First synthesis of α-(3-R-1-adamantyl)sulfoacetic acids and their derivatives

Article abstract of DOI:10.1016/j.tet.2012.04.006

By sulfonation of 3-R-1-adamantylacetic acids 1 with H₂SO ₄ in trifluoroacetic anhydride (TFAA), the previously unknown α-(3-R-adamantyl)sulfoacetic acids 2 were obtained. In the case of 1-adamantylacetic acid 1a, the use of ～1 equiv of H₂SO ₄ led to only 1-adamantylacetic acid 2a, while with an excess of the reactant the hydroxylation of the adamantane tertiary C-H bond also occurred. It is assumed that the bis(trifluoroacetyl)sulfate generated in situ from H ₂SO₄ and TFAA is responsible both for sulfonation and oxidation steps. The adamantylated sulfoacetic acids were used for the preparation of a series of derivatives by modifications of carboxylic, sulfonic acid, and tertiary adamantane OH-groups. Due to the use of TFAA as a medium, a series of derivatives of sulfoacetic acids was obtained directly from acids 1 within one-pot procedures. Some of the synthesized compounds possess anti-HSV activity.

Full text of DOI:10.1016/j.tet.2012.04.006

Tetrahedron 68 (2012) 4765e4772
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
First synthesis of
a-(3-R-1-adamantyl)sulfoacetic acids and their derivatives
Alexander Shmailov a, Ludmila Alimbarova b, Ivan Vatsouro a, Viktor Tafeenko a, Elvira Shokova a,
,
Vladimir Kovalev a
*
a Chemistry Department of Moscow State University, Lenin’s Hills, Moscow 119991, Russia
b Ivanovsky Institute of Virology, Gamalei 16, Moscow 123098, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
By sulfonation of 3-R-1-adamantylacetic acids 1 with H2SO4 in trifluoroacetic anhydride (TFAA), the
Received 21 December 2011
Received in revised form 27 March 2012
Accepted 2 April 2012
previously unknown
a-(3-R-adamantyl)sulfoacetic acids 2 were obtained. In the case of 1-
adamantylacetic acid 1a, the use of w1 equiv of H2SO4 led to only 1-adamantylacetic acid 2a, while
with an excess of the reactant the hydroxylation of the adamantane tertiary CeH bond also occurred. It is
assumed that the bis(trifluoroacetyl)sulfate generated in situ from H2SO4 and TFAA is responsible both
for sulfonation and oxidation steps. The adamantylated sulfoacetic acids were used for the preparation of
a series of derivatives by modifications of carboxylic, sulfonic acid, and tertiary adamantane OH-groups.
Due to the use of TFAA as a medium, a series of derivatives of sulfoacetic acids was obtained directly from
acids 1 within one-pot procedures. Some of the synthesized compounds possess anti-HSV activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 12 April 2012
Keywords:
Adamantanes
Sulfonation
Hydroxylation
Adamantylsulfoacetic acids
Antiherpetic activity
1. Introduction
acids: adamantane tertiary CeH bond hydroxylation in 5-(1-
adamantyl)pyrimidines by in situ generated bis(trifluoroacetyl)
The chemistry of adamantane derivatives has attracted consid-
erable attention due to their wide range of application as model
compounds and molecular building blocks in drug and polymer
syntheses,1 hosteguest chemistry, and nanotechnology.2 Despite
the fact that a huge number of adamantane derivatives have been
synthesized,3 the published data on the synthesis of adamantane-
derived sulfoacids are very limited. The parent 1-
adamantanesulfonic acid and some derivatives have been
obtained from adamantanes by treating with SOCl2/AlCl3 followed
by hydrolysis and oxidation by H2O2,4 or directly by photo-5 or
catalytic6 sulfoxidation with SO2/O2. The synthesis of 3-(1-
pyridinium)-1-adamantylmethanesulfonic acid by reaction of 3,7-
dimethylenebicyclo[3.3.1]nonane with Py$SO3 in pyridine was
also published.7 Several patents concerned with the synthesis and
application of 1-adamantanesulfonic acid were also observed.8
In line with our investigations on the synthesis and applications
of adamantane derivatives,9 we report a synthetic approach to
previously unknown (3-R-1-adamantyl)sulfoacetic acids 2 by sul-
fonation of the corresponding adamantylacetic acids 1 with H2SO4
in trifluoroacetic acid anhydride. The motivation for this research
was our recent study on the selective electrophilic reactions of
adamantane derivatives in TFAA in the presence of sulfuric or triflic
sulfate,9f
and
CF3SO3H-catalyzed
self-acylation
of
1-
adamantylacetic acid leading to 2,4-bis(1-adamantyl)acetoacetic
acid.9g
2. Results and discussion
2.1. Synthesis
First, the reaction of 1-adamantylacetic acid 1a with H2SO4 in
TFAA was studied. As sulfuric acid is easily converted to bis(tri-
fluoroacetyl)sulfate 3 when reacted with an excess of TFAA,10 the
following stepwise procedure was used in course of the research. A
mixture of sulfuric acid and TFAA was heated at reflux for 1.5 h,
then the substrate 1a was added and the reaction mixture was kept
at room temperature or heated (Scheme 1). It was found that at
reflux temperature, depending on the excess of H2SO4 used, the
reaction between 1-adamantylacetic acid 1a and bis(tri-
fluoroacetyl)sulfate led either to selective sulfonation of CH2CO2H-
group (w1 equiv of H2SO4) or to simultaneous sulfonation and
hydroxylation of the adamantane tertiary CeH bond (2.2 equiv of
H2SO4). As
adamantyl)sulfoacetic acids 2a,b were synthesized for the first
time. At room temperature, -(1-adamantyl)sulfoacetic acid 2a was
the only product from the reaction of 1a with both equimolar or
a result, a-(1-adamantyl)- and a-(3-hydroxy-1-
a
* Corresponding author. E-mail address: kovalev@petrol.chem.msu.ru (V. Kovalev).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.006

4766
A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
(CF3CO)2O
(CF3CO2)2SO2
H2SO4
O
3
O
O
O
SO3H
SO3H
HO
HO
HO
HO
1) 3 (~ 1eq)
TFFA, rt or
1) 3 (2.2 eq)
TFFA,
1) 3 (0.8 eq)
TFFA, rt
OH
OH
2) H2O
95%
2) H2O
75%
2) H2O
2a, 59-64%
1a
2b
1b
Scheme 1.
excess amount of H2SO4, while the acid 2b can be obtained under
these conditions from 3-hydroxy-1-adamantylacetic acid 1b.
The preparative syntheses of water-soluble acids 2a,b were
performed by selective sulfonation of 1a,b with 0.8 equiv of H2SO4
as no free sulfuric acid remains in this case, and the excess
unreacted acids 1a,b are easily separated from the quenched re-
action mixtures by extraction with diethyl ether.
The proposed mechanism of 1a sulfonation involves the for-
mation of mixed 1-adamantylacetic/trifluoroacetic anhydride with
the activated a-methylene group, which is easily sulfonated with
can be explained either by incomplete amidation of A, or by pres-
ence of other anhydrides in the reaction mixture after sulfonation.
The sulfamide structure of 5 was unambiguously proved by IR
and NMR spectroscopic data. The IR spectrum contains character-
istic absorption bands of CO2H (1702 cmꢀ1) and SO2NH (3467 cmꢀ1
for NH and 1200 cmꢀ1 for SO2); in the 13C NMR spectrum the signal
of the carbonyl groups at 169.22 ppm is closer to the CO resonance
of sulfoacid 2a (169.16 ppm) than that of bisamide 6 (164.41 ppm).
The structure of bisamide 6 was confirmed by X-ray analysis. A
suitable crystal was obtained by crystallization from 2-propanol.
The molecular structure of 6 and the crystal packing are presented
in Fig. 1, the crystallographic data are collected in Table 2
(Experimental section). In the solid state the infinite rods along
the b-axis are formed due to intermolecular hydrogen bonding
(N1eH101/O2i and N2eH102/O1i).
bis(trifluoroacetyl)sulfate to form the intermediate A (Scheme 2).
The necessity to activate the methylene group is confirmed by the
fact that the amide 4a with an excess of 3 undergoes only hy-
droxylation of adamantane nucleus (compound 4b), but not sul-
fonation of
removed, so the mixed anhydride A was used as an acylating and/or
sulfonating reactant to give some -(1-adamantyl)sulfoacetic acid
a-methylene group. The excess TFAA can be easily
Is it known that acid 1a can be converted to 1-adamantylnitrile
by treating with sodium nitrite in TFAA.11 When sodium nitrite was
added directly to the reaction mixture after the sulfonation of 1a
was complete, 1-adamantylnitrile 7 was obtained after additional
heating. Thus, the action of NOþ caused the elimination of both
carboxylic and sulfo groups from anhydride A.
a
derivatives in a one-pot manner. The acid 1a was first sulfonated
with the slight excess of H2SO4 (1.05 equiv), and, after the evapo-
ration of TFAA, treated with benzylamine in dry dichloromethane
to give mono- and bis(benzylamides) 5 and 6. While the formation
of bisamide 6 proves the structure of A, the formation of amide 5
Some chemical modifications of
a-(1-adamantyl)sulfoacetic
acid 2a are presented in Scheme 3. By heating with POCl3, acid 2a
was converted to bis(chloroanhydride) 8, which was reacted with
nucleophiles to form bisamide 12 and diphenylester 9. The selective
hydrolysis of 9 was achieved by heating the substrate in pyridine
containing 1.5 equiv of water. The X-ray data for 10 (Fig. 2, Table 2)
unambiguously prove that under these conditions, hydrolysis of the
sulfonate group occurs while the carboxylic ester group remains
unchanged. This result is in line with the published properties of
sulfoacetic acid diphenyl ester.12 When refluxed in ethanol con-
taining KOH, the decarboxylation of ester 9 takes place to give
phenyl 1-adamantylmethylsulfonate 11 in high yield, while the
parent sulfoacetic acid 2a is resistant to heating either in alkaline
(KOH) or strongly acidic (HCl) medium.
F3C
O
O
CN
3 (~ 1eq)
TFFA,
O S O
NaNO2
1a
O
O
O
7, 81%
A
F3C
1) - TFAA
2) PhCH2NH2
a
-Sulfoacetic acids are used for the preparation of 1,2,4-
thiadiazine-3,5-diones, which are of interest because of their re-
lation to barbituric acid.13 Following the published synthetic
approach,13b bis(chloroanhydride) 8 was converted to bisamide 12
and then to sulfonylurea potassium salt 13. But the ring closure step
in boiling pyridine to get the desired 6-(1-adamantyl)-1,2,4-
thiadiazine-3.5-dione B was unsuccessful due to hydrolysis of the
urea.
The synthesis of sulfoacid 2b derivatives can be also performed
in a one-pot manner starting directly from 1-adamantylacetic acid
1a. For instance, the adamantylated barbituric acid 14 was obtained
from 1a by consecutive sulfonation/hydroxylation, removal of the
excess TFAA, and heating with barbituric acid in TFA (Scheme 4). It
is reasonable to assume that in this case the role of the ada-
mantylating reactant plays the bis(anhydride)-monoester C. Similar
to intermediate A, after elimination of excess TFAA, intermediate C
reacted with benzylamine to give a mixture of mono- and bisa-
mides 15 and 16.
O
O
S
O
O
O
S
O
H
Ph
N
H
OH
N
H
Ph
N
Ph
+
6, 30%
5, 34%
O
O
N
N
1. 3 (2.2 eq)
TFFA,
2) H2O
OH
4a
4b, 68%
Scheme 2.

A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
4767
Fig. 2. Molecular structure of pyridinium salt 10.
O
O
S
O
O
O
1) 3 (2.2 eq)
∇
O
CF3
CF3
TFFA,
O
F3C
1a
O
O
C
- TFAA
barbituric acid
TFA
PhCH2NH2
Fig. 1. Molecular structure (a) and crystal packing (b) of bisamide 6.
As a-(3-hydroxy-1-adamantyl)sulfoacetic acid 2b is resistant to
heating in an acidic medium, it can be used for TFA-mediated
adamantylation of C- and N-nucleophiles. The reaction of 2b with
O
O
O
S
O
SO3H
R
HO
N
Ph
H
O
+
H
N
PyH
2a
6, 40%
OH
O
S
O
O
O
N
O
PhCH2NH2
O
POCl3
H
PhO
15, R = OH, 30%
16, R = NHCH2Ph, 33%
Py
14, 62%
H2O (1.5 eq)
SO3Ph
Scheme 4.
O
O
10, 93%
SO2Cl
Cl
PhO
o-xylene and thiourea gave
adamantyl]sulfoacetic acid 17 and
a
-[3-(3,4-dimethylphenyl)-1-
PhOH
Et3N
a
-(3-thioureido-1-adamantyl)
sulfoacetic acid 18, respectively (Scheme 5).
As an extension of the sulfonation/hydroxylation method, the
interaction between 5-(3-carboxymethyl-1-adamantyl)uracil 19
and bis(trifluoroacetyl)sulfate was studied. Unexpectedly, even
when a large excess of H2SO4 was used, only sulfonation occurred
with no hydroxylation. The crude reaction mixture was quenched
with water or n-butylamine to get sulfoacid 20 and sulfamide 21,
respectively (Scheme 6). Probably, the presence of two electron-
withdrawing groups in the molecule (the uracil unit and the sul-
foacetic unit formed during sulfonation) deactivates the ada-
mantane tertiary CeH bond and makes the molecule resistant to
hydroxylation under these conditions.
SO3Ph
8
9, 62%
KOH
EtOH
NH3
11, 74%
NH2
O
O
KN
NH
S
O
O
HN
SO2NH2
KOCN
S
O
O
O
H2N
H2N
O
O
Py
2.2. Pharmacology
For
a-(3-R-1-adamantyl)sulfoacetic acids 2, 20, and selected
12, 96%
13, 68%
B
derivatives, the cytotoxicity and antiviral activity against herpes
Scheme 3.
simplex virus of types 1 and 2 (HSV-1 and HSV-2) in Vero cells were

4768
A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
sulfonation or simultaneous sulfonation and adamantane hydrox-
O
ylation can be realized. The crude anhydridic products of sulfona-
tion after removing of TFAA were further derivatized in a one-pot
manner by interaction with different O-,N-nucleophiles or
through transformations of released CO2H and SO3H-groups. Thus,
the 2-(3-R-1-adamantyl)sulfoacetic acid derivatives with ester,
amide, and sulfamide functionalities and also the product of de-
carboxylation were obtained. The product of sulfonation/hydrox-
SO3H
HO
o-xylene
TFA
17, 85%
2b
ylation of acetic acid 1ada-(3-hydroxy-1-adamantyl)sulfoacetic
O
acid 2adwas also used as an adamantylating reactant either in acid
form or as crude anhydride-monoester form (one-pot). Some of the
synthesized compounds were tested for their antiviral activity
against HSV-1 and HSV-2.
SO3H
HO
thiourea
TFA
S
NH2
N
H
18, 82%
4. Experimental
4.1. General
Scheme 5.
1H and 13C (APT) NMR spectra were measured with a Bruker
Avance 400 spectrometer with solvent signals as internal reference.
Doubled NMR signals, belonging to diastereotopic atoms, are
O
O
HO
HO
SO2R
1) 3 (2.2 eq)
∇
marked with asterisks . IR spectra were recorded with a Thermo
*
TFFA,
Scientific Nicolet IR 200 FTIR spectrometer. ESI mass spectra were
recorded with an Agilent 1100 LC/MS instrument. X-ray measure-
ments were performed with an Enraf-Nonius CAD-4 diffractometer.
Chemicals were of commercial grade and used without further
purification. 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 1a,15 3-hydroxy-1-adamantylacetic acid
1b,15 and 5-(3-carboxymethyl-1-adamantyl)uracil 199f were pre-
pared according to published procedures.
2) - TFAA
NH
NH
O
3) H2O or n-BuNH2
O
O
N
H
N
H
O
20, R = OH, 71%
21, R = NHBu-n, 68%
19
Scheme 6.
examined according to the previously reported method.14 From the
MIC50 and MCC50 values presented in Table 1, it appears that most
of substances tested possess low cytotoxicity and display moderate
antiviral activity, yet significantly inferior to the reference phar-
maceutical acyclovir. Pyridinium methanesulfonate 10 displayed
the most pronounced antiviral activity toward HSV-2 and had
a selectivity index (SI¼MCC50/MIC50) >20, while the sulfoacetic
acid 2b showed no antiviral activity.
4.2. Synthesis
4.2.1.
a-(1-Adamantyl)sulfoacetic acid (2a). Method A: A mixture of
sulfuric acid (98%, 0.06 mL, 1.05 mmol) and TFAA (1.7 mL) was
heated at reflux (oil bath, 65 ꢁC) for 1.5 h and cooled. 1-
Adamantylacetic acid 1a (0.19 g, 1.0 mmol) was added and the re-
sultant mixture was refluxed (oil bath, 75 ꢁC) for 4 h. After cooling,
the excess TFAA was removed under reduced pressure, the residue
was treated with cold water (1 mL), the solid formed was filtered,
washed with diethyl ether, and dried. Yield: 59% (0.16 g). Method B:
A cooled TFAA-solution of bis(trifluoroacetyl)sulfate prepared from
H2SO4 (94%, 0.045 mL, 0.8 mmol) and TFAA (0.9 mL) as described in
method A, was added to the solution of 1-adamantylacetic acid 1a
(0.19 g,1.0 mmol) in TFAA (0.9 mL). The mixture was stirred for 24 h
at room temperature and then poured into water (20 mL). The re-
sultant suspension was stirred at 95 ꢁC for 3 h in an open flask,
cooled to room temperature, extracted with diethyl ether, and the
water fraction was evaporated under reduced pressure. The residue
was re-evaporated twice with dry benzene. Yield: 64% (0.14 g),
white solid, mp 163e167 ꢁC. Anal. Calcd for C12H18O5S (274.34): C,
52.54; H, 6.61. Found: C, 52.80; H, 6.31. IR (KBr, cmꢀ1): 1715 (CO),
Table 1
Cytotoxicity and anti-HSV activity of selected compounds in Vero cells culture (mg/
a
cmꢀ3
)
b
Compound
MCC50
HSV-1
HSV-2
MIC50
c
MIC50
SI
4
SI
2ad
2b
1000
1000
1000
>1000
250
250
NA
100
NA
100
50
50
100
0.2
10
10
>20
5
5e
100
100
250
500
0.4
10
>10
1
1
1250
10
12
20
Zovirax
500
500
5
2500
a
The data from three independent experiments, each duplicated; deviations
below 10%.
1172 (SO2). 1H NMR (400 MHz, CDCl3):
2.00e1.35 (m, 15H, HAd) ppm. 13C NMR (100 MHz, CDCl3):
(CO), 76.6 (CHCO), 39.8, 36.7 (CHA2d), 35.0 (CAd), 28.2 (CHAd) ppm.
d
¼3.11 (s, 1H, CHCO),
b
MCC50dminimum cytotoxic concentration causing 50% growth inhibition of
Vero cells.
MIC50dminimum inhibitory concentration reducing the cytopathogenic effect
of virus by 50%.
d
¼169.1
c
d
As pyridinium salt.
e
4.2.2.
a-(3-Hydroxy-1-adamantyl)sulfoacetic acid (2b). Method A:
As sodium salt.
Acid 2b was obtained from 1-adamantylacetic acid 1a (0.39 g,
2.0 mmol), H2SO4 (98%, 0.23 mL, 4.3 mmol), and TFAA (3.4 mL) as
described for 2a (method A). After removal of TFAA, the residue was
dissolved in water and allowed to stay overnight. The clear water
solution was decanted and treated with 0.5 M BaCl2 until pre-
cipitation was complete, and then treated with Na2CO3 to pH 8. The
solution was filtered and acidified with HCl to pH 2. The water was
3. Conclusions
Bis(trifluoroacetyl)sulfate prepared in situ from H2SO4 and TFAA
was used for selective sulfonation of the a-methyl group of (3-R-1-
adamantyl)acetic acid 1. In the case of 1-adamantylacetic acid 1a,
under a controlled excess of H2SO4 used, either the selective

A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
4769
removed under reduced pressure, and the dry solid residue was
extracted repeatedly by dry methanol. The methanol solution was
evaporated to dryness. Yield: 75% (0.44 g). Method B: Acid 2b was
obtained from 3-hydroxy-1-adamantylacetic acid 1b (0.42 g,
2.0 mmol), H2SO4 (94%, 0.09 mL, 1.6 mmol), and TFAA (3.4 mL) as
described for 2a (method B). Yield: 95% (0.44 g), light yellow solid
(hygroscopic), mp 200e203 ꢁC (decomp.). Anal. Calcd for
C12H18O6S$H2O (308.36): C, 46.74; H, 6.54. Found: C, 46.99; H,
6.34%. IR (KBr, cmꢀ1): 1708 (CO), 1170 (SO2). 1H NMR (400 MHz,
NMR (100 MHz, DMSO-d6):
d
¼169.2 (CO), 134.0 (CAr), 128.9, 128.7,
128.5 (CHAr), 76.4 (CHCO), 42.4 (NCH2), 39.7, 36.6 (CHA2d), 34.7 (CAd),
28.1 (CHAd) ppm.
4.2.6. N-Benzyl-a-(1-adamantyl)-a-(benzylsulfamoyl)acetamide
(6). Method A: Obtained by chromatographic purification
(dichloromethane/methanol, 99:1) of the dichloromethane fraction
from the synthesis of 5. Yield: 30% (0.27 g). Method B: A mixture of
2-(1-adamantyl)sulfoacetic acid 2a (0.14 g, 0.5 mmol) and POCl3
(2 mL) was heated at 125 ꢁC for 5 h. The excess POCl3 was removed
under reduced pressure, and the residue was dissolved in dry
dichloromethane (4 mL). After cooling to 0e5 ꢁC, a solution of
benzylamine (0.16 mL, 1.5 mmol) and triethylamine (0.21 mL,
1.5 mmol) in dichloromethane (3 mL) was added. The mixture was
stirred at room temperature for 24 h, diluted with dichloro-
methane, and washed with 2 M HCl. The organic fraction was dried
by MgSO4, concentrated, and the residue was purified by column
chromatography (dichloromethane/methanol, 99:1). Yield: 40%
(0.09 g), white solid, mp 154e156 ꢁC. Anal. Calcd for C26H32N2O3S
(452.62): C, 69.00; H, 7.13; N, 6.19. Found: C, 69.32; H, 7.01; N, 6.50.
IR (KBr, cmꢀ1): 3370, 3210 (NH), 1660 (CO), 1149 (SO2). 1H NMR
DMSO-d6):
d
¼3.17 (s, 1H, CHCO), 2.04 (br s, 2H, CHAd), 1.95e1.30 (m,
12H, CHA2d) ppm. 13C NMR (100 MHz, DMSO-d6):
d
¼170.0 (CO), 75.5
(CHCO), 66.9 (CAd), 48.0, 44.7 (CH2Ad), 38.3 (CAd), 38.0, 35.4 (CHA2d),
30.1
*
,
30.0
*
(CHAd) ppm. MS (ESI): m/z¼288.9 [MꢀH]ꢀ, for
C12H17O6S (289.07).
4.2.3. N,N-Diethyl-
a-(1-adamantyl)acetamide (4a). A mixture of 1-
adamantylacetic acid 1a (0.78 g, 4.0 mmol) and SOCl2 (5 mL) was
heated at reflux for 3 h and cooled. The excess SOCl2 was removed
under reduced pressure and the residue was re-evaporated twice
with dry benzene. The resultant oil was dissolved in dry benzene
(10 mL), and diethylamine (2.1 mL, 20 mmol) was added dropwise
at stirring, and the mixture was allowed to stay overnight at room
temperature. The solvent was evaporated under reduced pressure
and the residue treated with 2 M HCl (15 mL) and extracted with
dichloromethane. The organic fraction was washed with water,
dried with MgSO4, and the solvent evaporated. Yield: 79% (0.79 g),
colorless oil. Anal. Calcd for C16H27NO (249.40): C, 77.06; H, 10.91;
N, 5.62. Found: C, 77.23; H, 10.82; N, 5.81. IR (KBr, cmꢀ1): 1621 (CO).
(400 MHz, CDCl3):
d
¼7.38e7.17 (m, 10H, ArH), 6.88 (br s, 1H,
NHSO2), 4.79 (br s, 1H, NHCO), 4.50 (dd, 2J¼14.4 Hz, 3J¼6.2 Hz, 1H,
NCH2), 4.40 (dd, 2J¼14.4 Hz, 3J¼5.6 Hz, 1H, NCH2), 4.21 (dd,
2J¼13.9 Hz, 3J¼6.5 Hz, 1H, NCH2), 4.16 (dd, 2J¼13.9 Hz, 3J¼5.5 Hz,
1H, NCH2), 3.64 (s, 1H, CHCO), 2.15e1.55 (m, 15H, HAd) ppm. 13C
NMR (CDCl3):
d
¼164.4 (CO), 137.6, 136.5 (CAr), 128.8, 128.7, 128.0,
128.0, 127.9, 127.7 (CHAr), 79.9 (CHCO), 47.5 (CH2NCO), 43.9
1H NMR (400 MHz, CDCl3):
d
¼3.28 (m, 4H, NCH2), 2.02 (m, 2H,
(CH2NSO2), 40.4 (CH2Ad), 37.0 (CAd), 36.3 (CHA2d), 28.5 (CHAd) ppm.
CH2CO), 1.88 (br s, 3H, CHAd), 1.67e1.51 (m, 12H, CHA2d), 1.06 (m, 6H,
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d¼170.3 (CO), 45.7 (CH2CO),
4.2.7. 1-Adamantylnitrile (7). The reaction mixture obtained after
sulfonation of 1-adamantylacetic acid 1a (0.19 g, 1.0 mmol) with
H2SO4 (98%, 0.06 mL, 1.1 mmol) in TFAA (3.4 mL) as described for 2a
(method A) was cooled to room temperature and NaNO2 (0.15 g,
2.2 mmol) was added. The mixture was refluxed (oil bath, 55 ꢁC) for
4 h, cooled, and the solvent evaporated under reduced pressure.
The residue was washed with water, methanol and dried. Yield:
81% (0.13 g), white solid, mp 191e193 ꢁC (lit. 193e196 ꢁC11). 1H
42.6 (CH2Ad), 39.8 (NCH2), 36.7 (CH2Ad), 33.4 (CAd), 28.6 (CHAd), 14.3,
13.2 (CH3) ppm.
4.2.4. N,N-Diethyl-a-(3-hydroxy-1-adamantyl)acetamide
(4b). Obtained from acetamide 4a (0.25 g, 1.0 mmol), H2SO4 (98%,
0.12 mL, 2.2 mmol), and TFAA (1.7 mL) as described for 2a (method
A). The residue formed after removal of TFAA was heated with 1 M
NaOH at 50 ꢁC for 2 h, cooled, acidified with HCl to pH 2, and the
solution extracted with dichloromethane. The organic solution was
dried by MgSO4 and the solvent evaporated. Yield: 68% (0.18 g),
colorless oil. Anal. Calcd for C16H27NO2 (265.40): C, 72.41; H, 10.25;
N, 5.28. Found: C, 72.02; H, 9.96; N. 5.15. IR (KBr, cmꢀ1): 1623 (CO).
NMR (400 MHz, CDCl3):
d
¼2.10e1.85 (m, 9H, CHAdþCH2Ad),
1.80e1.65 (m, 6H, CHA2d) ppm. 13C NMR (100 MHz, CDCl3):
d
¼125.3
(CN), 39.9, 35.8 (CHA2d), 34.1 (CAd), 27.2 (CHAd) ppm.
4.2.8. Diphenyl-a-(1-adamantyl)sulfoacetate (9). Obtained from 2-
1H NMR (400 MHz, CDCl3):
d
¼4.44 (br s, 1H, OH), 3.35e3.25 (m, 4H,
(1-adamantyl)sulfoacetic acid 2a (0.27 g, 1.0 mmol), POCl3 (2 mL),
phenol (0.38 g, 4.0 mmol), and triethylamine (0.83 mL, 6.0 mmol)
in dichloromethane (6 mL) as described for 6 (method B). The crude
product was purified with column chromatography (dichloro-
methane/hexane, 1:1). Yield: 62% (0.26 g), colorless needles, mp
138e142 ꢁC (decomp.). Anal. Calcd for C24H26O5S (426.54): C, 67.58;
H, 6.14. Found: C 67.99, H 6.31. IR (KBr, cmꢀ1): 1758e1745 (CO),1135
NCH2), 2.16e2.09 (br s, 4H, CH2COþCHAd), 1.70e1.45 (m, 12H,
CHA2d), 1.14e1.02 (m, 6H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼170.3 (CO), 68.7 (CAd), 50.0 (CH2Ad), 44.5 (CH2CO), 44.2 (CHA2d),
42.8 (NCH2), 41.2 (CH2Ad), 40.1 (NCH2), 36.7 (CAd), 35.2 (CHA2d), 30.5
(CHAd), 14.2, 13.1 (CH3) ppm.
4.2.5.
a-(1-Adamantyl)-a-(benzylsulfamoyl)acetic acid (5). The re-
(SO2). 1H NMR (400 MHz, CDCl3):
d
¼7.45e7.13 (m, 10H, ArH), 4.20
action mixture obtained after sulfonation of 1-adamantylacetic acid
1a (0.39 g, 2.0 mmol) with H2SO4 (98%, 0.12 mL, 2.2 mmol) in TFAA
(3.4 mL) as described for 2a (method A) was concentrated to dry-
ness under reduced pressure. The residue was dissolved in dry
dichloromethane (20 mL), and a solution of benzylamine (0.66 mL,
6.0 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dichloro-
methane (4 mL) was added with cooling (0e5 ꢁC). The mixture was
allowed to stay overnight at room temperature and quenched with
2 M HCl. After 24 h, the water fraction (as suspension) was sepa-
rated and filtered, the solid was washed with water and dried.
Yield: 34% (0.25 g), white solid, mp 175e179 ꢁC. Anal. Calcd for
C19H25NO4S (363.48): C, 62.79; H, 6.93; N, 3.85. Found: C, 62.50; H,
6.85; N, 3.71. IR (KBr, cmꢀ1): 3467 (NH), 1702 (CO), 1200 (SO2). 1H
(s, 1H, CHCO), 2.30e1.90 (m, 6H, CHA2d), 2.11 (br s, 3H, CHAd),
1.82e1.68 (m, 6H, CHA2d) ppm. 13C NMR (100 MHz, CDCl3):
d
¼162.8
(CO), 150.1, 148.9 (CAr), 129.9, 129.6, 127.3, 126.5, 122.1, 121.2 (CHAr),
76.7 (CHCO), 34.9 (CH2Ad), 37.8 (CAd), 36.2 (CHA2d), 28.4 (CHAd) ppm.
4.2.9.
a-(Phenoxycarbonyl)-a-(1-adamantyl)methanesulfonic acid,
pyridinium salt (10). A mixture of ester 9 (0.21 g, 0.5 mmol), water
(0.014 mL, 0.75 mmol), and dry pyridine (3 mL) was heated at
120 ꢁC for 12 h. The solvent was evaporated and the resultant solid
was washed with diethyl ether. Yield: 93% (0.20 g), colorless crys-
tals, mp 119e123 ꢁC (decomp.). Anal. Calcd for C18H21O5S$C5H6N
(429.54): C, 64.31; H, 6.34; N, 3.26. Found: C, 63.95; H, 6.11; N, 3.45.
IR (KBr, cmꢀ1): 1748 (CO), 1253e1164 (SO2). 1H NMR (400 MHz,
NMR (400 MHz, DMSO-d6):
d
¼7.50e7.35 (m, 5H, ArH), 4.07e3.97
DMSO-d6):
d
¼8.85 (br s, 2H, ArHPy), 8.36 (br s, 1H, ArHPy), 7.90 (br s,
(m, 2H, NCH2), 3.08 (s, 1H, CHCO), 2.00e1.50 (m, 15H, HAd) ppm. 13
C
2H, ArHPy), 7.40e6.95 (m, 5H, ArHPh), 3.94 (s, 1H, CHCO), 2.25e1.95

4770
A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
(m, 9H, CHAdþCHA2d), 1.80e1.60 (m, 6H, CHA2d) ppm. 13C NMR
HAd) ppm. 13C NMR (100 MHz, DMSO-d6):
(CPyr), 151.5 (CPyr), 76.1 (CHCO), 61.4 (CHPyr), 42.8, 38.9 (CHA2d), 38.1
(CAd), 36.2 (CHA2d), 35.5 (CH2Ad), 28.6 (CHAd) ppm.
, 28.5
d
¼168.95 (COOH), 168.7
(100 MHz, DMSO-d6):
d
¼167.8 (CO), 150.6 (CAr,Ph), 145.6, 142.1
(CHAr,Py), 129.3 (CHAr,Ph), 127.1 (CHAr,Py), 125.8, 121.5 (CHAr,Ph), 76.2
*
*
(CHCO), 40.0, 36.6 (CHA2d), 36.5 (CAd), 28.5 (CHAd) ppm.
4.2.14.
a
-(3-Hydroxy-1-adamantyl)-
a-(benzylsulfamoyl)acetic acid
4.2.10. Phenyl
a-(1-adamantyl)methanesulfonate (11). A mixture of
(15) and N-benzyl
a-(3-hydroxy-1-adamantyl)-a-(benzylsulfamoyl)
ester 9 (0.15 g, 0.35 mmol), NaOH (0.02 g, 0.5 mmol), water (1 mL),
and ethanol (2 mL) was heated at 85 ꢁC for 20 h and then stirred at
room temperature for 12 h. The solid formed was filtered off, and
the filtrate acidified with HCl to pH 2, and concentrated to dryness.
The residue was washed with water (1 mL) and dried. Yield: 74%
(0.07 g), white solid, mp 159e162 ꢁC (decomp.). Anal. Calcd for
C17H22O3S (306.43): C, 66.64; H, 7.24. Found: C, 66.90; H, 7.40. 1H
acetamide (16). The reaction mixture obtained after sulfonation/
hydroxylation of 1-adamantylacetic acid 1a (0.39 g, 2.0 mmol) with
H2SO4 (98%, 0.23 mL, 4.4 mmol) in TFAA (3.4 mL) as described for
2a (method A) was concentrated to dryness under reduced pres-
sure. The residue was dissolved in dry dichloromethane (10 mL),
and a solution of benzylamine (2.18 mL, 20.0 mmol) in dichloro-
methane (5 mL) was added at cooling (0e5 ꢁC). The mixture was
allowed to stay for 24 h at room temperature and washed with 1 M
HCl, water, and dried by MgSO4. The solvent was evaporated and
the residue was subjected to column chromatography (dichloro-
methane/ethanol, 20:1). Compound 15: Yield: 30% (0.23 g), white
solid, mp 198e203 ꢁC. Anal. Calcd for C19H25NO5S (379.48): C,
60.14; H, 6.64; N, 3.69. Found: C, 60.43; H, 6.78; N, 3.57. 1H NMR
NMR (400 MHz, DMSO-d6):
d
¼7.50e7.10 (m, 5H, ArH), 3.09 (br s,
2H, CH2S), 2.20e1.50 (m, 15H, HAd) ppm. 13C NMR (100 MHz,
DMSO-d6):
d
¼149.3 (CAr), 129.9, 127.0, 122.0 (CHAr), 63.0 (CH2S),
41.7, 36.3 (CHA2d), 33.4 (CAd), 28.3 (CHAd) ppm.
4.2.11.
