The Radziszewski oxidation of cycloalkylidene-α-(thiazol- 2-yl)acetonitriles: A new approach toward spirooxiranes

Article abstract of DOI:10.1002/jhet.493

Upon treatment with H₂O₂/KOH in EtOH or with Na ₂CO₃/H₂O₂ in acetone, cycloalkylidene-α-(4-arylthiazol-2-yl)acetonitriles afforded 2-(4-arylthiazol-2-yl)-1-oxaspiro[2.5]octane-2-carboxamides and 2-(4-arylthiazol-2-yl)-1-oxaspiro[2.4]heptane-2-carboxamides in excellent yields (76-100%).

Full text of DOI:10.1002/jhet.493

162
The Radziszewski Oxidation of Cycloalkylidene-a-(thiazol-
2-yl)acetonitriles: A New Approach Toward Spirooxiranes
Vol 48
Victor V. Dotsenko,a,b* Sergey G. Krivokolysko,a and Victor P. Litvinovcy
aChemEx Laboratory, Vladimir Dal’ East Ukrainian National University, 91034 Lugansk, Ukraine
bPhysico-Chemical Department, State Enterprise ‘‘Luganskstandartmetrology’’,
91021 Lugansk, Ukraine
cZelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
117913 Moscow, Russian Federation
*E-mail: victor_dotsenko@bigmir.net
yDeceased.
Received January 2, 2010
DOI 10.1002/jhet.493
Published online 6 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
Upon treatment with H2O2/KOH in EtOH or with Na2CO3/H2O2 in acetone, cycloalkylidene-a-(4-
arylthiazol-2-yl)acetonitriles afforded 2-(4-arylthiazol-2-yl)-1-oxaspiro[2.5]octane-2-carboxamides and 2-
(4-arylthiazol-2-yl)-1-oxaspiro[2.4]heptane-2-carboxamides in excellent yields (76–100%).
J. Heterocyclic Chem., 48, 162 (2011).
INTRODUCTION
cessfully accomplished with only a few epoxidizing
agents such as dioxiranes [14] (for reviews on the diox-
irane epoxidation see [15]), monoperphtalic acid [16], p-
Oxiranes were found to belong to one of the most
promising classes of heterocyclic compounds. As they
are versatile, highly reactive, and chemically flexible
reagents, a considerable attention has been devoted to
both the methods of epoxidation and reactions of oxir-
anes (for recent reviews on the methods of epoxidation
and chemical transformations of oxiranes see, e.g., [1–
6]). Spirooxiranes (or 1-oxaspiro[2.n]alkanes) are of spe-
cial interest because their biological profile and specific
reactions, in some cases, could be vastly different from
those reported for other oxiranes [2,7]. A couple of nat-
urally occurred spirooxiranes have been reported to pos-
sess fungicidal, phytotoxic, insecticidal, and cytotoxic
activity [1,8].
nitroperbenzoic acid [17], m-chloroperbenzoic acid
R
V
(MCPBA)–NaHCO3 system [18], or Oxone (2KHSO5
ꢀ KHSO4 ꢀ K2SO4)–cyclohexanone–phosphate buffer
[19]. Noteworthy that organic peroxy acids could be
used for epoxidation of methylenecycloalkanones, but
reaction is frequently accomplished with low ratio of
exo/endo enantiomers [2] and often complicated by side
reactions such as acid-promoted oxirane ring cleavage
and rearrangements [2,6,7,20]. For instance, the epoxi-
dation of methylenecyclopropanes with MCPBA is
accompanied by rearrangement resulted in formation of
cyclobutanones as sole products [21]. When camphene
and 1-methylenecycloalkanones were treated with
MeCO3H, corresponding aldehydes derived from Mein-
wald-type rearrangement and glycol monoacetates were
obtained along with minor amounts of desired 1-oxaspiro
[2.n]alkanes [2,22].
Both isomerization and ring opening can be avoided
in nonacidic media; thus, a successful epoxidation with
MeCO3H can be achieved in a buffered reaction media
upon mild conditions only [23]. Another procedure to
effect the epoxidation of methylenecycloalkanes uses
peroxycarboximidic acids (RC(¼¼NH)OOH) easily gen-
erated in situ from H2O2 and RCBN, usually in a
slightly alkaline medium. This method is known as
Payne epoxidation [24] (for more recent developments
An evident approach to the simpliest 1-oxaspiro[2.-
n]alkanes is based on the rather uneffective two-step
halohydrine procedure [9]. Spirooxiranes could also be
obtained from cycloalkanones upon treatment with a
couple of sulfur ylides (e.g., by Corey-Chaykowski reac-
tion, for reviews see [10]), diazoalkanes [2,11], organo-
lithium compounds [12], by Darzens reaction [13], etc.
However, less is known about methods of direct
epoxidation of 1-methylenecycloalkanes leading to spi-
rooxiranes, probably because of a heightened tendency
toward cleavage of spirooxirane moiety in acidic media,
even under mild conditions. The direct epoxidation of 1-
methylenecycloalkanes to spirooxiranes has been suc-
C
V
2010 HeteroCorporation

January 2011
The Radziszewski Oxidation of Cycloalkylidene-a-(thiazol-2-yl)acetonitriles:
A New Approach Toward Spirooxiranes
163
Scheme 1
Our interests in the chemistry of cyanothioacetamide
(1) [34] prompted us to investigate the oxidation of un-
saturated nitriles derived from compound 1. Recently,
we showed that oxidation of arylmethylene cyanothioa-
cetamides (2) under Radziszewski conditions proceeds
with involvement of both conjugated cyano group and
thioamide moiety giving rise to 3-aryl-2,2-oxiranedicar-
boxamides (3) [35] (Scheme 1).
see also [25]) and could be considered as a development
of the classical Radziszewski method of oxidative hy-
drolysis of nitriles.
Encouraged with these results, we decided to extend
this method to cycloalkylidene-a-(4-arylthiazol-2-yl)ace-
tonitriles, which are seemed to be a good starting point
for the synthesis of 1-oxaspiro[2.n]alkane derivatives.
The absence of an acid is the major advantage of the
Payne epoxidation as only neutral amides are formed as
by-products. In contrast with peroxy acids, peroxycar-
boximidic acids appear to be milder reagents and those
substrates containing carbonyl groups tend not to react
to give Baeyer-Villiger by-products [24c]. However, the
literature contains only a few reports on the epoxidation
of methylenecycloalkanes effected by peroxycarboximi-
dic acids. Thus, 1-oxaspiro[2.n]alkanes were obtained
from corresponding alkenes upon treatment with
PhCBN/H2O2/NaHCO3 [24c] or Cl3CCBN/H2O2 in the
presence of K2HPO4 [2,23c]. Tsuno and Sugiyama have
reported that 5-cycloalkylidene Meldrum’s acids easily
react with H2O2 in acetonitrile to afford spirooxiranes in
good yields [26]. Finally, ethyl cycloalkylidenecyanoa-
cetates reacted with H2O2 in the presence of sodium
tungstate to give 2-ethoxycarbonyl-1-oxaspiro[2.n]al-
kane-2-carboxamides [27] because of specific behavior
of unsaturated nitriles under Radziszewski reaction
conditions.
RESULTS AND DISCUSSION
Cycloalkylidene-a-(4-arylthiazol-2-yl)acetonitriles
(4a–f) were obtained from easily available 2-cyano-2-
cycloalkylideneethanethioamides (5a–c) [36] and a-
bromo ketones 6a–e via modified Hantzsch procedure,
as shown in Scheme 2.
Starting 2-(4-tert-butylcyclohexylidene)-2-cyanoetha-
nethioamide (5b) was prepared by Knoevenagel conden-
sation of cyanothioacetamide 1 with 4-tert-butylcyclo-
hexanone.
Scheme 2
At the end of 19th century, Radziszewski described
an original method for preparation of amides by treat-
ment of nitriles with alkaline hydrogen peroxide [28].
This reaction became a standard route for synthesis of
amides from nitriles, and many variations of this proce-
dure have been subsequently reported (for instance, see
[29]; the Radziszewski reaction has been reviewed
[30]).
In 1932, Murray and Cloke [31] have found that a,b-
unsaturated nitriles undergo the double C¼¼C bond
epoxidation under Radziszewski conditions, along with
expected transformation of cyano group into amide moi-
ety. The mechanism of epoxidation remained unclear
until mid-1950s when Payne has suggested and proved
[24a,32] that initial formation of peroxycarboximidic
acids from unsaturated nitriles and H2O2 takes place,
following the intramolecular epoxidation. Since that
time some modifications and extensions of the method
have been described [33]. Apart from its synthetic
potential and usability, epoxidation of unsaturated
nitriles under Radziszewski conditions is of considerable
interest in the light of recent data on the biological ac-
tivity of 2,3-epoxy amides [1].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

164
V. V. Dotsenko, S. G. Krivokolysko, and V. P. Litvinov
Vol 48
a Perkin–Elmer C, H, and N analyzer; their results were found
to be in good agreement with the calculated values (60.2%).
IR spectra were recorded on an IKS-29 spectrophotometer in
We found that unsaturated nitriles 4 could be easily
converted into spiroepoxyamides 7 upon short-time treat-
ment with alkaline H2O2 solution in EtOH (method A,
yields 76–90%). It is strongly believed that the reaction
proceeds through the formation of peroxycarboximidic
intermediate 8, following the intramolecular epoxidation.
