The reaction of 2-(tetrazol-5-yl)alkyl ketones and of 2-(tetrazol-5-yl)alkanoic acid derivatives with lead tetraacetate. A novel method of preparation of alk-2-ynyl ketones and alk-2-ynoic acid derivatives

Article abstract of DOI:10.1039/b005286h

The majority of tetrazolylacetyl derivatives 2 and 7, when treated with lead tetraacetate in dry 1,4-dioxane at room or lower temperature, are oxidized with elimination of molecular nitrogen mainly to the corresponding alkynoyl derivatives 4 and 8, respectively. