Convenient Synthesis of Ethyl 5-Oxohomoadamantane-4-carboxylate: A Useful Precursor of Polyfunctional Homoadamantanes

Article abstract of DOI:10.1055/s-0037-1610312

A facile and convenient synthesis of ethyl 5-oxohomoadamantane-4-carboxylate is reported, and its chemical properties as a cage analogue of acetoacetic ester are investigated. Various derivatives of homoadamantane were synthesized through the reaction of 5-oxohomoadamantane-4-carboxylate with electrophilic agents, binucleophiles, and hydrazoic acid. Some new unusual products were obtained by the reaction of that β-keto ester with nitric acid and nitrosyl chloride. Cage compounds synthesized could be used as precursors for the diverse condensed heterocyclic compounds with potential viral ion channel abrogating activity that possess conformationally rigid lipophilic moieties.

Full text of DOI:10.1055/s-0037-1610312

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
I. M. Tkachenko et al.
Paper
Synthesis
Convenient Synthesis of Ethyl 5-Oxohomoadamantane-4-carbox-
ylate: A Useful Precursor of Polyfunctional Homoadamantanes
Ilya M. Tkachenkoa
Victor B. Rybakovb
Yuri N. Klimochkin*a
0
0
0
0-0
0
0
2-
0
3
8
6-4
1
8
4
N
R
NH
O
N
NH
O
R
O
O
CO2Et
O
N2CHCO2Et
AlCl3
CO2Et
COOEt
S
a Department of Organic Chemistry, Chemical
Technological Faculty, Samara State Technical
University, 244 Molodogvardeyskaya st., Samara
443100, Russian Federation
N
N
O
N
81%
N
HN
NH
NH
O
CO2R
orgchem@samgtu.ru
CO2H
b Chemistry Department, Faculty of Chemistry,
Moscow State University, 1–3 Leninskie gory,
Moscow 119991, Russian Federation
Received: 03.09.2018
Accepted after revision: 12.10.2018
Published online: 08.11.2018
HO
N
NH2•HCl
O
NH2•HCl
DOI: 10.1055/s-0037-1610312; Art ID: ss-2018-z0591-op
Abstract A facile and convenient synthesis of ethyl 5-oxohomoada-
mantane-4-carboxylate is reported, and its chemical properties as a
cage analogue of acetoacetic ester are investigated. Various derivatives
of homoadamantane were synthesized through the reaction of 5-oxo-
homoadamantane-4-carboxylate with electrophilic agents, binucleop-
hiles, and hydrazoic acid. Some new unusual products were obtained by
the reaction of that β-keto ester with nitric acid and nitrosyl chloride.
Cage compounds synthesized could be used as precursors for the di-
verse condensed heterocyclic compounds with potential viral ion chan-
nel abrogating activity that possess conformationally rigid lipophilic
moieties.
Amantadine© analogues
antimicrobial, antifungal
and antiviral activities
H
O
H
O
O
O
Ph
O
O
OH
Ph
O
OH
O
H2N
Sampsoniones A and B
activity against tumor cells
NMDA antagonist
Key words cage compounds, homoadamantane, β-keto ester, ho-
mologation, tetrazole
Figure 1 Several examples of bioactive and biogenic homoadaman-
tanes
Since a long time, adamantane derivatives have attract-
ed the attention of chemists. The biological activity of ada-
mantane derivatives has been presented in numerous re-
views.1 The presence of saturated cage moiety in some
known bioactive compounds could be the starting point on
the road to solve the problem of bioavailability due to its
compactness and high lipophilicity, which allows to pass
through the blood brain barrier2 and to penetrate the cell
membranes.3
The adamantane homologue homoadamantane and its
derivatives are poorly studied in comparison to adaman-
tanes themselves. At present, there is not enough informa-
tion on the biological activity of homoadamantane deriva-
tives. Although homoadamantane skeleton could be rarely
found in nature, some of them are active against tumor
cells4 There are evidences of their antiviral,5a,b antimicrobi-
al, antifungal,5b and NMDA antagonist activity5c (Figure 1).
Several publications in medicinal chemistry are dedicat-
ed to the search for new cage antiviral drug candidates. In
previous works, we have described the synthesis of some
cage compounds and their antiviral activity6a,b The main
way to fight the viral infections is the abrogation of the key
viral proteins. Influenza A virus strains became resistant to
adamantane pharmaceuticals due to the mutation of M2
ion channel. It is worth noting that hepatitis C virus (HCV)
has a similar size of P7 ion channel in regard to mutant in-
fluenza A M2 proton channel. It is known that antiviral
drug candidates with ion channel abrogating activity
should be sufficiently bulky.6c,d Consequently, our research
was focused on the synthesis of some condensed and annu-
lated functionalized hydrocarbon cages. It was suggested
that homoadamantane with functions at positions 4 and 5
would be the most successful candidate to be the potential
viral channel blocker.6b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
I. M. Tkachenko et al.
Paper
Synthesis
Enols are common intermediates in the design of a wide
range of organic compounds such as diverse scaffolds for
medicinal chemistry.7a–d Ethyl 5-oxohomoadamantane-4-
carboxylate (1) is the cage analogue of acetoacetic ester and
promising precursor of some homoadamantane-containing
compounds, including homoadamantane-fused heterocy-
cles. We had assumed that the retro-Claisen C–C bond
cleavage of 1 would form the corresponding bicyc-
lo[3.3.1]nonane derivatives.8 In addition, we were hopeful
to define the scope of the typical methods of acetoacetic es-
ter chemistry in relation to our object of study. This is one
of the objectives in that work.
Table 1 Optimization for Target β-Keto Ester 1 Synthesis
O
EXn
O
O
O
N2CHCOOEt
LA
O
+
OEt
OEt
1
2, X = Hal
O
OH
COOEt
COOEt
1a
1b
There is one main method for the preparation of 1,
namely the Büchner–Curtius–Schlotterbeck9 homologation
of adamantan-2-one using BF3·OEt2 as catalyst.10 However,
the reaction leads to the formation of stable by-product 2
(EXn = BF2), which decrease the total yield of 1. Although
the by-product 2 (EXn = BF2) could be transformed to the
target keto ester 1 by treating with a strong base, the yield
is far from quantitative. An alternative is to use triethyloxo-
nium tetrafluoroborate,11 which requires preliminary
preparation. Consequently, the use of both catalytic sys-
tems is associated with certain synthetic difficulties.
