Mechanism of dehydration of 2-CH2R-and 2-CHR2-4- hydroxy-Δ2-thiazolines as intermediates in the Hantzsch thiazole synthesis and factors impeding the synthesis of 2-Me-, 2-Ar-, and 2-Het-substituted thiazoles and thiazolo[5,4-b]indoles

Article abstract of DOI:10.1007/s11172-007-0220-z

Based on the results of studies of the deuterium exchange and dehydration of 4-hydroxy-Δ²-thiazolines and 2-R-4-acetyl-8b-hydroxy-3a,8b- dihydro-4H-thiazolo[5,4-b]indoles containing the α-methylene (methine) unit at the C(2) atom, the mechanism of dehydration of these compounds generated as intermediates in the Hantzsch synthesis of thiazoles and 2-R-4-acetyl-4H-thiazolo[5,4-b]indoles was proposed. This mechanism includes an additional step of the formation of the corresponding Δ³- thiazolines. According to the results of quantum chemical calculations, this is energetically more favorable than the dehydration in terms of the commonly accepted mechanism. In some cases, an acidic medium impedes the dehydration of 4-hydroxy-Δ²-thiazolines or their cyclic analogs. The proposed mechanism provides an explanation for the empirical data on the differences in the reactivities of both thioamides and α-haloketones, which have remained unexplained in terms of the commonly accepted mechanism. The spontaneous thiazole synthesis is virtually impossible starting from thioamides of aromatic or heteroaromatic acids and α-haloketones bearing electron-withdrawing α substituents or cyclic bromoindoxyl-type haloketones. In the thiazole synthesis from these starting components, it is expedient to perform dehydration under basic catalysis.

Full text of DOI:10.1007/s11172-007-0220-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 7, pp. 1447—1455, July, 2007
1447
Mechanism of dehydration
2
of 2ꢀCH Rꢀ and 2ꢀCHR ꢀ4ꢀhydroxyꢀ∆ ꢀthiazolines as intermediates
2
2
in the Hantzsch thiazole synthesis and factors impeding
the synthesis of 2ꢀMeꢀ, 2ꢀArꢀ, and 2ꢀHetꢀsubstituted thiazoles
and thiazolo[5,4ꢀb]indoles
a
a
b
b
b
bꢀ
A. Yu. Lepeshkin, K. F. Turchin, E. G. Gal´pern, I. V. Stankevich, K. A. Lyssenko, and V. S. Velezheva
aCenter for Drug Chemistry, AllꢀRussian Chemical and Pharmaceutical Research Institute,
7
Zubovskaya ul., 119815 Moscow, Russian Federation.
Fax: +7 (495) 246 7805
b
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
2
8 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 9333. Eꢀmail: vel@ineos.ac.ru
Based on the results of studies of the deuterium exchange and dehydration of 4ꢀhydroxyꢀ
ꢀthiazolines and 2ꢀRꢀ4ꢀacetylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazolo[5,4ꢀb]indoles conꢀ
∆2
taining the αꢀmethylene (methine) unit at the C(2) atom, the mechanism of dehydration of
these compounds generated as intermediates in the Hantzsch synthesis of thiazoles and
2
ꢀRꢀ4ꢀacetylꢀ4Hꢀthiazolo[5,4ꢀb]indoles was proposed. This mechanism includes an additional
3
step of the formation of the corresponding ∆ ꢀthiazolines. According to the results of quantum
chemical calculations, this is energetically more favorable than the dehydration in terms of the
commonly accepted mechanism. In some cases, an acidic medium impedes the dehydration of
2
4
ꢀhydroxyꢀ∆ ꢀthiazolines or their cyclic analogs. The proposed mechanism provides an explaꢀ
nation for the empirical data on the differences in the reactivities of both thioamides and
αꢀhaloketones, which have remained unexplained in terms of the commonly accepted mechaꢀ
nism. The spontaneous thiazole synthesis is virtually impossible starting from thioamides of
aromatic or heteroaromatic acids and αꢀhaloketones bearing electronꢀwithdrawing α´ subꢀ
stituents or cyclic bromoindoxylꢀtype haloketones. In the thiazole synthesis from these starting
components, it is expedient to perform dehydration under basic catalysis.
Key words: thiazoles, 2ꢀRꢀthiazolo[5,4ꢀb]indoles, Hantzsch reaction, deuterium exchange,
2
4
ꢀhydroxyꢀ∆ ꢀthiazolines, 2ꢀRꢀ4ꢀacetylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazolo[5,4ꢀb]indoles,
3
dehydration, ∆ −thiazolines, isomerization, cations, quantum chemical calculations, DTFꢀPBE.
1
tions.4,5 The Me, Ar, and Het substituents at position 2 of
the hydroxythiazoline ring impede or completely inhibit
the dehydration, whereas substituents containing the
αꢀmethylene (methine) unit at the C(2) atom substanꢀ
tially facilitate the reaction. The aboveꢀconsidered data
cannot be explained in terms of the commonly accepted
mechanism of the Hantzsch reaction.6
It is reasonable to expect that the scope of this reacꢀ
tion would be broadened if one will answer the questions
as to why the dehydration of intermediate hydroxy comꢀ
pounds is the rateꢀdetermining step in the thiazole synꢀ
thesis only in some cases and whether it is possible, based
on the nature of the substituents at the C(2) atom of the
hydroxythiazoline ring, to know in advance whether the
dehydration will be spontaneous or it will require special
conditions. For this purpose, we investigated the distinꢀ
In our previous publication, it has been shown that
the structures of αꢀhaloketones and thioamides have a
substantial effect on the course of the Hantzsch reaction
(
the importance of this reaction in modern studies was
considered in the publication ) and, in some cases, enꢀ
sure complete inhibition of the thiazole synthesis. Howꢀ
ever, the factors responsible for the abnormal course of
2
3
,7
2
this reaction, which produces 4ꢀhydroxyꢀ∆ ꢀthiazolines
or 4ꢀacetylꢀ2ꢀRꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazoꢀ
lo[5,4ꢀb]indoles instead of thiazoles or 2ꢀRꢀ4ꢀacetylꢀ4Hꢀ
thiazolo[5,4ꢀb]indoles (Hantzsch reaction products) from
some αꢀhaloketones and thioamides, remain unclear. It is
2
known that not nearly all 4ꢀhydroxyꢀ∆ ꢀthiazolines or
their heterocyclic analogs, which are intermediates in the
thiazole synthesis, can undergo dehydration under these
reaction conditions or even under more drastic condiꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1394—1402, July, 2007.