Murray and Cloke [31] had shown that unsaturated
nitriles could be successfully oxidized by means of
H2O2 in the presence Na2CO3 as a catalyst in acetonic
solution. The Na2CO3/acetone system appears to be
more efficient than KOH/EtOH because it gives a better
yields (up to quantitative) and has a better solvability;
the last factor plays a role in the case of certain unsatu-
rated nitriles, which are hardly soluble in aqueous
EtOH. The specific and superior action of the system
Na2CO3–H2O2 could be explained by a weaker and
milder basic nature of Na2CO3 than KOH and by a new
potent oxidant formation in situ, sodium carbonate ses-
quiperhydrate 2Na2CO3 ꢀ 3H2O2, also referred as ‘‘so-
dium percarbonate’’ (SPC). The chemistry of SPC has
been reviewed [37]. Although SPC has proved to be
readily available, cheap, and effective oxidant, only a
few reports on the Radziszewski nitrile hydrolysis
[31,38,39] or Payne epoxidation [40] with SPC are
known to date. Therefore, we attempted to repeat the
oxidation of unsaturated nitriles 4 with Na2CO3–H2O2
in acetonic solution (method B). Comparing the methods
A and B, one can note that method B is preferable over
the method A because of higher yields (almost quantita-
tive), milder conditions, and shortened reaction time.
All the obtained compounds 7a–f are colorless crys-
talline solids, easily soluble in hot EtOH, acetone,
DMSO, or DMF, and insoluble in water, hydrocarbons,
benzene, or CCl4. The structures of spiroepoxyamides 7
were supported by the spectral data and microanalysis
analysis data as well. Thus, the IR spectra of 7 revealed
the lack of conjugated ACBN group; instead, broad and
intensive bands corresponding to C(O)NH2 moiety
appeared at m ¼ 3405–3380 (NAH) and 1683–1655
1
Nujol mulls. The H-NMR spectra were performed on Bruker
Avance II 400 (399.97 MHz) spectrometer in DMSO-d6 solu-
tions with Me4Si as the internal standard. The 13C-NMR spec-
tra were performed on Bruker Avance DRX 500 (125.771
MHz) spectrometer in CDCl3. The purity of all obtained com-
R
V
pounds was checked by TLC on Silufol UV 254 plates (sor-
bent—Silpearl, large-pore silica gel after Pitra with lumines-
cent indicator for UV 254 on the aluminum foil, binder—
starch) in the acetone–heptane (1:1) system; spots were visual-
ized with iodine vapors and UV light. Cyanothioacetamide (1)
was prepared by known procedure [41]. Unsaturated thioa-
mides 5a,b were obtained from cyanothioacetamide (1) and
cycloalkanones by slightly modified Knoevenagel procedure
described by Elgemeie et al. [36].
2-Cyano-2-cyclopentylideneethanethioamide (5a). A 500-
mL one-necked round-bottom flask equipped with the Dean-
Stark trap and a reflux condenser was charged with 20.0 mL
(0.226 mol) of cyclopentanone, 20.0 g (0.2 mol) of cyanothioa-
cetamide (1), 150 mL of benzene, 0.7 mL (7 mmol) of piperi-
dine, and 0.5 mL (8.7 mmol) of AcOH. The reaction mixture
was heated under reflux until no more water separated in the
Dean-Stark trap (about 4 h). Benzene was removed in vacuo to
give 40–45 mL of red viscous syrup. It was treated with 100
mL of boiling ether, filtered through a paper filter, and left to
stand in refrigerator overnight. The product was filtered off and
washed subsequently with cold ether, H2O, and cold ether to
give 19.2 g (58%) of pure thioamide 5a as yellow crystalline
solid, mp 115–118ꢂC (ether) (Ref. [36]: 108ꢂC); IR and 1H-
NMR spectra were found to be in agreement with those reported
in Ref. [36]. Anal. Calcd. for C8H10N2S (166.25): C, 57.80; H,
6.06; N, 16.85; Found: C, 58.03; H, 6.10; N, 16.74.
2-(4-tert-Butylcyclohexylidene)-2-cyanoethanethioamide
(5b). This compound was prepared as follows: a 250-mL one-
necked round-bottom flask equipped with the Dean-Stark trap
and a reflux condenser was charged with 15.4 g (0.1 mol) of 4-
(tert-butyl)cyclohexanone (purchased from Acros), 10.0 g (0.1
mol) of cyanothioacetamide (1) [41], 100 mL of benzene, 0.2
mL (2 mmol) of piperidine, and 2.0 mL (35 mmol) of AcOH.
The reaction mixture was heated to reflux whereupon the
required amount of liberated water (about 2.0 mL) was collected
in the Dean-Stark trap, which usually takes 4–5 h. Thereafter,
benzene was removed in vacuo, and a deep-yellow oily residue
was treated with 100–120 mL of boiling ether. After cooling to
ambient temperature, a yellow crystalline solid began to sepa-
rate. The mixture was allowed to stand overnight, and then the
product was filtered off and washed subsequently with cold
ether, H2O, and cold ether to give 17.7 g (75%) of pure thioa-
mide 5b as yellow powder, mp 134–136ꢂC (ether); 1H-NMR
(400 MHz, DMSO-d6): d ¼ 10.31 and 9.67 (both br s, 2H,
C(S)NH2), 2.69–1.13 (m, 9H, (CH2CH2)2CH), 0.83 (s, 9H, t-
C4H9) ppm; 13C-NMR (125 MHz, CDCl3): d ¼ 194.10, 160.80,
116.39, 110.54, 46.83, 40.55, 40.48, 40.38, 40.31, 40.22, 40.16,
40.15, 40.05, 39.98, 39.89, 39.72, 39.55, 34.06, 32.64, 31.37,
28.52, 28.14, 27.85. Anal. Calcd. for C13H20N2S (236.38): C,
66.06; H, 8.53; N, 11.85; Found: C, 66.20; H, 8.55; N, 11.86.
2-Cyano-2-cyclohexylideneethanethioamide (5c). A solu-
tion of 15.0 g (0.15 mol) of cyanothioacetamide (1), 16.0 mL
(0.155 mol) of cyclohexanone, 0.6 mL (6 mmol) of piperidine,
1
(C¼¼O) cmꢁ1. The H-NMR spectra revealed signals of
C(O)NH2 protons as two broadened peaks at d 7.60–
7.30 ppm and sharp characteristic singlets at d 7.95–
7.66 ppm corresponding to thiazole C(5)H protons.
In conclusion, we have developed a simple and con-
venient method to obtain new spirooxiranes, 1-oxaspir-
o[2.5]octane-2-carboxamide and 1-oxaspiro[2.4]heptane-
2-carboxamide derivatives, based on the Radziszewski
oxidation of cycloalkylidene acetonitriles by means of
H2O2/KOH in EtOH or SPC in acetonic solution.
EXPERIMENTAL
Melting points were measured on a Kofler hot-stage appara-
tus. Elemental analyses for C, H, and N were conducted using
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
The Radziszewski Oxidation of Cycloalkylidene-a-(thiazol-2-yl)acetonitriles:
A New Approach Toward Spirooxiranes
165
and 0.5 mL (8.7 mmol) of AcOH was heated under reflux for
6 h in a Dean-Stark apparatus. Benzene was removed in
vacuo, and the residue was treated with 100 mL of boiling
ether and left to stand at ambient temperature. When no crys-
tals appeared after cooling, crystallization was induced by the
addition of a seed crystal or scratching with glass rod. A mix-
ture was left to stand in refrigerator overnight, and yellow
crystalline product was filtered off and washed subsequently
with cold ether, cold EtOH, and cold ether to give 18.9 g
(70%) of pure thioamide 5c, mp 133–135ꢂC (ether) (Ref. [36]:
119ꢂC); IR and 1H-NMR spectra were found to be in agree-
ment with those reported in Ref. [36].
methylphenyl)ethanone 6b as beige crystalline solid, yield 1.68
g (80%), mp 95–96.5ꢂC (EtOH); IR (nujol): m ¼ 2220 (CBN),
1
1603 (C¼¼C) cmꢁ1; H-NMR (400 MHz, DMSO-d6): d ¼ 7.85
(s, 1H, thiazolyl C(5)H), 7.78 (br d, 2H, J ¼ 7.8 Hz, arom.
C(2)H, C(6)H), 7.19 (br d, 2H, J ¼ 7.8 Hz, arom. C(3)H,
C(5)H), 2.38 (s, 3H, ArCH3), 2.45–2.30, 2.20–2.04, and 1.43–
1.25 (3 m, 9H, (CH2)2CH(CH2)2), and 0.91 (s, 9H, t-C4H9)
ppm. Anal. Calcd. for C22H26N2S (350.53): C, 75.38; H, 7.48;
N, 7.99; Found: C, 75.50; H, 7.47; N, 8.02.