Lewis acid Solvent, temperature
N2CHCO2Et (equiv) Yield (%)
BF3·OEt2
TiCl4
CH2Cl2, 0 °C
4.0
3.5
4.5
7.0
41a (1); 24a (2)
no reaction
12b (1)
CH2Cl2, 0 °C or 30 °C
CH2Cl2, 30 °C
SnCl4
AlCl3
CH2Cl2, 30 °C
58a (1)
AlCl3
AlCl3
DCE, 35 °C
DCE, 0 °C
4.0
7.5
81a (1)
78a (1)
a Product yield.
b The percentage of product according to GC data.
We have undertaken some modifications of the target
β-keto ester 1 synthesis to simplify synthetic procedure and
to increase the product yield. In this regard, several other
Lewis acids were applied to the synthesis of target β-keto
ester. It was found that TiCl4 is not applicable to this trans-
formation, because there was no evidence of product for-
mation. When SnCl4 was used, formation of 1 was detected
using GLC, but the conversion rate of starting homoada-
mantan-2-one was too low. Reaction of adamantane-2-one
with ethyl diazoacetate in the presence of AlCl3 was carried
out in CH2Cl2 and 1,2-dichloroethane (DCE) in the tempera-
ture range 30–35 °C (Table 1). At higher temperatures, the
formation of by-products with higher molecular weight
was found. However, when the reaction was carried out at
0–25 °C, large excess of ethyl diazoacetate was required.
Obviously, an aluminum enolate complex 2 (MeXn = AlCl2)
is much more labile than other LA complexes and in this
case treating the reaction mixture only with aqueous 4 M
HCl was enough for the workup procedure. The application
of large excess of ethyl diazoacetate has always been related
to its Lewis acid catalyzed decomposition.12 Perhaps the ex-
cess of ethyl diazoacetate depends on the rate of its degra-
dation according to the nature and solubility of Lewis acid.
Moderate solubility of AlCl3 in DCE allows it possible to use
less amount of ethyl diazoacetate, than in CH2Cl2. Actually,
the most facile and convenient system to synthesize target
keto ester is AlCl3/DCE. The final product represents as the
mixture of isomers 1a and 1b in a ratio of 2:3 according to
1H NMR spectrum. Surprisingly, tautomers could be sepa-
rated using GLC, which could be associated with unusually
high activation energy barrier of the tautomerization.
Considering the stability of tautomers 1a,b and an influ-
ence of constrained homoadamantane cage on the course of
some reactions, several properties of 1 have been studied.
Routine retro-Claisen cleavage of 1 using concentrated KOH
solution in ethanol and alkali metal alkoxides under argon
atmosphere leads to ketonic cleavage product 3. Reaction of
1 with excess of benzylamine leads to a mixture of sym-
dibenzylurea and ketone 3 (Scheme 1). The situation is sim-
ilar in the case when aniline and acetoacetate were used as
described by Roberts.13 All of these reactions were carried
out under reflux. Besides, unusual oxidation process has
been observed at room temperature. In cases when strong
bases (alkali metal alkoxides, NaH, BuLi) were used, oxida-
tion of enolate occurred in contact with air. Thus, the reac-
tion yields keto ester 4 possessing the hydroxyl substituent
at 5 position. This is the first example of a β-keto ester oxi-
dation by air oxygen.
O
O
COOEt
NaOR/ROH, Δ , or KOH/ROH, Δ, or BnNH2, Δ
R = Me, Et, i-Pr
1
3
82%
O
OH
RONa/ROH or NaH/THF
air
COOEt
4
74%
Scheme 1 ‘Ketonic cleavage’ of β-keto ester 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
I. M. Tkachenko et al.
Paper
Synthesis
Schmidt reaction of keto ester 1 with more than two
molar equivalents of NaN3 in sulfuric acid medium14 under
mild conditions leads to tetrazoles 5 and 6. Selectivity of
this process decreases dramatically when internal tempera-
ture of the reaction mixture exceeds 5 °C and lactam 7 is
formed along with tetrazoles 5 and 6 (Scheme 2). Lactam 7
could be obtained in moderate yield when the reaction was
carried out in refluxing chloroform. The keto acid 8 is
formed together with tetrazole 6 when the ratio of sodium
azide to substrate is 1:1. Keto acid 8 undergoes decarboxyl-
ation in organic solvents. For this reason, it cannot be final-
ly characterized by NMR spectrum, but its structure has
been confirmed by reaction of 8 with SOCl2 and ethanol to
form the corresponding alkenyl chloride 9. Ketone 3 was
formed during this reaction because of the same rate of de-
carboxylation. Molecular structure of 5 was confirmed by
single crystal X-ray diffraction data.15
formed in strong acidic medium using nitrosation mixture
of NaNO2/HCl in THF, nitrate 11 was obtained in good yield
exclusively. The molecular structure of 11 was confirmed by
single crystal X-ray diffraction analysis.16 The chloride 12
was formed when the reaction was carried out with a mix-
ture of AlCl3/alkyl nitrite.
O
O
OH
NO2
fuming HNO3
COOEt
COOEt
10
57%
4
38%
O
NaOH
EtOH
NO2
10a
64%
O
N
N
O
O
COOEt
N
ONO2
COOEt
NaN3 (3 equiv)
H2SO4
NH
COOH
AlkONO
HCl
N
H2SO4
10
38%
COOEt
CHCl3
reflux
< 5 °C
1
5
7
11
74%
62% from 1
46%
O
N
N
Cl
COOEt
O
N
NaN3 (3 equiv)
N
AlkONO
AlCl3
H2SO4
5
58%
7
9%
COOEt
COOH
> 5 °C
12
95%
6
22%
1
O
O
NaNO2/HCl
THF
11
87%
NaN3 1 equiv
H2SO4
5
24%
COOH
15–20 °C
– CO2
Scheme 3 Nitration and nitrosation of 1
8
3
57%
Cl
In both cases, a blue to green coloring of the reaction
mixture was observed after the reagent was added to 1,
caused by the presence of nitrogen oxides in the reaction
1) SOCl2
2) EtOH
H2SO4
COOEt
+
9
76%
mixture. Nitration agents generates NO2 , which could act
+
as SET-oxidizing agent.17 It can be assumed that NO2 oxi-
Scheme 2 Schmidt reaction of 1
dizes enol to cation radical that undergoes proton abstrac-
tion and subsequent addition of nitrogen oxide to radical
center with oxygen or nitrogen atom. Also, the formation of
alcohol 4 under nitration reaction conditions is possible
through the radical process due to oxidation by atmospher-
ic oxygen.18
Oxidation of 1 with peroxy acids (Scheme 4) leads to
formation of expected19 alcohol 4. The action of excess of
30% hydrogen peroxide solution with one molar equivalent
of KOH on 1 leads to oxidative cleavage of β-keto ester moi-
ety to form endo-endo-dicarboxylic acid 13 in good yield.