066ꢀ5285/07/5607ꢀ1447 © 2007 Springer Science+Business Media, Inc.
1

1448
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
guishing features of the mechanism (the soꢀcalled gross
percentage of dideuterated compound 2b(D2) was calcuꢀ
lated as the difference between 100% and the total perꢀ
centage of 2b and 2b(D1). Special experiments showed
that the deuterium exchange of the methyl and methylene
8
a
mechanism according to March ) of dehydration of inꢀ
2
termediate 4ꢀhydroxyꢀ∆ ꢀthiazolines and 2ꢀRꢀ4ꢀacetylꢀ
8
bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazolo[5,4ꢀb]indoles
containing various substituents at position 2 of the
hydroxythiazoline ring. Apparently, the question about
the influence of the nature of substituents (2ꢀCH3,
protons of the 2ꢀCH R groups in thiazoles 2a,b,e in a
2
DMSOꢀd —CD OD—D O—DCl solution at ~20 °C
6
3
2
for 1 h is negligible.
2
ꢀCH R, and 2ꢀCHR ) reduces to the question about the
2 2
prototropic transformations of the protons in these subꢀ
stituents. To tackle this question, we monitored the deuꢀ
terium exchange in 2ꢀmethylꢀ and 2ꢀbenzylhydroxyꢀ
thiazolines, their indole analogs, and the dehydration
Scheme 1
1
products of the latter by H NMR spectroscopy and mass
spectrometry. In addition, we studied the pathway of deꢀ
hydration of intermediate hydroxy compounds, which difꢀ
fer in the nature of the substituents at positions 2, 4, and 5
of the hydroxythiazoline ring, under standard and milder
conditions. We investigated 2ꢀmethylꢀ and 2ꢀbenzylꢀ4ꢀ
2
hydroxyꢀ∆ ꢀthiazolines 1a—c, 4ꢀacetylꢀ8bꢀhydroxyꢀ2ꢀ
methylꢀ3a,8bꢀdihydroꢀ4Hꢀthiazolo[5,4ꢀb]indole (1d),
and 4ꢀacetylꢀ2ꢀbenzylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀ
thiazolo[5,4ꢀb]indole hydrobromide (1e) as intermediꢀ
ates in the synthesis of the corresponding thiazoles 2a—c
and thiazolo[5,4ꢀb]indoles 2d,e.
Upon dissolution in DMSOꢀd —CD OD (5 : 1, v/v),
6
3
hydroxy compounds 1a,e remain unchanged, which alꢀ
lowed the estimation of the deuterium exchange rate in
each case. The deuterium exchange of both methylene
1
: R = H (a, d), Ph (b, e); n = 0 (d), 1 (e)
protons of the CH Ph group in hydrobromide 1e was
2
In
the
course
of
dissolution
in
the
found to occur in solution rather rapidly to form diꢀ
DMSOꢀd —CD OD—D O—DCl system used for the
deuterated (2ꢀCD Ph) hydrobromide 3 (see Scheme 1);
6
3
2
2
monitoring, hydroxythiazoline 1b was transformed into
thiazoles 2b, 2b(D1), and 2b(D2) (Scheme 1). The ratio
between monodeuterated, dideuterated, and nondeuꢀ
terated thiazoles 2b(D1) : 2b(D2) : 2b was ~55 : 10 : 35. At
the same time, it should be taken into account that the
deuterium exchange can be influenced by water that is
eliminated upon dehydration and is present in deuterated
solvents. The degree of deuterium exchange was deterꢀ
mined by comparing the integrated intensities of the sigꢀ
the halfꢀexchange time was ~10 min. No signals of the
dehydration product were observed in the NMR specꢀ
trum of deuterated derivative 3 upon storage of this soluꢀ
tion for 1—2 h.
Unlike compound 1e, hydroxythiazoline 1a
is
subjected
to
dehydration
in
a
DMSOꢀd —CD OD—D O—DCl solution to give thiꢀ
6
3
2
azole 2a; the halfꢀlife period was approximately equal to
15 min. In the course of the complete transformation of
hydroxythiazoline 1a into thiazole 2a, ~3.5% of the total
amount of the protons in the Me groups were subjected to
the deuterium exchange. An analysis of these results
showed that, under the experimental conditions in an
nals for the protons of the 2ꢀCH and 2ꢀCHD groups with
2
the constant integrated intensities of the signals for the
1
aromatic protons in the H NMR spectra of compounds
2
a, 2b, and 1e (6 H, 11 H, and 9 H, respectively). The

2
Dehydration of hydroxyꢀ∆ ꢀthiazolines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1449
acidic medium, the rate of deuterium exchange of the
in particular, by an increase in the duration of dehydraꢀ
tion of 2ꢀmethylhydroxythiazoline 1a by more than an
order of magnitude compared to the dehydration of
2ꢀbenzylhydroxythiazoline 1b.
A comparison of the results of the deuterium exchange
and dehydration of hydroxy compounds 1a,b,e in an acidic
medium showed that 2ꢀbenzylhydroxythiazoline 1b is
characterized by a high rate of the deuterium exchange of
protons in the 2ꢀCH R substituent substantially depends
2
on the nature of this substituent (R = H or Ph in hydroxy
compounds 1a and 1b,e, respectively). It was also found
that the rate of deuterium exchange in 2ꢀbenzylꢀsubstiꢀ
tuted hydroxy compounds 1b,e is substantially higher than
that in 2ꢀmethylꢀ4ꢀhydroxythiazoline 1a.
In addition, we compared the dehydration rates
under analogous conditions (Scheme 2) for 2ꢀmethylꢀ
substituted compounds 1a,d, on the one hand, and
protons in the 2ꢀCH R substituent and an exceptionally
2
high rate of dehydration giving rise to thiazole. 2ꢀBenzylꢀ
hydroxydihydrothiazoloindole 1e, in which the deuterium
exchange of methylene protons occurs at a high rate, is
also subjected to dehydration to give thiazoloindole, alꢀ
though the duration of its dehydration is greater than that
observed in the aboveꢀconsidered case. 2ꢀMethylhydroxyꢀ
thiazoline 1a is characterized by a low rate of the deuteꢀ
rium exchange of methyl protons. However, according to
our data, compound 1a is rather easily dehydrated in an
acidic medium. Therefore, there are substantial differꢀ
ences in the rates of both the deuterium exchange and the
dehydration of the corresponding hydroxy compounds.
