.53 (C=O), 163.76 (CONH), 67.82
(AdCH), 55.06 (AdCH2), 41.62, 39.65, 36.50, 36.39 (CH2Ad), 35.82,
33.03 (CAd), 27.98, 27.95 (CHAd) ppm. MS (ESI): m/z (%) = 385.4
(100) [M]+.
1
78.37, H 8.63, N 5.92. H NMR (400 MHz, CDCl3): δ = 9.33 (s, 1
H, NH), 7.98 (d, J = 8.2 Hz, 1 H, Py), 7.54 (t, J = 8.2 Hz, 1 H,
Py), 6.87 (d, J = 7.4 Hz, 1 H, Py), 3.43 (s, 1 H, AdCH), 2.47 (s, 3
H, CH3), 2.45 (d, J = 14.2 Hz, 1 H, AdCH2), 2.20 (d, J = 14.2 Hz,
1 H, AdCH2), 2.00 (br. s, 3 H, CHAd), 1.93 (br. s, 3 H, CHAd),
1.69–1.50 (m, 24 H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3):
δ = 211.09 (C=O), 164.88 (CONH), 157.09, 150.30 (CPy), 138.22,
119.14, 110.55 (CHPy), 72.87 (AdCH), 60.87 (AdCH2), 42.39, 40.56
(CH2Ad), 38.99 (CAd), 36.63, 36.39 (CH2Ad), 34.22 (CAd), 28.65,
28.48 (CHAd), 24.12 (CH3) ppm. MS (ESI): m/z (%) = 460.5 (100)
[M]+.
2-[2,4-Bis(1-adamantyl)acetoacetyl]hydrazinecarboxamide (11): Ob-
tained from 1 (1 mmol), semicarbazide hydrochloride (168 mg,
1.5 mmol), and triethylamine (0.48 mL, 3.5 mmol) as described for
8. Yield: 93% (200 mg), white solid, m.p. 139–141 °C. C25H37N3O3
(427.58): calcd. C 70.23, H 8.72, N 9.83; found C 70.30, H 8.85, N
2,4-Bis(1-adamantyl)-N-(4-methylphenyl)acetoacetamide (18): Ob-
tained from 1 (1 mmol) and 4-toluidine (107 mg, 1 mmol) as de-
scribed for 17. Yield: 52% (2 steps, 120 mg), white solid, m.p. 197–
200 °C. C31H41NO2 (459.67): calcd. C 81.00, H 8.99, N 3.05; found
1
C 81.18, H 8.90, N 3.26. H NMR (400 MHz, CDCl3): δ = 8.92 (s,
1
9.61. H NMR (400 MHz, CDCl3): δ = 8.61 (br. s, 1 H, NH), 8.52
1 H, NH), 7.46 (d, J = 8.1 Hz, 2 H, Tol), 7.13 (d, J = 8.1 Hz, 2 H,
Tol), 3.45 (s, 1 H, AdCH), 2.49 (d, J = 13.8 Hz, 1 H, AdCH2), 2.32
(s, 3 H, CH3), 2.17 (d, J = 13.8 Hz, 1 H, AdCH2), 2.01 (br. s, 3 H,
CHAd), 1.95 (br. s, 3 H, CHAd), 1.67–1.60 (m, 24 H, CH2Ad) ppm.
13C NMR (100 MHz, CDCl3): δ = 213.22 (C=O), 163.96 (CONH),
135.06, 133.79 (CTol), 129.38, 119.99 (CHTol), 72.62 (AdCH), 61.19
(AdCH2), 42.47, 40.60 (CH2Ad), 39.04 (CAd), 36.63, 36.42 (CH2Ad),
34.37 (CAd), 28.69, 28.49 (CHAd), 20.82 (CH3) ppm. MS (ESI): m/z
(%) = 460.4 (100) [M + H]+, 459.7 (70) [M]+.
(br. s, 1 H, NH), 5.76 (br. s, 2 H, NH2), 3.43 (s, 1 H, AdCH), 2.41
(d, J = 13.0 Hz, 1 H, AdCH2), 2.06 (d, J = 13.0 Hz, 1 H, AdCH2),
1.96 (br. s, 3 H, CHAd), 1.91 (br. s, 3 H, CHAd), 1.70–1.51 (m, 24
H, CH2Ad) ppm. 13C NMR (100 MHz, CDCl3): δ = 210.62 (C=O),
167.78 (CONH), 160.04 (CONH2), 71.21 (AdCH), 60.59 (AdCH2),
42.23, 40.28 (CH2Ad), 38.58 (CAd), 36.75, 36.33 (CH2Ad), 34.60
(CAd), 28.60, 28.50 (CHAd) ppm. MS (ESI): m/z (%) = 352.3 (100)
[M – NH2NHCONH2]+.
1-Adamantyl-1-(1-adamantylacetyl)ketene
(12):
Triethylamine
1,3-Bis(1-adamantyl)acetone (22): A mixture of acid 3 (or anhydride
2) obtained from 1 (1 mmol), water (2.7 mL), acetic acid (4.5 mL),
and H2SO4 (0.5 mL) was stirred at reflux for 5 h and cooled. The
solid formed was filtered, washed with water, and dried. Yield: 92%
(150 mg), white solid, m.p. 235–240 °C (ref.[19] 235–249 °C). 1H
(0.28 mL, 2 mmol) was added to a cooled (0–5 °C) solution of 2
(obtained from 1 mmol of 1) in dry CH2Cl2 (4 mL). The mixture
was stirred at room temperature for 1 h and then concentrated un-
der reduced pressure. From the solid residue the target product was
extracted with dry hexane (3ϫ3 mL). Yield: 97% (170 mg), light-
yellow solid, m.p. 93–95 °C. IR (neat): ν = 2091 cm–1. 1H NMR
NMR (400 MHz, CDCl3): δ = 2.12 (s, 4 H, AdCH2), 1.95 (br. s, 6
˜
H, CHAd), 1.90 (br. s, 3 H, CHAd), 1.70–1.60 (m, 24 H, CH2
)
Ad
(400 MHz, C6D6): δ = 2.06 (s, 2 H, AdCH2), 2.02–1.90 (m, 12 H,
CHAd, CH2Ad), 1.71–1.63 (m, 18 H, CH2Ad) ppm. 13C NMR
(100 MHz, C6D6): δ = 198.70 (C=O), 191.22 (C=C=O), 63.21
(C=C=O), 56.32 (AdCH2), 41.87, 40.21, 36.05, 36.90 (CH2Ad),
33.47 (CAd), 33.21 (CH2Ad), 28.26, 28.14 (CHAd) ppm.[34] MS
(ESI): m/z (%) = 352.0 (100) [M]+.
ppm. 13C NMR (100 MHz, CDCl3): δ = 210.9 (C=O), 58.77
(AdCH2), 42.50, 36.78 (CH2Ad), 33.65 (CAd), 28.59 (CHAd) ppm.
Reaction of 6 with Thiourea: To a stirred solution of thiourea
(87 mg, 1.14 mmol) in anhydrous ethanol (2 mL) was added a solu-
tion of NaOEt (52 mg, 0.76 mmol) in anhydrous EtOH (1 mL),
2,4-Bis(1-adamantyl)-N-[2-(3H-indol-3-yl)ethyl]acetoacetamide (16): followed after 5 min with ester 6 (170 mg, 0.38 mmol). The mixture
A solution of tryptamine (160 mg, 1 mmol) in dry CH2Cl2 (3 mL)
was added to a stirred solution of 12 (obtained from 1 mmol of 1)
in dry CH2Cl2 (3 mL). The mixture was stirred at room tempera-
ture for 4 h and then purified by chromatography (dry CH2Cl2).
Yield: 59% (2 steps, 150 mg), white solid, m.p. 105–107 °C.
was heated at reflux for 3 h, cooled, and concentrated. The residue
was acidified with 1  HCl to pH 6, and the solid formed was fil-
tered, washed with water, and dried. The product mixture was sepa-
rated by column chromatography (CH2Cl2 then CH2Cl2/MeOH,
99:1) to give thiouracils 23 and 24.
Eur. J. Org. Chem. 2010, 3754–3761
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3759

V. Kovalev, E. Shokova, A. Shmailov, I. Vatsouro, V. Tafeenko
FULL PAPER
(6E)-5-(1-Adamantyl)-6-(1-adamantylmethylene)-2-thioxotetra- 13C NMR (100 MHz, CDCl3): δ = 212.65 (C=O), 166.80 (CONH),
hydropyrimidin-4(1H)-one (23). Yield: 25% (39 mg), white solid,
138.21 (CPh), 128.5, 127.64, 127.30 (CHPh), 69.88 (tBuCH), 59.22
m.p. 230–245 °C (decomp.). C25H34N2OS (410.62): calcd. C 73.13, (tBuCH2), 43.47 (PhCH2), 35.96 [C(CH3)3], 31.41 [C(CH3)3], 29.48
1
H 8.35, N 6.82, S 7.81; found C 73.18, H 8.20, N 6.65, S 7.72. H [C(CH3)3], 28.42 [C(CH3)3] ppm.
NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H, NH), 8.46 (s, 1 H, NH),
Phenyl 2,4-Bis(isopropyl)acetoacetate (30): Obtained from 26
(2 mmol) and a solution of phenol (560 mg, 6 mmol) and triethyl-
amine (0.83 mL, 6 mmol) in dry CH2Cl2 (6 mL) as described for
6. The product was purified by column chromatography (CH2Cl2/
4.30 (s, 1 H, AdCH=C), 2.52 (s, 1 H, AdCH), 2.03 (br. s, 3 H,
CHAd), 2.02 (br. s, 3 H, CHAd), 1.85–1.65 (m, 24 H, CH2Ad) ppm.
13C NMR (100 MHz, CDCl3): δ = 174.87 (C=O), 166.32 (C=S),
127.97 (AdCH=C), 124.56 (C6U), 58.60 (AdCH), 42.95, 39.93
hexane, 1:1). Yield: 46% (130 mg), colorless oil. C16H22O3 (262.35):
(CH2Ad), 37.79 (CAd), 36.40, 36.36 (CH2Ad), 35.92 (CAd), 28.72,
calcd. C 73.25, H 8.45; found C 72.96, H 8.87. 1H NMR (400 MHz,
28.25 (CHAd) ppm.
CDCl3): δ = 7.37 (m, 2 H, Ph), 7.22 (m, 1 H, Ph), 7.04 (m, 2 H,
5-(1-Adamantyl)-6-(1-adamantylmethyl)-2-thioxo-2,3-dihydropyrim-
idin-4(1H)-one (24): Yield: 51% (80 mg), white solid, m.p. 340–
345 °C (decomp.). C25H34N2OS (410.62): calcd. C 73.13, H 8.35, N
6.82, S 7.81; found C 73.25, H 8.43, N 6.68, S 7.69. 1H NMR
(400 MHz, [D6]DMSO): δ = 12.20 (s, 1 H, NH), 11.01 (s, 1 H,
NH), 2.65 (s, 2 H, AdCH2), 2.12 (s, 3 H, CH2Ad), 1.97 (br. s, 3 H,
CHAd), 1.94 (br. s, 3 H, CHAd), 1.65–1.50 (m, 18 H, CH2Ad) ppm.
13C NMR (100 MHz, CDCl3, CF3CO2D): δ = 170.79 (C=O),
164.21 (C=S), 150.84 (C5U), 125.92 (C6U), 45.04 (AdCH2), 42.85,
40.95 (CH2Ad), 39.91 (CAd), 36.46, 36.35 (CH2Ad), 35.43 (CAd),
28.78, 28.72 (CHAd) ppm.
Ph), 3.43 (d, J = 9.4 Hz, 1 H, iPrCHCO), 2.55 [m, 1 H, (CH3)2CH],
2.53 (dd, J = 17.2, 7.0 Hz, 1 H, iPrCH2), 2.47 (dd, J = 17.2, 6.6 Hz,
1 H, iPrCH2), 2.23 [m, 1 H, (CH3)2CH], 1.09 (d, J = 6.7 Hz, 3 H,
CH3CH), 0.99 (d, J = 6.7 Hz, 3 H, CH3CH), 0.94 [d, J = 6.7 Hz,
6 H, (CH3)2CH] ppm. 13C NMR (100 MHz, CDCl3): δ = 203.98
(C=O), 167.54 (CO2Ph), 150.31 (CPh), 129.37, 125.98, 121.18
(CHPh), 66.71 (iPrCHCO), 51.71 (iPrCH2), 28.64, 23.88 [(CH3)
2CH], 22.35, 22.33, 20.45, 20.34 [(CH3)2CH] ppm.
1,3-Bis(tert-butyl)acetone (31): Obtained from 27 (100 mg,
0.47 mmol) as described for 22. The oil formed was taken up in
CH2Cl2, washed with water, dried, and then concentrated. Yield:
88% (70 mg), colorless oil (Lit.[30a] oil, b.p. 112.4 °C/76.5 Torr). 1H
NMR (400 MHz, CDCl3): δ = 2.26 (s, 4 H, tBuCH2), 0.99 [s, 18
H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 211.14
(C=O), 56.97 (tBuCH2), 31.01 [C(CH3)3], 29.67 [C(CH3)3] ppm.
Reaction of 6 with Cyanoacetamide: To a stirred warm solution of
6 (200 mg, 0.45 mmol) and cyanoacetamide (42 mg, 0.5 mmol) in
methanol (8 mL) was added a solution of KOH (38 mg, 0.68 mmol)
in methanol (0.7 mL). The mixture was stirred at reflux for 12 h,
cooled, and then concentrated. The paste-like residue was acidified
with 1  HCl to pH 6 and allowed to stand overnight. The water
solution was carefully decanted from the solid formed, the pro-
cedure was repeated with warm water until all the phenol was re-
moved. The solid was filtered and dried to give pure methyl ester
4 in 81% yield (140 mg).
X-ray Crystallographic Analysis of 7 and 23: Crystals of compounds
7 and 23 suitable for X-ray analysis were grown at room tempera-
ture from ethanol/CH2Cl2 (2:1) and ethanol/H2O (2:1) solutions,
respectively. The data were collected at room temperature
[295(2) K] by using graphite monochromated Cu-Kα (1.54179 Å)
radiation, ω-scan mode. The WinGX standard procedure was ap-
plied for data reduction.[35] Two standard reflections were mea-
sured every 120 min as intensity control. No absorption correction
was applied. The structure was solved and refined with the SHELX
program.[36] The non-hydrogen atoms were refined by using the an-
isotropic full-matrix least-squares procedure. The hydrogen atoms
attached to carbon atoms were placed in the calculated positions
and allowed to ride on their parent atoms [C–H 0.93–0.97 for 7
and 0.97–0.98 for 23; Uiso = 1.2Ueq (parent atom)]. Hydrogen
atoms attached to nitrogen and oxygen were determined from a
difference Fourier synthesis and refined freely. The isotropic dis-
placement parameters for freely refined hydrogen atoms are in the
range of 0.049(1)–0.07 Å for 7 and 0.04–0.07(1) Å for 23. Refine-
ment was made against all reflections. The threshold expression of
F2 Ͼ 2σ(F2) was used for calculation of R factors, the final values
of which are 0.086 for 7 and 0.071 for 23. Molecular geometry
calculations were performed with the SHELX program, and the
molecular graphics were prepared by using DIAMOND soft-
ware.[37] CCDC-765964 (for 7) and -765965 (for 23) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
2,4-Bis(tert-butyl)acetoacetic Acid (27): Obtained from 25 (1 mmol)
as described for 3. The oil formed after the evaporation of TFAA
was washed with cold water, and the wet residue slowly trans-
formed into a crystalline solid. Yield: 94% (105 mg), white solid,
m.p. 70–72 °C. (ref.[31] 78 °C) 1H NMR (400 MHz, CDCl3): δ =
3.46 (s, 1 H, tBuCH), 2.51 (d, J = 15.6 Hz, 1 H, tBuCH2), 2.38 (d,
J = 15.6 Hz, 1 H, tBuCH2), 1.08 [s, 9 H, C(CH3)3], 1.00 [s, 9 H,
C(CH3)3] ppm.
Phenyl 2,4-Bis(tert-butyl)acetoacetate (28): Obtained from 25
(1 mmol) and a solution of phenol (190 mg, 2 mmol) and triethyl-
amine (0.41 mL, 3 mmol) in dry CH2Cl2 (6 mL) as described for
6. The product was purified by column chromatography (CH2Cl2/
hexane, 1:1). Yield: 76% (110 mg), colorless oil. C18H26O3 (290.40):
calcd. C 74.45, H 9.02; found C 73.97, H 8.95. 1H NMR (400 MHz,
CDCl3): δ = 7.37 (m, 2 H, Ph), 7.23 (m, 1 H, Ph), 7.04 (m, 2 H,
Ph), 3.59 (s, 1 H, tBuCH), 2.58 (d, J = 16.4 Hz, 1 H, tBuCH2),
2.50 (d, J = 16.4 Hz, 1 H, tBuCH2), 1.18 [s, 9 H, C(CH3)3], 1.06 [s,
9 H, C(CH3)3] ppm. 13C NMR (100 MHz, CDCl3): δ = 203.86
(C=O), 167.25 (CO2Ph), 150.35 (CPh), 129.42, 125.98, 121.33
(CHPh), 68.21 (tBuCH), 56.90 (tBuCH2), 34.78 [C(CH3)3], 31.15
[C(CH3)3], 29.47 [C(CH3)3], 28.18 [C(CH3)3] ppm.
2,4-Bis(tert-butyl)-N-benzylacetoacetamide (29): Obtained from 25
(1 mmol), benzylamine (0.21 mL, 2 mmol), and triethylamine
(0.41 mL, 3 mmol) as described for 6. Yield: 79% (120 mg), white
solid, m.p. 121–122 °C. C19H29NO2 (303.44): calcd. C 75.21, H
9.63, N 4.62; found C 75.63, H 9.42, N 4.37. H NMR (400 MHz,
CDCl3): δ = 7.20–7.73 (m, 6 H, NH, Ph), 4.44 (dd, J = 14.8, 5.8 Hz,
1 H, PhCH2), 4.39 (dd, J = 14.8, 5.8 Hz, 1 H, PhCH2), 3.49 (s, 1 H,
Crystal Data for 7: C31H41NO2, M = 459.7, monoclinic, a =
13.056(4) Å, b = 25.726(2) Å, c = 14.877(1) Å, β = 94.48(1)°, V =
4981.8(4) Å3, space group P21/n, Z = 8, Dcalcd. = 1.226 gcm–3,
µ(Mo-Kα) = 0.917. Crystal size = 0.28ϫ0.14ϫ0.14 mm; 8392 re-
flections of which 3701Ͼ2σ(I).
1
Crystal Data for 23: C25H34N2O·C2H6O, M = 456.67, monoclinic,
tBuCH), 2.53 (d, J = 15.0 Hz, 1 H, tBuCH2), 2.30 (d, J = 15.0 Hz, 1 a = 6.803(2) Å, b = 15.954(2) Å, c = 23.138(3) Å, β = 90.85(1)°, V
H, tBuCH2), 1.03 [s, 9 H, C(CH3)3], 0.97 [s, 9 H, C(CH3)3] ppm.
= 2510.8(8) Å3, space group P21/c, Z = 8, Dcalcd. = 1.208 gcm–3,
3760
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3754–3761

2,4-Bis(1-adamantyl)acetoacetic Acid and Its Derivatives
[19] H. Stetter, G. Becker, Justus Liebigs Ann. Chem. 1976, 1992–
1996.
[20] H. Stetter, E. Rauscher, Chem. Ber. 1960, 93, 2054–2057.
[21] F. N. Stepanov, L. I. Sidorova, N. A. Dovgan’, Zh. Org. Khim.
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Received: March 5, 2010
Published Online: May 19, 2010
Eur. J. Org. Chem. 2010, 3754–3761
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3761