The halogenation of 1 (Scheme 5) with elemental bro-
mine or chlorine in the presence of acidic catalyst proceeds
in good to excellent yields. Halides 12 and 14 do not under-
go halogen substitution reactions even with good nucleop-
Some unusual products were observed in the reaction
of 1 with several nitrating agents, namely acetyl nitrate,
fuming nitric acid, or nitrating mixture. Hydroxylation
product 4 was formed in the reaction along with desired ni-
tro derivative 10. It was found that the hydrolysis of 10
leads to decarboxylation while treating with ethanolic
NaOH solution. For this reason, the isolation of 10 should be
performed without neutralization of reaction mixture.
Reaction of 1 with nitrosation agents (Scheme 3), gener-
ated by mixing of alkyl nitrite with HCl or H2SO4 leads to
two major products under temperatures lower than 0 °C.
The mixture of products contains nitro derivative 10 and
nitrate 11 in good overall yield. When the reaction was per-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
I. M. Tkachenko et al.
Paper
Synthesis
COOH
O
O
OH
COOEt
H
RCO3H
R = m-ClC6H4, CF3
H2O2
KOH
COOEt
COOH
H
4
1
13
60–76%
73%
Scheme 4 Peroxide oxidation of 1
hiles like N3 that could be explained by hindrance of
nucleophilic attack from the rear and low cation stability
due to closely spaced two electron-withdrawing groups.
denced by the presence of signal at ca. 171 ppm in 13C NMR
spectra and a doublet at 3.16 ppm in 1H NMR spectra. In ad-
dition, the double bond is formed due to tosyl group elimi-
nation from that nitrogen atom. Pyrimidinthione 17 was
obtained by treating the sodium enolate of 1 with thiourea
(Scheme 6).
–
O
O
O
Br
COOEt
Cl
Br2
HCl/KMnO4
C6H6
COOEt
COOEt
AcOH
Selective keto group reduction of 1 with sodium boro-
hydride and subsequent E1cB elimination is the simplest
preparation route for alkene 20 (Scheme 7) – probable cage
Michael acceptor. Reduction of 1 was carried out in metha-
nol, because it was not possible to perform this reaction
with acceptable selectivity when using other solvents. The
transesterification by-product, fortunately, was not ob-
served and target hydroxy ester 18 was obtained in good
yield. The next elimination stage was carried out with pre-
liminary in situ preparation of trifluoroacetate 19, which
14
87%
1
12
96%
Scheme 5 Halogenation of 1
Reaction of 1 with tosylhydrazide in ethanol leads to N-
tosylpyrazolone 15 formation. However, when reaction was
carried out in toluene, pyrazolone 16 without tosyl substit-
uent was observed. The exo-cage C=N bond of 16 is evi-
Ts
N
NH
EtOH
O
S
O
S
HN
15
62%
NH
O
TsNH-NH2
ZnCl2
H2N
NH2
COOEt
EtOH/NaOEt
N
1
NH
17
58%
O
PhCH3
16
57%
Scheme 6 Synthesis of some homoadamantane-fused heterocycles
O
F3C
OH
O
O
1. NaH
2. (CF3CO)2O
NaBH4
COOEt
COOEt
COOEt
MeOH
THF
1
18
87%
19
92%
NaH
THF
COOEt
20
76%
Scheme 7 Synthetic route to caged alkene 20
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
I. M. Tkachenko et al.
Paper
Synthesis
was treated with one molar equivalent of sodium hydride. It
is worth noting that using mesylate instead trifluoroacetate
at elimination step leads to formation of starting keto ester
1. It is not excluded that in this case sigmatropic rearrange-
ment takes place and a reduction of the sulfo group occurs.
This is observed by the discharge of a bad smell.
mL) containing 50 g of crushed ice. The organic layer was separated,
washed with sat. aq NaHCO3 and dried (Na2SO4). The solvent was re-
moved and the product distilled under reduced pressure; bp 115–120
°C/2 × 10–2 Torr); yield: 19.10 g (81%); colorless oil.9a
Ethyl 4-Hydroxy-5-oxotricyclo[4.3.1.13,8]undecane-4-carboxylate
(4)
Thus, expected nucleophilic cleavage of products with
β-keto ester moiety was not detected, but undesired aceto-
acetic esters-like ‘ketonic cleavage’ has been observed. It
could be explained by higher carbonyl reactivity of ester
carbonyl group. Such routine nitration and nitrosation reac-
tions of 1 turned out more ambiguous than expected be-
cause 1 most likely could be easily oxidized to stable radi-
cal. It was found that unusual transformation of α-C–H
bond in the β-keto ester in the presence of nitrogen oxides
during these reactions takes place. Among other things, ox-
idation of 1 by the atmospheric oxygen to the OH derivative
was observed in the presence of strong bases. Mechanistic
features of these processes will be considered in more de-
tailed manner in subsequent papers. Consequently, the
main point that surfaced during our research was that the
object of study was unconventional among the same type
of cyclic and acyclic β-keto esters and still requires further
study. Based on former studies,20 some new homoadaman-
tane-fused heterocycles and homoadamantane derivatives
were synthesized. Also new facile synthetic route to en-
do,endo-bicyclo[3.3.1]nonane-3,7-dicarboxylic acid (13)
was defined and optimized. We are hopeful that some of
the cage compounds synthesized in this study could be con-
sidered as scaffolds for the synthesis of potential viral ion
channel inhibitors with lipophilic and compact bicyc-
lo[3.3.1]nonane or homoadamantane units.
NaH Procedure (Scheme 1): NaH (60% in mineral oil; 0.22 g, 5.5 mmol)
was added in portions to a solution of 1 (1.20 g, 5.1 mmol) in anhyd
THF (10 mL). The reaction vessel was closed with a CaCl2 guard tube
and the contents were stirred for 24 h. The solvent was removed us-
ing a rotary evaporator and the oily residue was diluted with CH2Cl2
(10 mL). The organic layer was washed with H2O, dried (Na2SO4), and
evaporated; yield 0.95 g (74%); colorless oil.
IR (ATR): 3469, 2910, 1722, 1697, 1446 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 5.92 (br s, 1 H, OH), 4.05–4.14 (m, 2
H, OCH2), 2.71–2.73 (m, 1 H, CH), 2.01–2.05 (m, 1 H, CH), 1.83–1.96
(m, 6 H, 2 × CH2, 2 × CH), 1.73–1.79 (m, 2 H, CH2), 1.49–1.64 (m, 4 H,
2 × CH2), 1.63 (t, 3J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 213.38 (C=O), 173.22 (C=O), 84.56
(COH) 61.32 (CH2O), 48.10 (CH), 36.56 (CH), 35.45 (CH2), 35.04 (CH2),
33.06 (CH2), 30.59 (CH2), 30.21 (CH2), 26.51 (CH), 26.10 (CH), 14.48
(CH3).
Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.71; H, 8.02.
m-CPBA Procedure (Scheme 4): m-CPBA (2.58 g, 15.0 mmol) was sus-
pended in CH2Cl2 (25 mL) and a solution of 1 (1.20 g, 5.1 mmol) in
CH2Cl2 (5 mL) was added and refluxed with stirring for 6 h. The result-
ing mixture was washed with sat. aq NaHCO3 (10 × 10 mL), H2O (5 ×
10 mL), and dried (Na2SO4). The solvent was evaporated on a rotary
evaporator and the residual oil was purified by silica gel chromatogra-
phy using CHCl3 as eluent; yield: 0.77 g (60%); colorless oil.
CF3CO3H Procedure (Scheme 4): H2O2 (0.4 mL, 30%) was added drop-
wise to a solution 1 (0.7 g, 2.9 mmol) in CF3CO2H (5 mL) and the mix-
ture was stirred at r.t. for 2 h. The resulting solution was diluted with
H2O (10 mL), neutralized by NaHCO3, and extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4) and the solvent was
evaporated. The residual colorless oil did not require subsequent puri-
fication; yield 0.56 g (76%); colorless oil.
FTIR spectra were taken on a Shimadzu IR Affinity-1 spectrophotom-
eter with single-reflection ATR accessory. 1H NMR spectra and 13C
were recorded on a Jeol JNM ECX-400 spectrometer (400 and 100
MHz, respectively), chemical shifts and coupling constants were re-
corded in units of parts per million and hertz, respectively. Internal
standard: TMS. Gas chromatography were performed on a GC Thermo
Focus GC, a quartz column DB-5MS 30 m × 0.32 mm, column tem-
perature 80–340 °C (20 °C/min). Elemental analysis was performed
on a CHNS EuroVector EA-3000 EA analyzer with L-cystine as a stan-
dard. Melting points were determined by capillary method on a SRS
OptiMelt MPA100 apparatus and are uncorrected. Monitoring of the
reaction was done by TLC on Merck plates (display with I2 vapor and
UV light).
Ethyl 5,6,7,8,9,10,11,12-Octahydro-6,10:8,12-dimethanotetrazolo-
[1,5-a]azecine-5-carboxylate (5)
To a mixture of 1 (0.62 g, 2.6 mmol) and concd H2SO4 (5 mL) was add-
ed NaN3 (0.84 g, 13.2 mmol) at 0–5 °C in portions with vigorous stir-
ring. The mixture was stirred for 5 h in an ice-salt bath and poured
onto 40 g of crushed ice, neutralized with NaHCO3, and extracted
with CHCl3. The combined extracts were dried (Na2SO4) and concen-
trated. The residual oil was triturated with EtOAc and the resulting
solid was collected by filtration. Recrystallization from EtOAc afford-
ed the product as a white solid; yield: 0.53 g (74%); mp 98.8–99.8 °C
(EtOAc).
IR (ATR): 2935, 1745, 1448 cm–1
.
Ethyl 5-Oxotricyclo[4.3.1.13,8]undecane-4-carboxylate (1)
1H NMR (400 MHz, DMSO-d6): δ = 5.76 (d, 3J = 6.0 Hz, 1 H, CHN tetra-
zole), 4.16 (q, CH2, 3J = 7.1 Hz, 2 H), 3.90–3.95 (m, 1 H, CH), 2.91–2.98
(m, 1 H, CH), 2.06–2.28 (m, 3 H, CH2, 0.5 CH2), 1.94–2.02 (m, 1 H, 0.5
CH2), 1.85–1.90 (m, 2 H, 2 × CH), 1.34–1.60 (m, 6 H, 3 × CH2), 1.14–
1.18 (t, 3J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 169.44 (C), 159.26 (C), 67.57 (CH),
62.36 (CH2), 34.92 (CH2), 32.53 (CH2), 30.53 (СH2), 30.23 (CH2), 30.15
(CH2), 27.55 (CH), 24.92 (CH), 24.32 (CH), 23.68 (CH), 14.44 (CH3).
To a solution of adamantan-2-one (15 g, 100 mmol) in 1,2-dichlo-
roethane under argon atmosphere was added anhyd AlCl3 (16 g, 120
mmol) with vigorous stirring. The temperature of the reaction mix-
ture rose to 35 °C and the mixture was stirred until the temperature
came down to 25 °C. The resulting suspension was heated to 30–35 °C
and freshly prepared ethyl diazoacetate (45.6 g, 400 mmol) was add-
ed at a rate of 5 mL/min. The completion of the reaction was moni-
tored by GC. The resulting solution was poured into aq 5 M HCl (100
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
I. M. Tkachenko et al.
Paper
Synthesis
Anal. Calcd for C12H16N4O2: C, 60.85; H, 7.30; N, 20.28. Found: С,
60.92; Н, 7.34; N, 20.27.
The oily residue was dissolved in MeCN, refluxed with activated char-
coal, filtered, and allowed to crystallize; yield: 0.73 g (62%); white sol-
id; mp 192.3–198.1 °C (dec.).
Optimization of Schmidt Reaction Conditions
5-Oxotricyclo[4.3.1.13,8]undecane-4-carboxylic Acid (8)
Ethyl 5,6,7,8,9,10,11,12-Octahydro-6,10:8,12-dimethanotetrazo-
lo[1,5-a]azecine-5-carboxylate (5), 5,6,7,8,9,10,11,12-Octahydro-
6,10:8,12-dimethanotetrazolo[1,5-a]azecine-5-carboxylic Acid (6),
and 6-Oxo-5-azatricyclo[5.3.1.13,9]dodecane-4-carboxylic Acid (7)
Compound 1 (1.00 g, 4.2 mmol) was dissolved in concd H2SO4 (5 mL)
and allowed to stand overnight. The resulting solution was poured
onto 20 g of crushed ice, the solid formed was collected by filtration,
and dried in a dessicator over CaCl2 until the constant weight; yield:
0.66 g (76%): white solid; mp 170.4–172.8 °C (dec.).
IR (ATR): 3100-2300, 2908, 2845, 1629, 1575, 1440, 1147 cm–1
.
6
To a mixture of 1 (0.90 g 3.8 mmol), concd H2SO4 (10 mL) was added
NaN3 (1.26 g, 19.3 mmol) at a temperature not more than 25 °C in
portions with vigorous stirring. The mixture was stirred for an addi-
tional 7 h. The white solid precipitated from H2SO4 was collected by
filtration and washed with cold H2O. Recrystallization from MeCN af-
forded 6 as a white solid; yield: 0.18 g (22%); mp 148.7–150.1 °C
(dec.)
Ethyl 5-chlorotricyclo[4.3.1.13,8]undec-4-ene-4-carboxylate (9)
Acid 8 (0.5 g, 2.4 mmol) was refluxed with SOCl2 (1 mL, 13.7 mmol) in
a water bath for 0.5 h. Absolute EtOH (1 mL) and then cold H2O (5 mL)
were added. The resulting emulsion was extracted with CHCl3, the
CHCl3 layer was dried (Na2SO4), and concentrated. Purification by col-
umn chromatography on silica gel using CHCl3 as eluent furnished 9
as a colorless oil; yield: 0.46 g (76%).
IR (ATR): 3314, 2918, 1732, 1456 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 13.60 (br s, 1 H, CO2H), 5.58 (t, 3J =
5.8 Hz, 1 H, CH), 3.91 (t, 3J = 8.9 Hz, 1 H, CH), 2.91–2.97 (m, 1 H, CH),
1.94–2.26 (m, 4 H, 2 × CH2), 1.88 (m, 2 H, CH2), 1.57 (m, 1 H, 0.5 CH2)
1.49–1.53 (m, 4 H, 2 × CH2), 1.32–1.36 (m, 1 H, 0.5 CH2).
13C NMR (100 MHz, DMSO-d6): δ = 170.90 (CO2H), 159.15 (C=N),
67.90 (CHN), 35.11 (CH2), 32.62 (CH2), 30.73 (СH2), 30.31 (CH2), 30.04
(CH2), 27.21 (CH), 24.94 (CH), 24.39 (CH), 23.73 (CH).
IR (ATR): 2914, 2846, 1724, 1442, 1251, 1029, 761 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 4.07–4.11 (q, 3J = 7.1 Hz, 2 H, CH2),
2.52, 2.57 (m, 2 H, 2 × CH), 2.02–2.04 (m, 2 H, 2 × CH), 1.83–1.86 (m, 2
H, CH2), 1.71–1.81 (m, 6 H, 3 CH2), 1.67–1.69 (m, 2 H, CH2), 1.61–1.20
(t, 3J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 168.27 (C=O), 141.98 (CCl), 138.26
(C), 60.98 (CH2), 44.47 (CH), 35.28 (CH2), 34.13 (CH), 33.42 (2 × CH2),
31.94 (2 × CH2), 28.08 (2 × CH), 14.51 (CH3).
Anal. Calcd for C12H16N4O2: C, 58.05; H, 6.50; N, 22.57. Found: С,
58.11; H, 6.54; N, 22.53.
Anal. Calcd for C14H19ClO2: C, 69.21; H, 7.74. Found: C, 69.14; H, 7.70.
7
Ethyl 4-Nitro-5-oxotricyclo[4.3.1.13,8]undecane-4-carboxylate (10)
The H2SO4 filtrate was poured onto 20 g of crushed ice, neutralized
with NaHCO3, and extracted with CHCl3. The combined organic ex-
tracts were dried (Na2SO4) and concentrated. The residual oil was dis-
solved in EtOAc and the resulting crystalline mass was collected by
filtration to afford 5 as a white solid; yield: 0.60 g (58%). The last fil-
trate was concentrated, dissolved in MeCN, and the solvent was de-
canted. Recrystallization from MeCN afforded 7 as a white solid;
yield: 0.08 g (9%); mp 191.0–195.4 °C (dec.).
Fuming HNO3 (0.58 mL, 139.7 mmol) was added dropwise to 1 (3 g,
12.7 mmol) in CH2Cl2 at 10 °C and the mixture was stirred for 1 h at
r.t. The resulting blue liquid was poured onto 10 g of crushed ice and
extracted with CH2Cl2. The combined organic layers were dried (Na2-
SO4), and the solvent was evaporated. The residual oily mixture was
separated by gradient silica gel chromatography using CCl4/CHCl3 as
eluent; yield: 2.03 g (57%); colorless oil.
IR (ATR): 2916, 2862, 1743, 1716, 1554, 1450 cm–1
.
IR (ATR): 3165, 3051, 2910, 1699, 1620, 1454 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 4.22–4.35 (m, 2 H, CH2O), 2.99–
3.00 (m, 1 H, CH), 2.78–2.71 (m, 1 H, CH), 2.06–2.16 (m, 2 H, CH2),
1.80–2.02 (m, 7 H, 3 CH2 + СH), 1.58–1.63 (m, 3 H, CH2 + CH), 1.19 (t,
3J = 7.08 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 201.54 (C=O), 164.68 (C=O),
106.66 (CNO2), 63.93 (CH2O), 48.33 (CH), 36.01 (CH2), 35.08 (CH2),
34.22 (CH2), 33.87 (CH), 32.65 (CH2), 30.76 (CH2), 26.34 (2 × CH2),
33.87 (CH2), 25.99 (CH), 26.34 (CH), 14.17 (CH3).
1H NMR (400 MHz, DMSO-d6): δ = 12.86 (br s, 1 H, CO2H), 6.67 (d, 3J =
2.0 Hz, 1 H, NH), 3.91–3.94 (dd, 3J = 2.0 Hz, 1 H, CH), 2.75–2.81 (m, 1
H, CH), 2.59–2.64 (m, 1 H, CH), 1.99–2.901 (m, 1 H, CH), 1.83–1.91 (m,
3 H, CH2 + CH), 1.60–1.77 (m, 5 H, 2 × CH2 + 0.5 CH2), 1.41–1.44 (m, 3
H, CH2 + 0.5 CH2).
13C NMR (100 MHz, DMSO-d6): δ = 178.61 (C), 174.59 (C), 62.55 (CH),
37.84 (CH), 34.92 (CH2), 34.82 (СH2), 33.76 (CH2), 30.75 (2 × CH2),
30.65 (CH2), 29.40 (CH), 25.05 (CH), 24.63 (CH).
Anal. Calcd for C14H19NO5: C, 59.78; H, 6.81; N, 4.98. Found: C, 59.83;
H, 6.79; N, 4.93.
Anal. Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.49;
H, 7.71; N, 6.24.
Subsequent elution by CHCl3 gave 1.21 g (38%) of 4 as a colorless oil.
6-Oxo-5-azatricyclo[5.3.1.13,9]dodecane-4-carboxylic Acid (7)
5-Nitrotricyclo[4.3.1.13,8]undecan-4-one (10a)
To a mixture 1 (1.55 g 6.5 mmol), concd H2SO4 (15 mL), and CHCl3 (30
mL) was added NaN3 (1.26 g, 19.3 mmol) at a temperature not more
than 25 °C in portions with vigorous stirring. The mixture was stirred
for 5 h at r.t., refluxed with stirring for 30 h, and then poured onto 10
g of crushed ice. The resulting solution was neutralized by the addi-
tion of aq NaHCO3, and extracted with EtOAc. The combined organic
extracts were dried (Na2SO4) and evaporated on a rotary evaporator.
A mixture of 10 (0.5 g, 1.8 mmol) and KOH (0.14 g, 2.5 mmol) in EtOH
(5 mL) was heated under reflux for 1 h and then neutralized with aq 5
M HCl. The resulting mixture was extracted with CHCl3 and the com-
bined CHCl3 layers were dried (Na2SO4). Solvent removal gave color-
less crystals, which were recrystallized from acetone; yield: 0.24
(64%); colorless crystals; mp 151.3–152.5 °С (acetone).
IR (ATR): 2933, 2918, 2879, 1716, 1560, 1543, 1448, 1369 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
I. M. Tkachenko et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 5.99 (s, 1 H, CH), 2.73–2.77 (m, 1 H,
CH), 2.55–2.58 (m, 1 H, CH), 1.80–2.03 (m, 8 H, 4 × СH2), 1.76–1.86
(m, 1 H, CH), 1.54–1.68 (m, 3 H, СH2 + CH).
13C NMR (100 MHz, DMSO-d6): δ = 205.49 (C=O), 98.95 (CH), 46.70
(CH), 37.49 (CH2), 35.16 (CH), 34.94 (CH2), 31.56 (CH), 31.40 (CH2),
28.89 (CH2), 26.49 (CH), 26.25 (CH).
endo,endo-Bicyclo[3.3.1]nonane-3,7-dicarboxylic Acid (13)
A mixture of 1 (1.1 g, 4.7 mmol), 30% H2O2 (10 mL), and KOH (1.04 g,
18.6 mmol) was stirred at r.t. until homogeneous (25–30 h). The re-
sulting mixture was diluted with H2O (5 mL), extracted with CH2Cl2 (5
mL), and the aqueous phase was acidified with aq 2 M HCl. The crys-
talline precipitate was collected by filtration, dried, and recrystallized
from EtOAc; yield: 0.72 g (73%); colorless crystals; mp 179.1–179.4 °С21
(EtOAc).
Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.20;
H, 7.25; N, 6.65.
Ethyl 4-Bromo-5-oxotricyclo[4.3.1.13,8]undecane-4-carboxylate
(14)
Ethyl 4-(Nitrooxy)-5-oxotricyclo[4.3.1.13,8]undecane-4-carboxyl-
ate (11)
To a stirred solution of 1 (0.50 g, 2.1 mmol) in AcOH (5 mL) was added
Br2 (0.15 mL, 3.5 mmol) at r.t. in one portion and the stirring was con-
tinued until the color of the bromine disappeared. The solvent was re-
moved using a rotary evaporator and the residual yellow oil was dis-
solved in CHCl3 (10 mL). The CHCl3 layer was washed with sat. aq
NaHCO3 (5 mL), dried (Na2SO4), and filtered through 1 cm silica gel
pad and washed with CHCl3. The solvent was evaporated on a rotary
evaporator; yield 0.58 g (87%); slightly yellow oil.
Aq 9 M HCl (2.3 mL) was added dropwise to a suspension of NaNO2
(0.35 g, 5.1 mmol) and 1 (1.0 g, 4.2 mmol) in THF (20 mL) at 0–5 °C.
The mixture became blue in color and stirred for an additional 1 h in
an ice-salt bath and then THF was evaporated. Residual emulsion was
extracted with CH2Cl2, the combined organic extracts were dried
(Na2SO4), and evaporated under vacuum. The residual oil was purified
by silica gel chromatography using CCl4 as eluent; yield: 1.10 g (87%);
colorless crystals; mp 79.0–80.1 °C (hexane).
IR (ATR): 2914, 2854, 1728, 1708, 1444 cm–1
.
IR (ATR): 2918, 2895, 1732 1714, 1643, 1452, 1284, 839 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 4.14–4.25 (m, 2 H, CH2O), 2.87–
2.90 (m, 1 H, CH), 2.55–2.59 (m, 1 H, CH), 2.01–2.12 (m, 2 H, 2 × CH),
1.82–1.97 (m, 4 H, 2 × CH2), 1.78–1.80 (m, 2 H, CH2), 1.50–1.67 (m, 4
H, 2 × CH2), 1.89 (t, 3J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 205.72 (C=O), 169.66 (C=O), 76.55
(CBr), 63.18 (CH2O), 48.01 (CH), 39.26 (CH), 34.88 (CH2), 34.46 (CH2),
34.10 (CH2), 32.42 (CH2), 29.66 (CH2), 26.08 (CH), 25.76 (CH), 14.26
(CH3).
1H NMR (400 MHz, DMSO-d6): δ = 4.27 (dt, 3J = 7.08 Hz, 2J = 0.92 Hz, 2
H), 2.88–2.91 (m, 1 H, CH), 2.29–2.33 (m, 1 H, CH), 2.18–2.24 (m, 1 H,
0.5 СH2), 1.96–2.07 (m, 3 H, 0.5 СH2 + CH2), 1.86–1.89 (m, 2 H, CH2),
1.75–1.81 (m, 1 H, 0.5 СH2), 1.62–1.67 (m, 1 H, 0.5 СH2), 1.50–1.58 (m,
4 H, CH2), 1.21 (t, 3J = 7.08 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 207.14 (C=O), 167.76 (C=O), 95.95
(CONO2), 63.16 (CH2O), 48.33 (CH), 36.01 (CH2), 47.52 (CH2), 38.85
(CH2), 35.21 (CH2), 34.41 (CH), 32.75 (CH2), 30.93 (CH2), 29.00 (CH2),
26.19 (CH), 25.55 (CH), 14.17 (CH3).
Anal. Calcd for C14H19BrO3: C, 53.35; H, 6.08. Found: C, 53.42; H, 6.10.
Anal. Calcd for C14H19NO6: C, 56.56; H, 6.44; N, 4.71. Found: C, 56.51;
H, 6.46; N, 4.66.
Tosyl-1,4,5,6,7,8,9,10-octahydro-4,8:6,10-dimethanocyclono-
na[c]pyrazol-3(2H)-one (15)
Ethyl 4-Chloro-5-oxotricyclo[4.3.1.13,8]undecane-4-carboxylate
(12)
A mixture of 1 (0.5 g, 2.1 mmol) and ZnCl2 (0.04 g, 0.3 mmol) in EtOH
(20 mL) was refluxed for 25 h. The resulting suspension was filtered
and then the filtrate was concentrated. The residual oil was dissolved
in EtOAc (5 mL) and allowed to crystallize. Subsequent recrystalliza-
tion from EtOAc gave 15 as a white solid; yield: 0.47 g (62% in proce-
dure); mp 210.8–211.6 °C (EtOAc).
KMnO4 Procedure (Scheme 5): To a suspension of KMnO4 (0.44 g, 2.8
mmol) in benzene was added 1 (0.65 g, 2.1 mmol) and then concd HCl
(0.25 mL) with vigorous stirring. The mixture was allowed to stand
until the chlorine odor disappeared. The organic phase was decanted,
washed with H2O (10 mL), dried (Na2SO4), and the solvent was evapo-
rated to constant weight on a rotary evaporator. The residual colorless
oil was pure enough and did not require subsequent purification;
yield: 0.72 g (96%); colorless oil.
IR (ATR): 3352, 3226, 2904, 2891, 1608 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ =10.08 (br s, 2 H, NH), 2.68–2.69 (m,
2 H, CH), 2.04 (m, 2 H, 2 × CH), 1.80–1.88 (m, 4 H, 2 × CH2), 1.53–1.70
(m, 6 H, 3 × CH2).
13C NMR (100 MHz, DMSO-d6): δ = 156.57 (C), 151.49 (C), 108.77 (C),
36.68 (CH2), 36.17 (2 × CH2), 34.61 (2 × CH2), 30.74 (CH), 29.05 (2 ×
CH), 25.67 (CH).
IR (ATR): 2916, 2854, 1732, 1712, 1446, 771 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 4.16–4.27 (m, 2 H, CH2O), 2.86–
2.89 (m, 1 H, CH), 2.41–2.44 (m, 1 H, CH) 1.76–2.04 (m, 8 H, 3 × CH2 +
2 × CH), 1.48–1.65 (m, 4 H, 2 × CH), 1.16–1.21 (t, 3J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 205.83 (C=O), 169.36 (CO2Et),
80.56 (CCl), 63.26 (CH3CH2O), 48.38 (CH), 39.01 (CH), 34.83 (CH2),
34.28 (CH2), 34.12 (CH2), 31.41 (CH2), 29.69 (CH2), 26.09 (CH), 25.66
(CH), 14.29 (CH3CH2O).
Anal. Calcd for C19H22N2O3S: C, 63.66; H, 6.19; N, 7.82; S, 8.94. Found:
C, 63.59; H, 6.12; N, 7.89; S, 8.92.
3a,4,5,6,7,8,9,10-Octahydro-4,8:6,10-dimethanocyclonona[c]pyra-
zol-3(2H)-one (16)
Anal. Calcd for C14H19ClO3: C, 62.11; H, 7.07. Found: C, 62.18; H, 7.09.
A mixture of 1 (0.8 g, 3.4 mmol) and ZnCl2 (0.06 g, 0.5 mmol) in tolu-
ene (20 mL) was refluxed using a Dean–Stark apparatus for 25 h. The
suspension was filtered and concentrated to half the volume using a
rotary evaporator whereupon the residual oil crystallized over 25–30
h. Recrystallization from EtOAc furnished a white solid; yield: 0.42 g
(57%); mp 185.2–186.7 °C (EtOAc).
Butyl Nitrite/AlCl3 Procedure (Scheme 3): AlCl3 (0.35 g , 2.6 mmol) was
added in portions under stirring to a mixture of 1 (0.50 g 2.1 mmol)
and BuONO (0.55 g, 5.3 mmol), allowed to stand for 1 h, and then
quenched with 20 g of crushed ice containing concd HCl (5 mL). The
residual solution was extracted with CH2Cl2, the combined organic
extracts were washed with sat. aq NaHCO3 (2 × 10 mL), dried (Na2-
SO4), and evaporated under vacuum to give the product as a colorless
oil.
IR (ATR): 3495, 2902, 1718, 1691 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
I. M. Tkachenko et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 7.69 (br s, 1 H, NH), 3.15–3.17 (d,
3J = 6.4 Hz, 1 H, CH), 2.00–2.92 (m, 2 H, 2 × CH), 1.70–1.94 (m, 8 H, 3 ×
CH2 + 2 × CH), 1.46–1.50 (m, 1 H, 0.5 CH2), 1.29–1.37 (m, 1 H, 0.5 CH),
1.17–1.25 (m, 1 H, 0.5 CH2), 1.07–1.11 (m, 1 H, 0.5 CH2).
1H NMR (400 MHz, DMSO-d6): δ = 7.69 (br s, 1 H, NH), 3.15–3.17 (d,
3J = 6.4 Hz, 1 H, CH), 2.00–2.92 (m, 2 H, 2 × CH), 1.70–1.94 (m, 8 H, 3 ×
CH2 + 2 × CH), 1.46–1.50 (m, 1 H, 0.5 CH2), 1.29–1.37 (m, 1 H, 0.5 CH),
1.17–1.25 (m, 1 H, 0.5 CH2), 1.07–1.11 (m, 1 H, 0.5 CH2).
13C NMR (100 MHz, DMSO-d6): δ = 178.28 (C=O), 171.12 (C=N), 58.42
(CH), 34.99 (CH), 32.86 (CH2), 29.68 (CH2), 29.45 (CH2), 26.54 (CH2),
24.12 (CH), 24.06 (CH).
13C NMR (100 MHz, DMSO-d6): δ = 178.28 (C=O), 171.12 (C=N), 58.42
(CH), 34.99 (CH), 32.86 (CH2), 29.68 (CH2), 29.45 (CH2), 26.54 (CH2),
24.12 (CH), 24.06 (CH).
Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.62;
H, 7.93; N, 13.74.
Anal. Calcd for C16H21F3O4: C, 57.48; H, 6.33. Found: C, 57.53; H, 6.31.
Ethyl Tricyclo[4.3.1.13,8]undec-4-ene-4-carboxylate (20)
2-Thioxo-1,2,3,5,6,7,8,9,10,11-decahydro-4H-5,9:7,11-dimethano-
cyclonona[d]pyrimidin-4-one (17)
To a stirred solution of 18 (0.30 g 1.3 mmol) in THF (5 mL) was added
NaH (60% in oil; 0.06 g, 1.5 mmol) in one portion. Trifluoroacetic an-
hydride (0.27 g, 1.3 mmol) was added dropwise at 0 °C. After stirring
the mixture for 1 h, an additional amount of NaH (60% in oil; 0.06 g,
0.15 mmol) was added and the mixture was refluxed for 1 h. The sol-
vent was evaporated, and H2O (5 mL) and CCl4 (5 mL) were added to
the residue. The organic layer was separated, dried (Na2SO4), filtered
through a 1 cm pad of silica gel, and concentrated; yield 0.21 g (76%);
colorless oil.
To a mixture of 1 (0.80 g, 3.4 mmol), (thio)urea (3.9 mmol), or guani-
dine carbonate (1.8 mmol) in absolute MeOH (9 mL) was added
NaOMe (0.54 g, 10 mmol) in MeOH (5 mL) under an argon atmo-
sphere. The resulting mixture was sonicated in an ultrasound wash-
ing bath for 1 h and then refluxed for 5 h. The solid precipitated was
collected by filtration, washed with H2O, dried, and recrystallized
from MeOH; yield: 0.5 g (58%); white solid; mp 319.0–323.2 °C (dec.).
IR (ATR): 3140, 2920, 2887, 1629, 1444 cm–1
.
IR (ATR): 2900, 2845, 1701, 1442, 1249, 1209, 1076, 1037 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 12.24 (s, 1 H, NH), 11.90 (s, 1 H,
NH), 3.13–3.16 (m, 1 H, CH), 2.77–2.80 (m, 1 H, CH), 1.99 (m, 2 H, 2 ×
CH), 1.68–1.84 (m, 8 H, CH2), 1.49–1.52 (m, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 174.18 (C=O), 161.54 (С=S), 159.82
(C), 121.30 (C), 35.34 (CH2), 33.56 (2 × CH2), 32.10 (2 × CH2), 27.95 (2 ×
CH), 26.19 (CH).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.33 (dd, 3J = 8.9 Hz, 4J = 1.6 Hz, 1
H, C=CH), 4.12–4.17 (q, 3J = 7.1 Hz, 2 H, CH2), 3.06–3.07 (m, 1 H, CH),
2.44–2.49 (m, 1 H, CH), 2.09–2.12 (m, 1 H, 2 × CH), 1.76–1.66 (m, 10
H, 5 × CH2), 1.26–1.29 (t, 3J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 168.41 (C=O), 149.04 (C=CH),
142.21 (C), 60.55 (CH2), 36.42 (CH2), 33.35 (2 × CH2), 32.84 (2 × CH2),
31.86 (CH), 30.89 (CH), 29.20 (2 × CH), 14.37 (CH3).
Anal. Calcd for C13H16N2OS: C, 62.87; H, 6.49; N, 11.28; S, 12.91.
Found: С, 62.92; H, 6.52; N, 11.31; S, 12.86.
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.29; H, 9.19.
Ethyl 5-Hydroxytricyclo[4.3.1.13,8]undecane-4-carboxylate (18)
Funding Information
To a stirred solution of 1 (0.70 g, 3.0 mmol) in MeOH (5 mL) was add-
ed NaBH4 (0.13 g, 3.5 mmol) at 35 °C in portions and the resulting
mixture was stirred for 0.5 h. The solvent was evaporated and cold
H2O (5 mL) and CCl4 (5 mL) were added to the residue. The organic
layer was separated and dried (Na2SO4). After evaporation of the sol-
vent, the oily residue was crystallized from n-hexane; yield: 0.61 g
(87%); colorless crystals; mp 56.1–57.3 °C (hexane).
The research was supported by the Ministry of Education and Science
of the Russian Federation within the framework of the Project part of
the State Assignment No. 4.6764.2017/BC and Russian Foundation for
Basic Research (Project No. 16-43-630823 A).
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IR (ATR): 3460, 2900, 2847, 1716, 1463, 1444, 1193, 1172 cm–1
.
Supporting Information
1H NMR (400 MHz, DMSO-d6): δ = 4.61 (br s, 1 H, OH), 4.23–4.26 (m, 1
H, CHOH), 3.91–4.03 (m, 2 H, CH2), 2.79–2.81 (m, 1 H, CH), 2.15–2.23
(m, 2 H, 2 × CH), 2.05–2.09 (m, 1 H, CH), 1.72–1.94 (m, 6 H, 3 × CH2),
1.41–1.68 (m, 5 H, 2 × CH2 + CH), 1.12–1.63 (t, 3J = 7.2 Hz, 3 H, CH3).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610312.
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o
n
13C NMR (100 MHz, DMSO-d6): δ = 173.96 (C=O), 171.12, 72.62
(CHOH), 59.59 (CH2), 55.95 (CH), 41.34 (CH2), 37.78 (CH), 37.22 (CH2),
31.90 (CH2), 31.41 (CH2), 31.31 (CH2), 30.99 (CH2), 27.84 (CH), 27.54
(CH), 14.71 (CH3).
References
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Ethyl 5-Trifluoroacetoxytricyclo[4.3.1.13,8]undecane-4-carboxyl-
ate (19)
To a stirred solution of 18 (0.50 g, 2.1 mmol) in THF (5 mL) was added
NaH (60% in oil; 0.09 g, 2.3 mmol) in one portion. Trifluoroacetic an-
hydride (0.44 g, 2.1 mmol) was added dropwise at 0 °C and the mix-
ture was stirred for 1 h at r.t. The solvent was removed, and H2O (5
mL) and CCl4 (5 mL) were added to the residue. The organic layer was
separated, dried (Na2SO4) and the solvent was removed by evapora-
tion; yield: 0.67 g (92%); slightly yellow oil.
IR (ATR): 2906, 2856, 1780, 1741, 1448, 1215, 1197 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
I. M. Tkachenko et al.
Paper
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I