The ease of dehydration of compounds 1b,e and the high
rate of deuterium exchange of methylene protons are inꢀ
dicative of the involvement of these protons in prototropic
transformations associated, apparently, with the formaꢀ
2
ꢀCH R(CHR )ꢀhydroxy compounds 1b,c,e—g, on the
2 2
other hand.
Scheme 2
, 2 R1
R2
R3
R1 + R2
R3
1
a
1, 2
d
Ph
H
Ме
Ме
1
0
tion of the corresponding methylene bases. Compounds
having such structures, dimeric and monomeric methylꢀ
ene bases based on quaternary benzothiazolium salts, have
found wide use in the synthesis of merocarbocyanine
b
c
f
Ph
CF3
Ph
H
H
H
H
CH Ph
e
CH Ph
2
2
CH Ph
2
CH ꢀ3ꢀindolyl
2
1
1,12
g
Ph
CHPh2
dyes.
The synthesis of monomeric 2ꢀmethyleneꢀ3ꢀ
methylbenzothiazoline by the reaction of tetramethylꢀ
Hydroxy compounds 1b,e—g are subjected to dehyꢀ
dration by heating in ethanol in the presence of mineral
guanidine with 2,3ꢀdimethylbenzothiazolium pꢀtolueneꢀ
1
3
sulfonate was documented. In the presence of trace
amounts of acids, dimeric 3ꢀmethylꢀ2ꢀmethylenebenzoꢀ
thiazoline is known to exist in equilibrium with the monoꢀ
mer, and the deuterium exchange of methylene and
methine protons, respectively, occurs in these bases imꢀ
acids (HCl or HBr) for 1 min to give thiazoles 2b,f,g and
1
thiazoloindole 2e in high yields. Under analogous condiꢀ
2
tions, 2ꢀbenzylꢀ4ꢀhydroxyꢀ4ꢀtrifluoromethylꢀ∆ ꢀthiazoꢀ
line (1c) is transformed into thiazole 2c in a yield of
only 29% (according to TLC, the dehydration of hydroxyꢀ
thiazoline 1c was completed when the heating time was
1
1
mediately after the addition of D O. For comparison,
2
the deuterium exchange of protons of the C(2)H group in
3
1
increased to 15 min; the yield of thiazole was 74%).
2ꢀ(2,3ꢀdimethylbenzothiazolꢀ2ꢀyl)methyleneꢀ3ꢀmethylꢀ
benzothiazoline derived from 2,3ꢀdimethylbenzothiazoꢀ
lium methyl sulfate proceeds under more drastic condiꢀ
Under the same conditions, 2ꢀmethyldihydrohydroxyꢀ
thiazoloindole 1d is not subjected to dehydration at all.
According to the published data,2,9 2ꢀmethylhydroxyꢀ
thiazolines, which were prepared by the reactions of
thioacetamide with bromoacetophenone and trifluoroꢀ
bromoacetone, underwent dehydration under much more
drastic conditions to give thiazoles. For example, hydroxyꢀ
thiazoline 1a was transformed into 2ꢀmethylꢀ4ꢀphenylꢀ
11
tions (under the action of D O in pyridine 20 °C at 48 h).
2
According to the above data, the high rate of deuteꢀ
rium exchange in hydroxythiazoline 1b observed in an
acidic medium can be attributed to the involvement of
methylene base 4b in this process (Scheme 3). Apparꢀ
ently, under the conditions of our experiment, the correꢀ
sponding base is formed from hydroxythiazoline 1a in a
small amount due to which its contribution to the deuteꢀ
rium exchange is insignificant. Methylene bases can play
the key role in the dehydration of 2ꢀbenzylhydroxyꢀ
thiazolines 1, in particular, of 1b and 1e, as well as of the
9
thiazole (2a) by refluxing in acetic acid. We showed that
this dehydration proceeds also under milder conditions,
i
i.e., on heating of hydroxythiazoline 1a in Pr OH in the
presence of an equimolar amount of HCl for 20 min.
2
Therefore, the dehydration of 4ꢀhydroxyꢀ2ꢀmethylꢀ∆ ꢀ
1
thiazolines requires longer time than the dehydration of
previously described hydroxythiazolines 1f,g containing
2
2
ꢀbenzylꢀ4ꢀhydroxyꢀ∆ ꢀthiazolines, which is evidenced,
the methylene or methine unit at position 2. To validate

1450
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
1
Table 1. Yields, physicochemical characteristics, elemental analysis data, massꢀspectrometric data, and the results of IR and H NMR
3
spectroscopy for ∆ ꢀthiazolines 4b,f,g
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular M+
formula
IR,
ν/cm
1H NMR,
(
%)
S
–
1
δ
1
2
C
H
N
NH C=N
5ꢀH2 2ꢀСH
s, 2 H) (s, 1 H)
4ꢀPh
R (R )
(
4
4
4
b
f
58 163—165* 76.58 5.27 5.61 12.72
6.49 5.18 5.57 12.75
C H NS 251
—
1605
4.96
4.91
4.74
7.11
7.99 (d, 2 H,
J = 8.0);
7.55, 7.42
(both m,
1
6
13
7
7
.55 (m, 3 H) 2 H each);
7
.23 (m, 1 H)
11.45 (s,
NH);
49 189—191* 74.35 4.91 9.66 11.17 C H14N2S 290 3390 1615
7.33 7.96 (m, 2 H);
7.52 (m, 3 H)
1
8
7
4.48 4.83 9.66 11.03
7
.05—7.95
(
5 H, indole)
7.20—7.55
(m, 10 H)
g
51 146—149* 80.59 5.30 4.21 9.89
0.73 5.20 4.28 9.79
C22H NS 327
—
1590
—
7.91 (d, 2 H,
J = 8.0);
17
8
7
(
.20—7.55
m, 3 H)
*
With decomposition.
this hypothesis, we performed the dehydration of
ꢀCH R(2ꢀCHR )ꢀhydroxythiazolines 1b,f,g under
milder conditions than those required for their transforꢀ
C(15)
C(12)
C(9)
2
2
2
C(14)
C(16)
C(17)
C(6)
C(11)
C(10)
N(3)
C(2)
mation into thiazoles. As expected, hydroxythiazolines
C(13)
3
C(7)
C(8)
1
b,f,g were transformed into ∆ ꢀthiazolines 4b,f,g in
C(4)
C(5)
49—58% yields upon their storage in dioxane with an
S(1)
C(18)
equimolar amount of acetic acid at 20 °C for 12 h
method A) (Table 1, see Scheme 3). According to TLC,
(
the reaction mixture contained also small amounts of thiꢀ
azoles 2b,f,g.