a-Carbamoyl-a-(1-adamantyl)methanesulfonamide (12). A
mixture of 2-(1-adamantyl)sulfoacetic acid 2a (0.14 g, 0.5 mmol)
and POCl3 (1 mL) was heated at 125 ꢁC for 4 h, cooled, and the
solvent evaporated under reduced pressure. The residue was dis-
solved in dry 1,4-dioxane (2 mL) and added to a cold 1,4-dioxane
saturated with gaseous NH3 (15 mL). The mixture was stirred at
room temperature for 12 h, and the solvent evaporated. The re-
sidual solid was stirred with water (3 mL) for 6 h, the solid formed
was collected, washed with water, acetone, and dried. Yield: 96%
(0.13 g), white solid, mp 194e199 ꢁC (decomp.). Anal. Calcd for
C12H20N2O3S (272.37): C, 52.92; H, 7.40; N, 10.29. Found: C, 52.57;
H, 7.59; N, 10.31. IR (KBr, cmꢀ1): 1674 (CO), 1150 (SO2). 1H NMR
(400 MHz, acetone-d6):
d
¼7.60e7.45 (m, 5H, ArH), 4.95 (br s, 1H,
NH), 4.40e4.30 (m, 2H, NCH2), 3.73 (s, 1H, CHCO), 2.21 (br s, 2H,
CHAd), 2.00e1.40 (m, 12H, CHA2d) ppm. Compound 16: Yield: 33%
(0.31 g), white needles, mp 174e177 ꢁC. Anal. Calcd for
C26H32N2O4S (468.62): C, 66.64; H, 6.88; N, 5.98. Found: C, 66.25; H,
6.63; N, 6.35. 1H NMR (400 MHz, CDCl3):
d
¼7.35e7.15 (m,10H, ArH),
6.92 (br s, 1H, NHSO2), 4.86 (br s, 1H, NHCO), 4.55e4.10 (m, 4H,
NCH2), 3.67 (s, 1H, CHCO), 2.05e1.45 (m, 14H, HAd) ppm. 13C NMR
(CDCl3):
d
¼164.2 (CO), 137.6, 136.6 (CAr), 128.8, 128.7, 128.0, 127.9,
127.8 (CHAr), 78.6 (CHCO), 68.5 (CAd), 47.9 (CH2NCO), 47.5 (CHA2d),
44.0 (CH2NSO2), 43.9 (CHA2d), 39.9 (CAd), 39.1, 39.0, 34.8 (CHA2d),
(400 MHz, DMSO-d6):
CONH2), 6.75 (br s, 2H, SO2NH2), 3.52 (s, 1H, CHCO), 2.10e1.50 (m,
15H, HAd) ppm. 13C NMR (100 MHz, DMSO-d6):
¼167.3 (CO), 77.9
(CHCO), 39.5, 36.3 (CHA2d), 35.6 (CAd), 28.0 (CHAd) ppm.
d
¼7.47 (br s, 1H, CONH2), 7.25 (br s, 1H,
30.4
*
, 30.3
*
(CHAd) ppm.
d
4.2.15.
a
-[3-(3,4-Dimethylphenyl)-1-adamantyl]sulfoacetic
acid
(17). A mixture of 2-(3-hydroxy-1-adamantyl)sulfoacetic acid 2b
(0.15 g, 0.5 mmol), o-xylene (0.08 mL, 0.65 mmol), and TFA (1 mL)
was refluxed (oil bath, 90 ꢁC) for 6 h, cooled, and the solvent
evaporated under reduced pressure. The solid formed upon addi-
tion of water was collected, washed with water, methanol, and
dried. Yield: 85% (0.16 g), white solid, mp 164e169 ꢁC. Anal. Calcd
for C20H26O5S (378.49): C, 63.47; H, 6.92. Found: C, 63.09; H, 6.69. IR
(KBr, cmꢀ1): 1712 (CO), 1239 (SO2). 1H NMR (400 MHz, DMSO-d6):
4.2.12.
a-Carbamoyl-a-(1-adamantyl)methanesulfonylurea, potas-
sium salt (13). A mixture of bisamide 12 (0.14 g, 0.5 mmol), KOCN
(0.045 g, 0.55 mmol), and dry ethanol (2.5 mL) was refluxed (oil
bath, 95 ꢁC) for 5 h. The reaction mixture was cooled and allowed to
stay at 0 ꢁC for 12 h. The solid formed was filtered, washed with
cold ethanol, and dried. Yield: 68% (0.12 g), white solid, mp
96e99 ꢁC (decomp.). Anal. Calcd for C13H20KN3O4S (353.49): C,
44.17; H, 5.70; N, 11.89. Found: C, 43.85; H, 6.09; N, 11.55. IR (KBr,
d
¼7.08e6.95 (m, 3H, ArH), 3.18 (s, 1H, CHCO), 2.18 (s, 3H, CH3), 2.14
(s, 3H, CH3), 2.06 (br s, 3H, CHAd), 2.03e1.50 (m,12H, CH2Ad) ppm. 13
C
cmꢀ1): 1673 (CO), 1137 (SO2). 1H NMR (400 MHz, DMSO-d6):
(br s, 1H, CONH2), 6.79 (br s, 1H, CONH2), 5.20e4.90 (br s, 2H,
KNCONH2), 3.71 (s, 1H, CHCO), 2.05e1.65 (m, 6H, CHA2d), 1.89 (br s,
3H, CHAd), 1.65e1.50 (m, 6H, CHA2d) ppm. 13C NMR (100 MHz,
d¼7.09
NMR (100 MHz, DMSO-d6):
d
¼169.8 (CO), 148.4, 135.7, 133.3 (CAr),
129.4, 126.2, 122.2 (CHAr), 76.3 (CHCO), 45.7, 42.3, 39.0 (CHA2d), 36.3
(CAd), 36.1 (CH2Ad), 35.9 (CAd), 28.9 (CHAd), 20.0, 19.1 (CH3) ppm. MS
(ESI): m/z¼378.7 [MþH]þ, for C20H26O5S$H (379.16).
DMSO-d6):
d
¼169.2 (CHCO), 162.4 (KNCONH2), 76.5 (CHCO), 39.8,
36.6 (CHA2d), 35.0 (CAd), 28.2 (CHAd) ppm.
4.2.16.
a-(3-Thioureido-1-adamantyl)sulfoacetic acid (18). Obtained
from 2-(3-hydroxy-1-adamantyl)sulfoacetic acid 2b (0.29 g,
1.0 mmol), thiourea (0.23 g, 3.0 mmol), and TFA (2 mL) as described
for 14 with prolonged (15 h) heating. Yield: 82% (0.27 g), white
solid, mp 223e226 ꢁC. Anal. Calcd for C13H20N2O5S2 (348.44): C,
44.81; H, 5.79; N, 8.04. Found: C, 44.45; H, 5.58; N, 8.49. 1H NMR
4.2.13. 5-[3-(
a
-Sulfocarboxymethyl)-1-adamantyl]barbituric
acid
(14). The reaction mixture obtained after sulfonation/hydroxyl-
ation of 1-adamantylacetic acid 1a (0.19 g, 1.0 mmol) with H2SO4
(98%, 0.12 mL, 2.2 mmol) in TFAA (1.7 mL) as described for 2a
(method A) was concentrated to dryness under reduced pressure.
TFA (2 mL) and barbituric acid (0.19 g, 1.5 mmol) were added and
the reaction mixture was refluxed (oil bath, 95 ꢁC) for 15 h. After
cooling, the solvent was removed under reduced pressure, water
was added, and the mixture was allowed to stay at 0 ꢁC for 12 h. The
solution was filtered, and the solvent evaporated. The residue was
extracted with ethanol (2 mL), the solvent evaporated, and the solid
residue washed with diethyl ether. Yield: 62%, yellow solid, mp
>300 ꢁC. Anal. Calcd for C16H20N2O8S (400.41): C, 48.00; H, 5.03; N,
7.00. Found: C, 48.32; H, 5.26; N, 6.75. IR (KBr, cmꢀ1): 1757e1678
(400 MHz, DMSO-d6):
3.24 (s, 1H, CHCO), 2.15e1.40 (m, 14H,
d
¼9.31 (s, 1H, CONH2), 9.13 (s, 1H, CONH2),
H
Ad) ppm. 13C NMR
(100 MHz, DMSO-d6):
d
¼169.4 (CO), 164.5 (CS), 75.3 (CHCO), 54.2
(CAd), 44.8, 42.9, 42.8, 37.5 (CH2Ad), 36.6 (CAd), 34.5 (CHA2d), 30.0
(CHAd) ppm.