2-[4-(4-Chlorophenyl)thiazol-2-yl]cyclohexylideneacetoni-
trile (4e). This compound was obtained from 1.08 g (6 mmol)
of 5c and 1.40 g (6 mmol) of 2-bromo-1-(4-chlorophenyl)etha-
none 6d as yellow needles, yield 1.50 g (80%), mp 93–94ꢂC
(4-Arylthiazol-2-yl)cycloalkylideneacetonitriles 4a–f. General
procedure. 2-Cyano-2-cycloalkylideneethanethioamide
1
(EtOH); IR (nujol): m ¼ 2211 (CBN), 1605 (C¼¼C) cmꢁ1; H-
5a–c
NMR (400 MHz, DMSO-d6): d ¼ 8.34 (s, 1H, thiazolyl C(5)H),
7.98 (br d, 2H, J ¼ 8.5 Hz, arom. C(2)H, C(6)H), 7.53 (br d,
2H, J ¼ 8.5 Hz, arom. C(3)H, C(5)H), 2.97 and 2.70 (both m,
each 2H, cycloalk. H2CAC¼¼), and 1.78–1.63 (m, 6H, cycloalk.)
ppm. Anal. Calcd. for C17H15ClN2S (314.84): C, 64.86; H,
4.80; N, 8.90; Found: C, 64.97; H, 4.79; N, 8.92.
(6 mmol) and corresponding a-bromo ketone 6a–e (6 mmol) were
dissolved in minimal amounts of DMF (2–3 mL). The mixture
was gently refluxed for 2–3 min, cooled, diluted with EtOH, and
left to stand overnight (for 6c–e—diluted with cold EtOH and
kept in freezer (þ4ꢂC) for 3 h). The precipitate formed was fil-
tered off, washed with 50% aq. EtOH and twice with cold EtOH.
The obtained compounds 4a–f were pure enough for analytical
purposes and are suitable for use without further purification.
Cyclopentylidene-2-(4-phenylthiazol-2-yl)acetonitrile
(4a). This compound was obtained from 1.00 g (6 mmol) of
2-cyano-2-cyclopentylideneethanethioamide 5a and 1.20 g (6
mmol) of a-bromoacetophenone 6a as beige crystals, yield
1.57 g (98%), mp 148–150ꢂC (EtOH); IR (nujol): m ¼ 2214
2-[4-(4-Bromophenyl)thiazol-2-yl]cyclohexylideneacetoni-
trile (4f). This compound was obtained from 1.08 g (6 mmol)
of 5c and 1.67 g (6 mmol) of 2-bromo-1-(4-bromophenyl)etha-
none 6e as sand-colored crystals, yield 1.57 g (73%), mp 103–
1
104ꢂC (EtOH) (Ref. [42]: 100–101ꢂC); IR and H-NMR spec-
tra were found to be identical with the one described in Ref.
[42]. Anal. Calcd. for C17H15BrN2S (359.29): C, 56.83; H,
4.21; N, 7.80; Found: C, 56.90; H, 4.21; N, 7.82.
2-(4-Arylthiazol-2-yl)-1-oxaspiro[2.n]alkane-2-carboxamides
(7a–f). General procedure.
(CBN), 1605 (C¼¼C) cmꢁ1
;
1H-NMR (400 MHz, DMSO-d6):
d 8.12 (s, 1H, thiazolyl C(5)H), 7.96 (br d, 2H, J ¼ 7.6 Hz,
phenyl C(2)H, C(6)H), 7.40 (m, 3H, phenyl C(3)H-C(5)H),
2.95 and 2.83 (2 m, 4H, cyclopent. C(2)H2, C(5)H2), and
1.93–1.82 (m, 4H, cyclopent. C(3)H2, C(4)H2) ppm. Anal.
Calcd. for C16H14N2S (266.37): C, 72.15; H, 5.30; N, 10.52;
Found: C, 72.25; H, 5.29; N, 10.54.
Method A. A suspension of finely powdered cycloalkylide-
neacetonitrile 4a–f (2 mmol) in 8–10 mL of EtOH was stirred at
room temperature while 0.5 mL (0.9 mmol) of 10% aqueous
KOH and an excess of 32% aqueous H2O2 (1.9 mL, 20 mmol)
were subsequently added dropwise. The mixture was slowly
heated under vigorous stirring until exothermic reaction was ini-
tiated and whereupon a clear, almost colorless solution formed
(Oxygen is extremely evolved). The mixture was stirred at
room temperature for 1 h and then was kept in freezer at þ4ꢂC
for 2 h. A colorless crystalline solid was filtered off and washed
with cold 50% aq. EtOH to afford pure oxaspiro[2.n]cycloal-
kane-2-carboxamides 7a–f. For analytical purposes, compounds
were recrystallized from appropriate solvents.