Fig. 1. Overall view of molecule 4b represented by displacement
ellipsoids (p = 50%).
Scheme 3
group P2 with two independent molecules per asymmetꢀ
1
ric unit. In the crystal, both molecules are planar and
have the Z configuration. It should be noted that one of
the independent molecules exists as a superposition of
two Z isomers, which are related by a pseudocenter of
symmetry lying on the N(3)—C(4) bond. The presence of
this disorder and, as a consequence, the weak reflection
ability of the crystal do not allow the detailed analysis of
the molecular geometry and the crystal packing.
2
1
4:
R1 = Ph, R = H (b); R = 3ꢀindolyl, R2 = H (f),
R
1
2
= R = Ph (g)
∆3
ꢀThiazoline 4b can also be synthesized in 67% yield
by the reaction of bromoacetophenone with thioamide of
∆ ꢀThiazolines 4b,f,g are, in turn, easily subjected to
3
i
isomerization into thiazoles 2b,f,g by heating in Pr OH in
phenylacetic acid and triethylamine in Me CO at ~20 °C
the presence of an equimolar amount of HCl over a short
period of time. The isomerization product is formed in a
virtually quantitative yield. Under the same conditions,
hydroxythiazolines 1a,c and hydrobromide 1e are transꢀ
formed into thiazoles 2a,c and thiazoloindole 2e, respecꢀ
tively (TLC data), but at a substantially lower rate.
2
for 8 h without the isolation of intermediate hydroxyꢀ
3
thiazoline 1b (method B). In addition, ∆ ꢀthiazoline 4b
can be prepared from hydroxythiazoline 1b by the reꢀ
action with a suspension of Et NH•HCl in Me CO
2
2
1
13
(
method C). The H and C NMR spectroscopic data
show that ∆ ꢀthiazolines 4b,f,g are formed as a single
geometric isomer. Compound 4b has a Z configuration
3
The study of the rate of deuteration of methylene base
4b in a DMSOꢀd —CD OD—DCl—D O solution in an
6
3
2
(
Xꢀray diffraction data).
NMR tube showed that the deuteration proceeds already
in the course of dissolution of the sample, which is acꢀ
companied by the transformation of ∆ ꢀthiazoline 4b into
The Xꢀray diffraction structure of molecule 4b is shown
3
in Fig. 1. Compound 4b crystallizes in the chiral space

2
Dehydration of hydroxyꢀ∆ ꢀthiazolines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1451
a mixture of monodeuterated, dideuterated, and nonꢀ
deuterated thiazoles 2b(D1), 2b(D2), and 2b (Scheme 4).
Table 2. Percentage of thiazoles 2b, 2b(D1), and 2b(D2)
in a mixture prepared by dehydration of hydroxythiazoline
3
1
b
(A) or isomerization of ∆ ꢀthiazoline 4b in the
C H OD—C H OH—D O—DCl system (B) determined by
2
5
2
5
2
1
Scheme 4
H NMR spectroscopy (I) and mass spectrometry (II)
Thiazole Molecular
formula
M+
Fraction (%)
A
B
I
II
I
II
2
2
2
b
C H NS
251
39
50
11
41
50
9
20
72
8
24
69
7
1
6
13
b(D1) C DH NS 252
b(D2) C D H NS 253
1
6
12
1
6
2
11
appeared to be similar to the data obtained when this
reaction was performed in an NMR tube (see Scheme 1).
3
The fact that the deuteration of ∆ ꢀthiazoline 4b affords
monoꢀ and dideuterated thiazoles 2b(D1) and 2b(D2) apꢀ
3
parently indicates that ∆ ꢀthiazoline 4b exists in an acidic
3
medium in equilibrium with monodeuterated ∆ ꢀthiazoꢀ
line 5, which undergoes isomerization after the attachꢀ
ment of a deuteron to give dideuterated thiazole 2b(D2)
(
see Scheme 4). By analogy, it can be suggested that
monodeuterated methylene base 6 is involved in the forꢀ
mation of dideuterated compound 3. Since compound 3
remains nondehydrated under the experimental condiꢀ
tions, it is clear that the deuteration rate is much higher
than the dehydration rate (see Schemes 1 and 4).
In addition, we performed the following two reactions
accompanied by the deuterium exchange: the dehydraꢀ
tion of 2ꢀbenzylꢀ4ꢀhydroxyꢀ4ꢀphenylꢀ∆ ꢀthiazoline (1b)
Therefore, thiazoles 2b,f,g are generated from both
2
3
hydroxythiazolines 1b,f,g and ∆ ꢀthiazolines 4b,f,g.
giving a mixture of thiazoles 2b, 2b(D1), and 2b(D2) and
the isomerization of 2ꢀbenzylideneꢀ4ꢀphenylꢀ∆ ꢀthiazoꢀ
line (4b), which also produces a mixture of the aboveꢀ
mentioned thiazoles. Both reactions were carried out unꢀ
der virtually the same conditions by heating the starting
compounds in a 9 : 1 EtOD—EtOH solution containing
Hence, the latter can be considered as intermediates in
the thiazole synthesis from αꢀhaloketones and thioamides
containing the αꢀmethylene (methine) unit. The results
of deuteration of compound 1e suggest that, in an acidic
medium, this compound initially undergoes isomerizaꢀ
tion into the corresponding methylene base, which is subꢀ
3
3
an equimolar amount of DCl in D O over a short period
jected to dehydration giving rise to ∆ ꢀthiazoline followed
2
of time. Crystalline mixtures of deuterated and nonꢀ
deuterated products were isolated after the treatment of
by isomerization of the latter into thiazoloindole 2e.
These results cannot be interpreted in terms of the
classical mechanism of the Hantzsch reaction, which inꢀ
volves the formation and dehydration of intermediate
the reaction mixture with aqueous NH to pH = 8. This
3
allowed the comparison of the yields of products with
different degrees of deuteration obtained in both reacꢀ
tions. The percentage of each product determined by
1
4
hydroxythiazolines 1 (Scheme 5). It is assumed that the
Oꢀprotonated form of hydroxythiazoline 7 undergoes deꢀ
hydration followed by elimination of the proton from
position 5, the reaction medium turning acidic as a result
1
H NMR spectroscopy and mass spectrometry (Table 2)
was similar in both reactions. As can be seen from Table 2,
1
4
both the dehydration of hydroxythiazoline 1b and the
of elimination of 1 equiv. of hydrogen halide.
3
isomerization of ∆ ꢀthiazoline 4b afford the same comꢀ
This mechanism provides an explanation for the relaꢀ
tionship between the structure of the starting αꢀhaloketone
and the ease of dehydration of hydroxythiazoline derived
from the starting compound. The fact that 4ꢀhydroxyꢀ2ꢀ
pounds 2b, 2b(D1), and 2b(D2) but in different ratios.
The dehydration gives approximately 60% of deuterated
thiazoles and 40% nondeuterated thiazole, whereas the
3
2
isomerization of ∆ ꢀthiazoline 4b affords the same prodꢀ
methylꢀ4ꢀtrifluoromethylꢀ∆ ꢀthiazoline and dihydroꢀ
ucts in 80 and 20% yields, respectively (see Table 2). It
should be noted that the aboveꢀgiven compositions of the
mixtures of dehydration products of hydroxythiazoline 1b
hydroxythiazoloindole 1d are difficult to subject to deꢀ
hydration can be explained in terms of the hindered catꢀ
ion mechanism of dehydration of tertiary alcohols. The

1452
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
Scheme 5
Scheme 6
dehydration of these compounds should afford relatively
unstable cations 8, which are destabilized by the elecꢀ
tronic (R1 = CF ) or steric effect of the substituent
3
1
2
(
R + R =
, see Scheme 5). The hindered
elimination in ring systems according to Bredt's rule8b is
attributed to instability of intermediate cyclic cations of
type 8. However, the classical mechanism does not take
into account the influence of the nature of the substituent
of cation 10a would be energetically less favorable by
–
1
~
5 kcal mol .
3
R at position 2 of hydroxythiazolines 1 on the ease of
their dehydration and does not explain why the dehydraꢀ
tion of compounds 1b,c,e—g giving rise to thiazoles proꢀ
ceeds much more easily than the dehydration of comꢀ
pounds 1a,d.
The exceptional ease of dehydration of
,10: R = Ph, R = H (a), R1 = Ph, R2 =Ph (b),
1
2
8
2
ꢀCH R(2ꢀCHR )ꢀ4ꢀhydroxythiazolines and their anaꢀ
R1 = CF , R2 = Ph (c)
2
2
3
logs can be explained in terms of the following mechaꢀ
nism using compound 1b as an example.
Therefore, the results of calculations confirm the proꢀ
In an acidic medium, the starting hydroxythiazoline
exists in equilibrium with classical hydroxonium cation
posed mechanism of dehydration of 2ꢀRCH (2ꢀR CH)ꢀ
4ꢀhydroxythiazolines.
2 2
7
b (see the classical mechanism of dehydration, Scheme 5)
Since the yields of the deuterated products in the
isomerization of ∆ ꢀthiazoline 4b appeared to be higher
3
and enamine hydroxonium cation 9b. The latter is transꢀ
formed into ∆ ꢀthiazoline 4b accompanied by elimination
of hydroxonium (Scheme 6). It should be noted that the
proton of the thiazole nitrogen atom, which is more acidic
than the proton at the C(5) atom, is involved in eliminaꢀ
tion of hydroxonium. The subsequent protonation and
3
than those in the transformation of hydroxythiazoline 1b
into thiazole 2b (see Table 2), it cannot be ruled out that
the latter process is accompanied by the partial dehydraꢀ
tion of the starting hydroxythiazoline according to the
classical mechanism. At the same time, this fact can be
attributed to other factors, for example, to those accountꢀ
ing for the influence of the reaction conditions, including
the presence of water.
3
deprotonation of ∆ ꢀthiazoline 4b afford the final thiꢀ
azole. Therefore, the dehydration of 2ꢀCH Ph(CHPh )ꢀ
2
2
4
ꢀhydroxythiazolines produces azadiene cations of type
3
1
0b, which are isomeric with cations 8 and are more stable
Since the formation of ∆ ꢀthiazolines from 4ꢀhydroxyꢀ
2
than the latter. This is also consistent with the data on the
deuterium exchange in compounds 1b,e, in which the
deuterium exchange occurs at a higher rate than that in
∆ ꢀthiazolines facilitates dehydration of the latter, the
spontaneous Hantzsch reaction of αꢀhaloketones with
thioamides containing the αꢀmethylene (methine) unit is,
3
4ꢀhydroxyꢀ2ꢀmethylthiazoline 1a.
apparently, attributed to the involvement of ∆ ꢀthiazolines
The calculations for isomeric cations 10b and 10c, 8b
and 8c by the DFTꢀPBE method showed that the former
in this process. The mechanism of isomerization of
∆ ꢀthiazolines calls for a special investigation. It should
3
cations are more stable than the latter by ~9 and
3
be taken into account that such methylene bases rapidly
and reversibly bind these reagents at the exocyclic C=C
kcal mol–1, respectively. To the contrary, the formation

2
Dehydration of hydroxyꢀ∆ ꢀthiazolines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1453
3
bond in the presence of water, alcohols, hydrogen haꢀ
lides, etc.12
2ꢀ(R R C=)ꢀ and 2ꢀ(RN=)ꢀ4ꢀphenylꢀ∆ ꢀthiazolines,
1 2
both thioamides containing the 2ꢀRCH (2ꢀR CH) subꢀ
2
2
The scope of the proposed mechanism of dehydration
of hydroxythiazolines would be extended to hydroxyꢀ
thiazolines containing the αꢀmethylene (methine) unit at
position 2, in which the substituents can stabilize the
resulting azadiene cations of type 10. In particular,
hydroxythiazolines, which we have synthesized by the
reaction of haloketones with thioamides of phenylacetic,
stituents and thioureas can be spontaneously transformed
into thiazoles in the Hantzsch reactions with αꢀhaloꢀ
ketones having various structures under the standard conꢀ
ditions. To the contrary, the spontaneous thiazole synꢀ
thesis is impossible using the reactions of thioamides of
aromatic or heteroaromatic acids or thioacetamide, on
the one hand, with αꢀhaloketones containing electronꢀ
withdrawing α´ꢀsubstituents or bromoindoxylꢀtype cyclic
αꢀhaloketones, on the other hand. In the latter case, thiꢀ
3
ꢀindolylacetic, diphenylacetic, cyanoacetic, and 3ꢀpheꢀ
1
,5
nylpropionic acids, satisfy this condition. To the conꢀ
trary, only the classical mechanism of dehydration acꢀ
companied by elimination of the proton from position 5 is
1
azoles can be synthesized only in two steps. If an
acidic medium impedes the dehydration of intermediates
2
2
possible for 2ꢀaryl(hetaryl)ꢀsubstituted 4ꢀhydroxyꢀ∆ ꢀ
(4ꢀhydroxyꢀ∆ ꢀthiazolines or their cyclic analogs), it is
thiazolines, which undergo dehydration in an acidic meꢀ
dium only under relatively drastic conditions. Evidently,
the reactions of 2ꢀmethylhydroxythiazolines, from which
methylene bases are difficult to synthesize, also proceed
by this mechanism (see the data on the deuterium exꢀ
change and the results of quantum chemical calculations).
The proposed mechanism provides an explanation for
expedient to perform this step under basic catalysis.
To summarize, the proposed mechanism provides an
explanation for the empirical data on the difference in the
reactivities of thioamides and αꢀhaloketones, which have
remained unexplained in terms of the commonly accepted
mechanism of the Hantzsch reaction. The results of the
present study ensure the prerequisites for broadening the
scope of this reaction. Stable methylene bases, viz.,
4
the earlier observed ease of formation of 2ꢀaminothiazoles
3
from α,α,αꢀtrifluoroꢀα´ꢀbromoacetone and thiourea or
phenylthiourea (Scheme 7). Apparently, the transformaꢀ
tion of immonium cations 11 and 12 into conjugated
immonium cations 13 (aza analogs of cation 10, see
Scheme 6) is the key step of dehydration. The final step of
the process involves the isomerization of cations 13 into
2ꢀRꢀmethyleneꢀ∆ ꢀthiazolines, described in the present
study are of interest for the synthesis of thiazoles funcꢀ
tionalized at position 2. In addition, these compounds
can find application as sensitizers, dyes, and fluorescent
1
5,16
labels for biomolecules.
2
ꢀaminothiazoles.
Experimental
Scheme 7
The elemental analysis for C, H, N, S was carried out on an
EAꢀ1108 analyzer (CHNS/O, TDK detector). The NMR specꢀ
tra were measured on a Varian Unity+400 spectrometer
1
13
(
400 MHz for H and 100.6 MHz for C) in DMSOꢀd6 or
CDCl3 using the signal of the residual protons of the solvent
δ 2.49) and the signal of the carbon atoms of the solvent (δ 39.6
(
1
13
and 76.9) as the internal standard for the H NMR and C NMR
spectra, respectively. The deuterium exchange in 2ꢀmethylꢀ and
2
ꢀbenzylꢀ4ꢀhydroxythiazolines 1a,b,e and in the dehydration
products of the latter, viz., thiazoles 2a,b,e, was studied by
1
H NMR spectroscopy at 20 °C in a DMSOꢀd —CD OD soluꢀ
6
3
tion (1 : 5, v/v, in the case of hydrobromide 1e) and in DMSOꢀd6
with the addition of a CD OD—D O—DCl mixture (in the case
3
2
of hydroxythiazolines 1a,b and thiazoles 2a,b,e). The water conꢀ
tent in the solvents was at most 0.5%. The transformations of
hydroxythiazolines 1a,b were monitored in DMSOꢀd with the
6
addition of a 3 : 2 : 1 CD OD—D O—DCl mixture (1/3 v/v).
3
2
The mass spectra were obtained on a Finnigan SSQꢀ710 instruꢀ
ment using the direct injection of samples into the ion source
(
the ionizing electron energy was 70 eV, the temperature of the
ionization chamber was 150 °C, samples were heated to 350 °C,
the heating rate was 163 deg min– ). The percentage of thiazoles
1
Based on the aboveꢀdescribed two mechanisms of deꢀ
2
b, 2b(D1), and 2b(D2) was calculated based on the mass specꢀ
2
hydration of 4ꢀhydroxyꢀ∆ ꢀthiazolines, the optimal reacꢀ
tion conditions can be chosen and the optimal approach
to the thiazole synthesis can be designed. Since the sponꢀ
taneous thiazole synthesis involves the formation of
trometric data taking into account the intensities of the peaks
17
for each of these thiazoles. The IR spectra were recorded on a
Perkin—Elmer 457 instrument (Nujol mulls). The calculations
for cations 8a—c and 10a—c were carried out by the DFT method

1454
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
with the use of the PBE exchangeꢀcorrelation potential.18 The
total energies were calculated both with and without the zeroꢀ
point energy correction. The tripleꢀzeta (TZ) basis set was used
for the sulfur atom, and the doubleꢀzeta (DZ) basis set was used
for all other atoms.19 The character of stationary points was
estimated from the number of negative eigenvalues of the
Gaussian. The calculations were performed with the use of the
PRIRODA program (version 1.10). The course of the reacꢀ
tions and the purity of the compounds were monitored by TLC
on Silufol UVꢀ254 plates (before chromatography of compounds
(d, C(3´), C(5´));* (d, C(2″), C(6″));* (d, C(3″), C(5″));*
1
1
131.36 ( J
= 161.4 Hz); 126.49 ( J
= 162.5 Hz):
C,H
C,H
(d, C(4´));* (d, C(4″)).*
Method C. Triethylamine hydrochloride (1.10 g, 10 mmol)
was added to acetone (20 mL). The suspension was refluxed for
10 min and cooled to 20 °C. Compound 1b (2.69 g, 10 mmol)
was added to the reaction mixture. The mixture was stirred at
20 °C for 12 h and diluted with water (10 mL). The product was
isolated and purified according to the method B. Compound 4b
was obtained in a yield of 1.51 g (60%).
2
0
1
3
4
b,f,g, the plates were kept in Et N vapor for 3 min) using a
4ꢀR ꢀ2ꢀR ꢀThiazoles 2b,f,g (general procedure). A solution
3
of HCl (d = 1.18 g cm– ; 0.9 mL, 10 mmol) in Pr OH (7 mL)
1
i
2
0 : 1 : 3 chloroform—acetone—hexane mixture as the eluent;
3
the visualization was carried out with UV light and iodine vapor.
The melting points and the results of IR spectroscopy, mass
was added to a boiling solution of the corresponding ∆ ꢀthiazoline
4b,f,g (10 mmol) in Pr OH (50 mL). The reaction solution was
i
1
spectrometry, and H NMR spectroscopy for compounds 2a—g
refluxed for 1 min, neutralized with aqueous NH to pH = 8,
3
are consistent with those published earlier.1
,21
The starting
and concentrated in vacuo. The residue was recrystallized from
i
thiazolines 1a—g were synthesized according to a known proceꢀ
dure.1
aqueous Pr OH. The yields of compounds 2b, 2f, and 2g (see
Ref. 1) were 2.38 g (95%), 2.61 g (90%), and 3.01 g (92%),
respectively.