4.2.17. 5-[3-(a-Sulfocarboxymethyl)-1-adamantyl]uracil
(20). Obtained from 5-(3-carboxymethyl-1-adamantyl)uracil 19
(0.15 g, 0.5 mmol), H2SO4 (98%, 0.06 mL, 1.1 mmol), and TFAA
(0.9 mL) as described for 2a (method A). The residue formed after
removal of TFAA was dissolved in 1 M NaOH (5 mL) and allowed to
stay for 12 h at room temperature. The solid formed upon addition
(CO), 1241e1147 (SO2). 1H NMR (400 MHz, DMSO-d6):
2H, NH), 3.11 (s, 1H, CHCO), 2.66 (s, 1H, CHPyr), 2.05e1.35 (m, 14H,
d¼11.07 (br s,

A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
4771
Table 2
of HCl was collected, washed with water, diethyl ether, and dried.
Crystal data and structure refinement details for 6 and 10
Yield: 71% (0.14 g), white solid, mp >300 ꢁC. Anal. Calcd for
C16H20N2O7S (384.41): C, 49.99; H, 5.24; N, 7.29. Found: C, 49.60; H,
Compound
CCDC #
Empirical formula
Crystal size, mm
T, K
6
10
859911
5.51; N, 7.35. 1H NMR (400 MHz, DMSO-d6):
d
¼10.84 (br s, 1H, NH),
859912
C26H32N2O3S
0.05ꢂ0.07ꢂ0.1
295
Monoclinic
P21/n
15.468(2)
9.3764(14)
17.277(3)
110.21(3)
2351.5(7)
4
1.278
1.461
3.31e70.95
ꢀ18 to 17, 0e11,
0e21
10.67e10.58 (m, 1H, NH), 6.85 (d, J¼5.8 Hz, 1H, CHPyr), 3.14 (s, 1H,
C12H16O5S$C5H6N
0.02ꢂ0.03ꢂ0.1
295
Triclinic
P-1
9.5931(12)
10.230(4)
13.120(3)
109.61, 95.90, 111.57(2)
1089.6(5)
2
1.309
1.606
3.70e71.91
CHCO), 2.10e1.45 (m, 15H, HAd) ppm. 13C NMR (100 MHz, DMSO-
d6):
d
¼169.7 (COOH), 163.4, 151.0 (CPyr), 136.3 (CHPyr), 119.7 (CPyr),
Crystal system
Space group
76.0 (CHCO), 42.5, 39.0, 38.9 (CHA2d), 35.9, 35.6 (CAd), 34.8 (CHA2d),
28.3 (CHAd) ppm. MS (ESI): m/z¼384.9 [MþH]þ, for C16H20N2O7S H
(385.41).
ꢀ
a, A
ꢀ
b, A
ꢀ
c, A
a
,
b
ꢀ
,
g
3
4.2.18. 5-[3-(a-Butylsulfamoylcarboxymethyl)-1-adamantyl]uracil
V, A
Z
(21). Obtained from 5-(3-carboxymethyl-1-adamantyl)uracil 19
(0.10 g, 0.33 mmol), H2SO4 (98%, 0.06 mL, 1.1 mmol), and TFAA
(0.9 mL) as described for 2a (method A). The residue formed after
removal of TFAA was dissolved in dry DMF (1 mL), and n-butyl-
amine (0.2 mL, 2.0 mmol) was added. The mixture was stirred for
12 h at room temperature, diluted with water, acidified with HCl to
pH 2, and allowed to stay at 0 ꢁC for 48 h. The solid formed was
collected, washed with water, and dried. Yield: 68% (0.10 g), white
solid, mp >300 ꢁC. Anal. Calcd for C20H29N3O6S (439.53): C, 54.65;
H, 6.65; N, 9.56. Found: C, 54.89; H, 6.72; N, 9.21. IR (KBr, cmꢀ1):
Dcalcd, g/cmꢀ3
m
, mm
range,
ꢁ
Q
Range of h, k, l
ꢀ11 to 11, ꢀ12 to 11,
0e16
4478
4281
3638
Reflections collected
Independent reflections
Observed reflections
4672
4530
2736
[I>2
R(F2)
Rw(F2)
Goodness of fit
s(I)]
0.063
0.15
1.024
0.208, ꢀ0.353
0.049
0.14
1.026
0.361, ꢀ0.270
1710 (CO), 1156 (SO2). 1H NMR (400 MHz, DMSO-d6):
d
¼6.84 (br s,
ꢀꢀ3
Drmin (e A
Drmax
,
)
1H, CHPyr), 3.12 (s, 1H, CHCO), 2.84e1.20 (m, 20H,
HAdþCH2CH2CH2), 0.87 (t, J¼7.3 Hz, 3H, CH3) ppm. 13C NMR
(100 MHz, DMSO-d6):
d
¼169.5 (COOH), 163.4, 150.9 (CPyr), 136.2
(CHPyr), 119.7 (CPyr), 76.5 (CHCO), 42.4, 38.9 (CH2Ad), 38.7 (NCH2),
35.8, 35.5 (CAd), 34.8 (CH2Ad), 29.1 (NCH2CH2), 28.3 (CHAd), 19.1
(CH2CH3), 13.5 (CH3) ppm.
were incubated for 72 h. At the indicated time, the cells were colored
with Trypan Blue, and the cell number was determined. The 50%
minimum cytotoxic concentration (MCC50) was defined as the
compound concentration required reducing the cell number by 50%.
4.3. X-ray crystallographic analysis
4.4.3. Antiviral assays. Vero cells were inoculated with HSV-1 or
HSV-2 at an input of 0.1 PFU (plaque formation units) per cell and
then incubated with a medium containing various concentrations
of studied compounds for 48 h (95e100% virus-inducted cytopa-
thicity in the untreated control). Antiviral activity was expressed as
the compound concentration required to reduce virus-inducted
cytopathicity by 50% (MIC50) compared to untreated control.
Crystals of compounds 6 and 10 suitable for X-ray analysis were
grown at room temperature from 2-propanol solutions. The data
were collected at room temperature [295(2) K] by using graphite
ꢀ
monochromated Cu K
a
(1.54179 A) radiation,
u
-scan mode. The
WinGX standard procedure was applied for data reduction.16 Two
standard reflections were measured every 120 min as intensity
control. No absorption correction was applied. The structure was
solved and refined with the SHELX program.17
Acknowledgements
The non-hydrogen atoms were refined by using the anisotropic
full matrix least-square procedure. The hydrogen atoms of 6 were
located from a difference Fourier map and refined freely. For 10 all
hydrogen atoms were placed in the calculated positions and
Financial support by the Russian Foundation for Basic Research
(grant # 09-03-00971) is gratefully acknowledged.
ꢀ
allowed to ride on their parent atoms [CeH 0.93e0.98, NH 0.86 A;
References and notes
Uiso¼1.2 Ueq(parent atom)]. The isotropic displacement parameters
1. (a) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J. Med. Chem. 2011, 46,
1949e1963; (b) Lamoureux, G.; Artavia, G. Curr. Med. Chem. 2010, 17,
2967e2978; (c) Zoidis, G.; Kolocouris, N.; Kelly, J. M.; Prathalingam, S. R.;
Naesens, L.; De Clercq, E. Eur. J. Med. Chem. 2010, 45, 5022e5030; (d) Novakov,
I. A.; Orlinson, B. S. Polymer Sci. C 2005, 47, 50e73.
for freely refined hydrogen atoms (6) are in the range of 0.05(1)e
2
ꢀ
0.11 A . Refinement was made against all reflections. Molecular
geometry calculations were performed with the SHELX program,
and the molecular graphics were prepared by using DIAMOND
software.18 The crystallographic data and structure refinement
details are presented in Table 2.