Cyclopentylidene-2-[4-(4-methylphenyl)thiazol-2-yl]aceto-
nitirile (4b). This compound was obtained from 1.00 g (6
mmol) of 5a and 1.28 g (6 mmol) of 2-bromo-1-(4-methylphe-
nyl)ethanone 6b as beige crystals, yield 1.62 g (96%), mp
161–161.5ꢂC (EtOH); IR (nujol): m ¼ 2218 (CBN), 1605
1
(C¼¼C) cmꢁ1; H-NMR (400 MHz, DMSO-d6): d 7.83 (s, 1H,
thiazolyl C(5)H), 7.81 (br d, 2H, J ¼ 8.0 Hz, arom. C(2)H,
C(6)H), 7.19 (br d, 2H, J ¼ 8.0 Hz, arom. C(3)H, C(5)H),
3.04 and 2.87 (2 m, 4H, cyclopent. C(2)H2, C(5)H2), 2.39 (s,
3H, CH3), and 1.99–1.87 (m, 4H, cyclopent. C(3)H2, C(4)H2)
ppm. Anal. Calcd. for C17H16N2S (280.39): C, 72.82; H, 5.75;
N, 9.99; Found: C, 72.93; H, 5.75; N, 10.01.
Method B. A 25-mL beaker was charged with corresponding
cycloalkylideneacetonitrile 4 (2 mmol) and 10 mL of acetone. To
a clear solution formed, an aqueous 10% Na2CO3 solution (0.4
mL, 0.4 mmol) and an excess of 32% aq. H2O2 (1.0 mL, 10
mmol) were subsequently added (the colorless precipitate of SPC
may form at first). The mixture was gently refluxed under vigor-
ous stirring for 5–7 min, allowed to cool, and thereafter treated
with ice-cold water (10 mL). The white crystalline solid was fil-
tered off and washed with a plenty of water and cold 50% aq.
EtOH to give pure oxaspiro[2.n]cycloalkane-2-carboxamides 7.
2-(4-Phenylthiazol-2-yl)-1-oxaspiro[2.4]heptane-2-carbox-
amide (7a). This compound was obtained as colorless crystals,
yield 76% (method A), mp 165–166.5ꢂC (EtOH); IR (nujol): m
Cyclopentylidene-2-[4-(4-methoxyphenyl)thiazol-2-yl]ace-
tonitirile (4c). This compound was obtained from 0.50 g (3
mmol) of 5a and 0.69 g (3 mmol) of 2-bromo-1-(4-methoxy-
phenyl)ethanone 6c as beige crystalline solid, yield 0.83 g
(93%), mp 133–134.5ꢂC (AcOEt); IR (nujol): m ¼ 2210
(CBN), 1610 (C¼¼C) cmꢁ1
;
1H-NMR (400 MHz, DMSO-d6):
d ¼ 7.86 (br d, 2H, J ¼ 8.7 Hz, arom. C(2)H, C(6)H), 7.75 (s,
1H, thiazolyl C(5)H), 6.92 (br d, 2H, J ¼ 8.7 Hz, arom.
C(3)H, C(5)H), 3.83 (s, 3H, OCH3), 3.03 and 2.87 (2 m, 4H,
cyclopent. C(2)H2, C(5)H2), and 1.98–1.89 (m, 4H, cyclopent.
C(3)H2, C(4)H2) ppm. Anal. Calcd. for C17H16N2OS (296.39):
C, 68.89; H, 5.44; N, 9.45; Found: C, 68.95; H, 5.42; N, 9.43.
(4-tert-Butylcyclohexylidene)-2-[4-(4-methylphenyl)thiazol-
2-yl]acetonitirile (4d). This compound was obtained from
1.40 g (6 mmol) of 5b and 1.28 g (6 mmol) of 2-bromo-1-(4-
¼ 3380 (NH2 amide), 1655 (C¼¼Oamide) cmꢁ1
;
1H-NMR (400
MHz, DMSO-d6): d ¼ 7.92 (br d, 2H, J ¼ 7.4 Hz, arom.
C(2)H, C(6)H), 7.81 (s, 1H, thiazolyl C(5)H), 7.59 (br s, 1H,
CONH2), 7.40–7.28 (m, 3H of arom. C(3)H–C(5)H and 1H of
CONH2 overlapped), and 2.03–1.66 (m, 8H, (CH2)4) ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

166
V. V. Dotsenko, S. G. Krivokolysko, and V. P. Litvinov
Vol 48
and Steric Effects of Alkene Peroxide Epoxidation; Bogorodsky
Pechatnik: Moscow, 1999; p 528 (in Russian).
Anal. Calcd. for C16H16N2O2S (300.38): C, 63.98; H, 5.37; N,
9.33; Found: C, 64.09; H, 5.38; N, 9.35.
[2] Kas’yan, L. I.; Seferova, M. F.; Okovitiy, S. I. Alicyclic
Epoxy Compounds. Methods of Synthesis; Dnepropetrovsky National
2-[4-(4-Methylphenyl)thiazol-2-yl]-1-oxaspiro[2.4]heptane-
2-carboxamide (7b). This compound was obtained as color-
less crystals, yield 81% (method A) or 95% (method B), mp
174–175ꢂC (dec.) (EtOH/acetone ¼ 1:1); IR (nujol): m ¼ 3400
University Publishing Office: Dnepropetrovsk, 2003;
Russian).
p 208 (in
(NH2 amide), 1660 (C¼¼Oamide) cmꢁ1
;
1H-NMR (400 MHz,
[3] Padwa, A.; Murphree, S. S. ARKIVOC 2006, 3, 6.