2
ꢀBenzylꢀ4ꢀtrifluoromethylthiazole (2c). A mixture of
∆2
.18 g cm ) HCl (0.45 mL, 5 mmol) in Pr OH (15 mL) was
ꢀhydroxythiazoline 1c (1.31 g, 5 mmol) and concentrated (d =
Thiazoles 2b, 2b(D1), and 2b(D2).** A solution of 6.1 M
–
1
i
1
DCl (0.36 г 2.42 mmol) in D O was added to a 9 : 1
2
refluxed for 1 min. Aqueous NH3 was added to the reaction
mixture to pH = 8. The reaction solution was cooled and conꢀ
C H OD—C H OH mixture (7 mL). The reaction solution was
heated to 75 °C, and then ∆ ꢀhydroxythiazoline 1b (0.65 g,
2
5
2
5
2
centrated in vacuo. A 2 : 1 petroleum ether—Et O mixture
2.42 mmol) was added. The reaction mixture was refluxed
2
2
(
30 mL) was added to the residue. Unconsumed ∆ ꢀhydroxyꢀ
for 40 s, neutralized with aqueous NH to pH = 8, and concenꢀ
3
thiazoline 1c was filtered off, the solvent was removed in vacuo,
and water (10 mL) was added to the residue. The crystals that
precipitated were filtered off and washed with water. Compound
trated in vacuo. Water (10 mL) was added to the residue. The
crystals were filtered off and washed with water. A mixture of
compounds 2b, 2b(D1), and 2b(D2) was obtained in a yield of
c was obtained in a yield of 0.35 g (29%).1
0.57 g (93%) (see Table 2). H NMR (DMSOꢀd ), δ, a mixture
1
2
6
2
2
ꢀMethylꢀ4ꢀphenylthiazole (2a). A mixture of ∆ ꢀhydroxyꢀ
thiazoline 1a (1.93 g, 10 mmol) and concentrated (d =
of thiazoles 2b, 2b(D1), and 2b(D2): 4.382 (s, 2 H, 2ꢀCH , 2b);
2
4.363 (s, 1 H, 2ꢀCHD, 2b(D1)); 7.93 (s, 1 H, H(5), 2b, 2b(D1),
2b(D2)); 7.97 (m, 2 H, H(2″), H(6″), 2b, 2b(D1), 2b(D2));
7.25—7.45 (m, 8 H, H(2´)—H(6´), H(3″)—H(5″), 2b, 2b(D1),
–
1
i
1.18 g mL ) HCl (0.90 mL, 10 mmol) in Pr OH (20 mL) was
refluxed for 20 min. Aqueous NH was added to the reaction
3
13
mixture to pH = 8, and the reaction solution was cooled and
concentrated in vacuo. The residue was recrystallized from aqueꢀ
ous ethanol (1 : 1). Compound 2a was obtained in a yield of
2b(D2)). C NMR (DMSOꢀd ), δ, a mixture of thiazoles 2b,
6
2b(D1), and 2b(D2): 169.980 (s, C(2), 2b); 169.942 (s, C(2),
2b(D1)); 169.904 (s, C(2), 2b(D2)); 154.1 (s, C(4), 2b, 2b(D1),
2b(D2)); 138.132 (s, C(1´), 2b); 138.100 (s, C(1´), 2b(D1));
1
.35 g (77%).21
1
2
3
4
ꢀPhenylꢀ2ꢀ(R R C)ꢀ∆ ꢀthiazolines 4b,f,g. Method A. Aceꢀ
138.067 (s, C(1´), 2b(D2)); 134.2 (s, C(1″), 2b, 2b(D1), 2b(D2));
1
tic acid (0.30 g, 5 mmol) was added to a solution of the correꢀ
129.0 (d, C(2´), C(6´), J
= 158.5 Hz, 2b, 2b(D1), 2b(D2));
= 160.0 Hz, 2b, 2b(D1), 2b(D2));
C,H
2
a
1
sponding ∆ ꢀhydroxythiazoline 1b,f,g (5 mmol) in dioxane
128.7 (d, C(3´), C(5´), J
C,H
a
1
(
30 mL) at 20 °C. After 12 h, the solvent was removed in vacuo,
128.8 (d, C(3″), C(5″), J
= 160.0 Hz, 2b, 2b(D1), 2b(D2));
C,H
i
b
1
b
and Pr OH (10 mL) was added to the residue. The crystals that
formed were filtered off and washed with aqueous Pr OH (1 : 1)
126.9 (d, C(4´), J
= 161.0 Hz, 2b, 2b(D1), 2b(D2)); 127.9
(d, C(4″), JC,H = 161.0 Hz, 2b, 2b(D1), 2b(D2)); 126.1
= 160.0 Hz, 2b, 2b(D1), 2b(D2)); 114.2
(d, C(5), JC,H = 189.0 Hz, 2b, 2b(D1), 2b(D2)); 38.811 (t,
2ꢀCH2, 1JC,H = 129.7 Hz, 2b); 38.500 (t, 2ꢀCHD, JC,D
C,H
i
1
1
and water. Acetone was used for recrystallization of comꢀ
(d, C(2″), C(6″), J
C,H
i
1
pound 4b; Pr OH, for compounds 4f,g (see Table 1).
1
Method B. Triethylamine (1.01 g, 10 mmol) and phenacyl
bromide (1.99 g, 10 mmol) were successively added to a solution
of thioamide of phenylacetic acid (1.51 g, 10 mmol) in acetone
=
c
19.8 Hz, 2b(D1)) .
A mixture of compounds 2b, 2b(D1), and 2b(D2) was synꢀ
(
20 mL) at 20 °C. After 8 h, water (10 mL) was added to the
thesized analogously in a yield of 0.58 g (95%) (see Table 2) by
the reaction of 6.1 M DCl (0.36 g, 2.42 mmol) with ∆ ꢀthiazoline
3
reaction mixture, and the crystals that formed were filtered off,
washed with aqueous acetone (1 : 1) and water, and recrystalꢀ
lized from acetone. Compound 4b was obtained in a yield of
1
(
1
4b (0.61 g, 2.42 mmol) in a 9 : 1 C H OD—C H OH mixꢀ
2
5
2
5
ture (7 mL).
1
3
.68 g (67%).* C NMR (CDCl ), δ: 155.39 (s, C(2)); 168.69
3
1
s, C(4)); 44.28 (t, C(5), J
= 143.5 Hz); 119.77 (d, 2ꢀCH,
C,H
JC,H = 158.2 Hz); 136.26 (s, C(1´)); 132.95 (s, C(1″));** 128.66
* The group of signals belongs to a group of atoms.
(1
1
JC,H = 161.0 Hz); 128.41 ( J
1
= 161.0 Hz); 127.95 ( J
1
=
** The atomic numbering scheme for compounds 2b(D1) and
2b(D2) is identical to that for compound 2b (see Scheme 1).
C,H
C,H
1
60.0 Hz); 127.93 ( J
= 159.5 Hz): (d, C(2´), C(6´));**
C,H
a,b
The inverse assignment of the signals denoted by the same
*
The atomic numbering scheme for compound 4b is identical to
letters is possible.
The multiplicities and the spinꢀspin coupling constants in the
spectrum measured with full proton spinꢀspin decoupling.
c
that for compound 2b (see Scheme 1).
* The group of signals belongs to a group of atoms.
*

2
Dehydration of hydroxyꢀ∆ ꢀthiazolines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1455
Crystals of 4b (C H NS) are monoclinic at 100 K, space
5. V. S. Velezheva, A. Yu. Lepeshkin, O. A. Fedotova, V. I.
Shvedov, K. F. Turchin, A. L. Sedov, and O. S. Anisimova,
Khim.ꢀfarm. Zh., 1996, 30, No. 10, 37 [Pharm. Chem. J.,
1996, 30, 643 (Engl. Transl.)].
6. A. Tarraga, P. Molina, D. Curiel, and M. D. Velasco, Tetraꢀ
hedron Lett., 2002, 43, 8453.
16
13
group P2 , a = 7.5834(18), b = 5.7045(13), c = 28.288(8) Å,
1
3
–3
β = 91.987(7)°, V = 1223.0(5) Å , Z = 4, d
= 1.365 g cm ,
calc
µ(MoꢀKα) = 2.43 cm–1, F(000) = 528. The intensities of
048 reflections were measured at 100 K on a Smart APEX CCD
diffractometer (λ(MoꢀKα) = 0.71072 Å, ωꢀscanning technique,
θ < 54°); 4018 independent reflections were used in the refineꢀ
6
2
7. J. Rudolph, Tetrahedron, 2000, 56, 3161.
ment. The experimental data were processed and merged, and
the absorption correction was applied with the use of the
SAINT Plus complex program22 and the SADABS program.23
The structure was solved by direct methods using successive
electron density maps. The hydrogen atoms were placed geoꢀ
metrically. An analysis of the Fourier maps showed that one of
independent molecules in the crystal structure is disordered as a
result of a superposition of two identical Z isomers, which are
related by a pseudocenter of symmetry lying on the N(3)—C(4)
bond). The refined occupancies for two positions of the molꢀ
ecule are 0.4 and 0.6, the carbon atoms of the phenyl rings
coinciding for both positions. Both the analysis of the reciprocal
lattice and an attempt to perform the refinement with considerꢀ
ation for the possible twinning did not allow the change of the
space group to exclude the disorder of the molecule.
8. M. B. Smith and J. March, in March’s Advanced Organic
Chemistry. Chemistry, Reactions, Mechanisms, and Structure,
Wiley, New York—Chichester—Weinheim—Brisbane—
Singapore—Toronto, 2001, (a) p. 274; (b) p. 1314.
9. K. Arakawa, T. Miyasaka, and H. Ohtsuka, Chem. Pharm.
Bull., 1972, 20, 1041.
10. V. Velezheva, A. Lepeshkin, and K. Turchin, Programme
and Abstrs, 11th Europ. Symp. on Organic Chemistry (Goteborg,
July 23—28, 1999), Goteborg, 1999, P181.
11. J.ꢀJ. Vorsanger, Bull. Soc. Chim. Fr., 1968, 964.
12. J.ꢀJ. Vorsanger, Bull. Soc. Chim. Fr., 1968, 955.
13. J. R. Owen, Tetrahedron Lett., 1969, 32, 2709.
14. J. V. Metzger, in Comprehensive Heterocyclic Chemistry,
Eds A. R. Katritzky and C. W. Rees, Pergamon, Oxford,
UK, 1984, 6, p. 236.
15. D. M. Sturmer, in Special Topics in Heterocyclic Chemistry,
Eds A. Weissberger and E. C. Taylor, Wiley, New York—
London—Sydney—Toronto, 1977, p. 441.
The refinement was carried out based on F 2 with anisoꢀ
hkl
tropic displacement parameters for nonhydrogen atoms and isoꢀ
tropic displacement parameters for hydrogen atoms. The final
R factors for the structure of 4b were R1 = 0.0795 (calcuꢀ
lated based on Fhkl for 2516 reflections with I > 2σ(I )) and
16. B. R. Renikuntla, H. C. Rose, J. Eldo, A. S. Waggoner, and
B. A. Armidage, Org. Lett., 2004, 6, 909.
17. J. H. Beynon, Mass Spectrometry and its Application in Orꢀ
ganic Chemistry, Elsevier, Amsterdam—London—New
York—Princeton, 1960.
2
wR2 = 0.2314 (calculated based on F hkl for all 4018 reflecꢀ
tions), the number of variables was 428, GOF = 1.001. All
calculations were performed with the use of the SHELXTL 5.10
program package.24
18. J. P. Perdew, K. Burke, and M. Ernzerhof, Phys. Rev. Lett.,
1
996, 11, 3865.
9. A. Schafer, C. Huber, and R. Alhrichs, J. Chem. Phys., 1994,
00, 5829.
0. D. Laikov, Chem. Phys. Lett., 1997, 281, 151.
1. H. Singh, S. Singh, and A. S. Cheema, J. Ind. Chem. Soc.,
1976, 53, 682.
2. SMART V5.051 and SAINT V5.00, Area Detector Control and
Integration Softwave, Bruker AXS Inc., Madison, WIꢀ53719,
USA, 1998.
3. G. M. Sheldrick, SADABS, Bruker AXS Inc., Madison,
WIꢀ53719, USA SHELX, 1997.
1
We thank O. S. Anisimova for help in interpreting the
mass spectra.
1
2
2
References
2
1
2
. A. Yu. Lepeshkin, K. F. Turchin, A. L. Sedov, and V. S.
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Received July 12, 2006;
in revised form April 12, 2007