2. (a) Mansoori, G. A. In Advances in Chemical Physics; Rice, S. A., Ed.; John Wiley &
Sons: Hoboken, NJ, USA, 2007; Vol. 136, p 207; (b) Ramezani, H.; Mansoori, G. A.
Top. Appl. Phys. 2007, 109, 44e71; (c) Ling, X. Y.; Reinhoudt, D. N.; Huskens, J.
Pure Appl. Chem. 2009, 81, 2225e2233; (d) Hohman, J. N.; Claridge, S. A.; Kim,
M.; Weiss, P. S. Mater. Sci. Eng. R 2010, 70, 188e208; (e) Garska, B.; Tabatabai,
M.; Ritter, H. Beilstein J. Org. Chem. 2010, 6, 784e788; (f) Park, J. H.; Hwang, S.;
Kwak, J. ACS Nano 2010, 4, 3949e3958; (g) Lee, C.-H.; Zhang, Y.; Romaya-
nantakit, A.; Galoppini, E. Tetrahedron 2010, 66, 3897e3903; (h) Vícha, R.;
4.4. Pharmacology
4.4.1. Cells and viruses. Vero cells culture (green monkey kidney
cells) was grown in Eagle’s medium (Institute of Poliomyelitis and
Viral Encephalitides, Moscow, Russia) supplemented with 10% fetal
calf serum (‘PanEco’, Moscow). Herpes simplex virus type 1 (strain
KL 1, HSV-1) and type 2 (strain VN, HSV-2) were from the Labora-
tory of Virus Museum (Ivanovsky Institute of Virology, Moscow,
Russia).
ꢂ
ꢁ
ꢂ
ꢁ
Rouchal, M.; Kozubkova, Z.; Kurtka, I.; Marek, R.; Branna, P.; Cmelik, R. Supra-
ꢂ
ꢁ
ꢁ
mol. Chem. 2011, 23, 663e677; (i) Blazek, V.; Bregovic, N.; Mlinaric-Majerski, K.;
ꢁ
Basaric, N. Tetrahedron 2011, 67, 3846e3857.
3. (a) Fort, R. C.; Schleyer, P. v. R. Chem. Rev. 1964, 64, 277e300; (b) Weidenhoffer,
Z.; Hala, S.;Scientific papers of the Institute of Chemical Technology, Prague,
1971; Vol. D22, pp 7e83. (c) Bingham, R. C.; Schleyer, P. v. R. Top. Curr. Chem.
1971, 18, 1e102; (d) Litvinov, V. P. Chem. Heterocycl. Compd. 2002, 38, 9e34; (e)
Moiseev, I. K.; Makarova, N. V.; Zemtsova, M. N. Russ. Chem. Rev. 1999, 68,
1101e1120; (g) Wanka, L.; Cabrele, C.; Vanejews, M.; Schreiner, P. R. Eur. J. Org.
ꢁ
ꢂ
ꢁ
ꢁ
Chem. 2007, 1474e1490; (h) Basaric, N.; Molcanov, K.; Matkovic, M.; Kojic-
4.4.2. Cytotoxicity assays. Vero cells in 96-well microtiter plates
ꢁ
ꢁ
Prodic, B.; Mlinaric-Majerski, K. Tetrahedron 2007, 63, 7985e7996; (i) Shokova,
E. A.; Kovalev, V. V. Russ. Chem. Rev. 2011, 80, 927e951.
were treated with different concentrations of the experimental
drugs (1.4ꢂ105 cells in 185
mL of the medium per well). Cell cultures
4. Stetter, H.; Krause, M.; Last, W.-D. Chem. Ber. 1969, 102, 3357e3363.

4772
A. Shmailov et al. / Tetrahedron 68 (2012) 4765e4772
€
5. Smith, G. W.; Williams, H. D. J. Org. Chem. 1961, 26, 2207e2212.
V.; Shokova, E.; Bolte, M.; Arnaud-Neu, F.; Bohmer, V.; Kovalev, V. Tetrahedron
6. Ishii, Y.; Matsunaka, K.; Sakaguchi, S. J. Am. Chem. Soc. 2000, 122, 7390e7391.
7. Sokolenko, V. A.; Gubernatorov, V. K. Russ. Chem. Bull. 1990, 39, 203.
8. (a) Kramer, G. M.; Exxon Research and Engineering Co. U.S. Patent 4,424,387,
1984; (b) Ishii, Y.; Nakano, T.; Daicel Chemical Industries, Ltd. U.S. Patent
6,403,521, 2002.
9. (a) Shokova, E. A.; Alimbarova, L. M.; Kovalev, V. V. Pharm. Chem. J. 1999, 33,
372e376; (b) Shokova, E. A.; Motornaya, A. E.; Shestakova, A. K.; Kovalev, V. V.
Tetrahedron Lett. 2004, 45, 6465e6469; (c) Motornaya, A. E.; Alimbarova, L. M.;
Shokova, E. A.; Kovalev, V. V. Pharm. Chem. J. 2006, 40, 68e72; (d) Babain, V. A.;
Alyapyshev, M. Yu.; Novakov, I. A.; Orlinson, B. S.; Savel’ev, E. N.; Shokova, E. A.;
Serebryannikova, A. E.; Kovalev, V. V. Russ. Chem. Bull. 2007, 56, 115e121; (e)
Kovalev, V. V.; Alimbarova, L. M.; Shokova, E. A.; Katrukha, G. S. Pharm. Chem. J.
2009, 43, 485e490; (f) Shmailov, A.; Alimbarova, L.; Shokova, E.; Tafeenko, V.;
Vatsouro, I.; Kovalev, V. Tetrahedron 2010, 66, 3058e3064; (g) Kovalev, V.;
Shokova, E.; Shmailov, A.; Vatsouro, I.; Tafeenko, V. Eur. J. Org. Chem. 2010,
3754e3761; (h) Vatsouro, I.; Serebryannikova, A.; Wang, L.; Hubscher-Bruder,
2011, 67, 8092e8101.
10. Tyobeka, T. E.; Hancock, R. A.; Weigel, H. Tetrahedron 1988, 44, 1971e1978.
11. Smushkevich, Y. I.; Smushkevich, V. Y.; Usorov, M. I. J. Chem. Res., Synop.1999, 407.
12. Hoogenboom, B. E.; El-Faghi, M. S.; Fink, S. C.; Hoganson, E. D.; Lindberg, S. E.;
Lindell, T. J.; Linn, C. J.; Nelson, D. J.; Olson, J. O.; Rennerfeldt, L.; Wellington, K.
A. J. Org. Chem. 1969, 34, 3414e3420.
13. (a) Lawson, A.; Tinkle, R. B. Chem. Rev. 1970, 70, 593e618; (b) Wawzonek, S.;
Abbott, R. L. J. Med. Chem. 1963, 6, 603e604.
14. De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.; Jones, A. S.; Torrence, P. F.;
Shugar, D. J. Infect. Dis. 1980, 141, 563e574.
15. Bott, K. Chem. Ber. 1968, 101, 564e573.
16. Harms, K.; Wocadlo, S. XCAD-4: Program for Processing CAD-4 Diffractometer
Data; University of Marburg: Germany, 1995.
17. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
18. Brandenburg, K. DIAMOND, Release 2.1d; Crystal Impact GbR: Bonn, Germany,
2000.