[4] Gorzinsky-Smith, J. Synthesis 1984, 629, and references cited
therein.
[5] Salomatina, O. V.; Yarovaya, O. I.; Barkhash, V. A. Russ J Org
Chem 2005, 41, 155.
DMSO-d6): d ¼ 7.80 (d, 2H, J ¼ 8.0 Hz, arom. C(2)H,
C(6)H), 7.73 (s, 1H, thiazolyl C(5)H), 7.59 and 7.39 (2 br s,
2H, CONH2), 7.19 (d, 2H, J ¼ 8.0 Hz, arom. C(3)H, C(5)H),
and 2.38–1.70 (m, 8H, (CH2)4) ppm. Anal. Calcd. for
C17H18N2O2S (314.41): C, 64.94; H, 5.77; N, 8.91; Found: C,
64.99; H, 5.77; N, 8.91.
2-[4-(4-Methoxyphenyl)thiazol-2-yl]-1-oxaspiro[2.4]heptane-
2-carboxamide (7c). This compound was obtained as colorless
crystals, yield 76% (method A), mp 161–162ꢂC (EtOH/acetone
[6] Kas’yan, L. I.; Kas’yan, A. O.; Okovitiy, S. I.; Tarabara, I.
N. Alicyclic Epoxy Compounds. The Reactivity; Dnepropetrovsky
National University Publishing Office: Dnepropetrovsk, 2003; p 516
(in Russian).
[7] The chemistry of spirooxiranes has been reviewed recently:
Kas’yan, L. I.; Kas’yan, A. O.; Tarabara, I. N. Russ J Org Chem 2001,
37, 1361.
¼ 1:1); IR (nujol): m ¼ 3380 (NH2 amide), 1655 (C¼¼Oamide
)
cmꢁ1; H-NMR (400 MHz, DMSO-d6): d ¼ 7.82 (d, 2H, J ¼
8.7 Hz, arom. C(2)H, C(6)H), 7.66 (s, 1H, thiazolyl C(5)H),
7.56 and 7.41 (2 br s, 2H, CONH2), 6.89 (d, 2H, J ¼ 8.7 Hz,
arom. C(3)H, C(5)H), 3.80 (s, 3H, OMe), and 1.98–1.64 (m,
8H, (CH2)4) ppm. Anal. Calcd. for C17H18N2O3S (330.41): C,
61.80; H, 5.49; N, 8.48; Found: C, 61.92; H, 5.50; N, 8.47.
6-tert-Butyl-2-[4-(4-methylphenyl)thiazol-2-yl]-1-oxaspiro[2.5]
octane-2-carboxamide (7d). This compound was obtained as
white powder, yield 84% (method A) or ꢃ100% (method B),
mp 185–187ꢂC (EtOH); IR (nujol): m ¼ 3405 (NH2 amide),
1
[8] For review on the naturally occurred spirooxiranes see: Jar-
vis, B. B.; Mazzola, E. P. Acc Chem Res 1982, 15, 388.
[9] Traynham, Y. G.; Pascual, O. S. Tetrahedron 1959, 7, 165.
[10] For reviews on the Corey-Chaykowski oxirane synthesis
´
see: (a) Aube J. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 819; (b)
Gololobov, Y. G.; Nesmeyanov, A. N.; Lysenko, V. P.; Boldeskul, I.
E. Tetrahedron 1987, 43, 2609.
[11] (a) Kohler, E. P.; Tishler, M.; Potter, H.; Thompson, H. T.
J Am Chem Soc 1939, 61, 1057; (b) Gutsche, C. D. In Organic Reac-
tions; Adams, R., Ed.; Wiley: New York, 1954; Vol. 8, p 364; (c)
Okaev, E. V.; Zvonok, A. M. Chem Heterocycl Compd 1995, 31, 249.
[12] For instance see: (a) Tarhouni, R.; Kirschleger, B.; Ram-
baud, M.; Villieras, J. Tetrahedron Lett 1984, 25, 835; (b) Einhorn, C.;
Allavena, C.; Luche, J. L. J Chem Soc Chem Commun 1988, 333.
[13] (a) Newman, M. S.; Magerlein, B. J. In Organic Reactions;
Adams, R., Ed.; Wiley: New York, 1949; Vol. 5, pp 413–440; (b) Bal-
lester, M. Chem Rev 1955, 55, 283; (c) Rosen, T. In Comprehensive
Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: Oxford,
UK, 1991; Vol. 2, pp 409–439; (d) Aggarwal, V. K.; Badine, D. M.;
Moorthie, V. A. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH Verlag: Weinheim, 2006; p 1.
1
1683 (C¼¼Oamide) cmꢁ1; H-NMR (400 MHz, DMSO-d6): d ¼
7.80 (d, 2H, J ¼ 8.0 Hz, arom. C(2)H, C(6)H), 7.73 (s, 1H,
thiazolyl C(5)H), 7.56 and 7.30 (2 br s, 2H, CONH2), 7.18 (d,
2H, J ¼ 8.0 Hz, arom. C(3)H, C(5)H), 2.37 (s, 3H, ArCH3),
1.86–1.11 (m, 9H, (CH2)2CH(CH2)2), and 0.87 (s, 9H, t-C4H9)
ppm. Anal. Calcd. for C22H28N2O2S (384.54): C, 68.72; H,
7.34; N, 7.28; Found: C, 68.81; H, 7.35; N, 7.30.
2-[4-(4-Chlorophenyl)thiazol-2-yl]-1-oxaspiro[2.5]octane-2-
carboxamide (7e). This compound was obtained as colorless
crystals, yield 84% (method A) or 97% (method B), mp 181–
182ꢂC (EtOH/acetone ¼ 1:1); IR (nujol): m ¼ 3365 (NH2 amide),
1645 (C¼¼Oamide) cmꢁ1
;
1H-NMR (400 MHz, DMSO-d6): d ¼
¨
[14] (a) Adam, W.; Hadjiarapoglou, L.; Jager, V.; Seidel, B.
7.96 (m, 3 H, signals overlapped: d, 2 H, Ar, J ¼ 8.5 Hz, and s,
thiazolyl C(5)H), 7.60 (br s, 1 H, CONH2), 7.39 (m, 3 H, signals
overlapped: d, 2 H, Ar, J ¼ 8.5 Hz, and s, 1 H, CONH2), 1.75
(m, 4 H, 2 CH2), and 1.51 (m, 6 H, (CH2)3) ppm. Anal. Calcd.
for C17H17ClN2O2S (348.85): C, 58.53; H, 4.91; N, 8.03; Found:
58.60; H, 4.90; N, 8.05.
Tetrahedron Lett 1989, 30, 4223; (b) Adam, W.; Hadjiarapoglou, L.;
Nestler, B. Tetrahedron Lett 1990, 31, 331; (c) Adam, W.; Hadjiarapo-
glou, L. Chem Ber 1990, 123, 2077; (d) Adam, W.; Hadjiarapoglou,
L.; Smerz, A. Chem Ber 1991, 124, 227.
[15] (a) Adam, W.; Curci, R.; Edwards, J. O. Acc Chem Res
1989, 22, 205; (b) Adam, W.; Hadjiarapoglou, L.; Curci, R.; Mello, R.
In Organic Peroxides; Ando, W., Ed.; Wiley: West Sussex, UK, 1992;
p 195.
2-[4-(4-Bromophenyl)thiazol-2-yl]-1-oxaspiro[2.5]octane-2-
carboxamide (7f). This compound was obtained as colorless
crystals, yield 90% (method A) or ꢃ100% (method B), mp 211–
213ꢂC (EtOH/acetone ¼ 1:1); IR (nujol): m ¼ 3375 (NH2 amide),
[16] Cope, A. C.; Burton, P. E. J Am Chem Soc 1960, 82, 5439.
[17] Sevin, A.; Dense, O. Bull Chim Soc Fr 1974, 5/6 (Part 2),
963.
1630 (C¼¼Oamide) cmꢁ1
;
1H-NMR (400 MHz, DMSO-d6): d ¼
7.95 (s, 1 H, thiazolyl C(5)H), 7.89 (d, 2 H, arom. C(2)H,
C(6)H, J ¼ 8.5 Hz), 7.58 (br s, 1 H, CONH2), 7.52 (d, 2 H,
arom. C(3)H, C(5)H, J ¼ 8.5 Hz), 7.35 (br s, 1 H, CONH2),
1.74 (m, 4 H, 2 CH2), and 1.50 (m, 6 H, (CH2)3) ppm. Anal.
Calcd. for C17H17BrN2O2S (393.31): C, 51.92; H, 4.36; N, 7.12;
Found: C, 52.00; H, 4.35; N, 7.10.
[18] (a) Knorr, R.; Freudenreich, J.; von Roman, Th.; Mehl-
staeubl, J.; Boehrer, P. Tetrahedron 1993, 49, 8837; (b) Fringuelli, F.;
Germani, R.; Pizzo, F.; Savelli, G. Tetrahedron Lett 1989, 30, 1427.
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3533.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
The Radziszewski Oxidation of Cycloalkylidene-a-(thiazol-2-yl)acetonitriles:
A New Approach Toward Spirooxiranes
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet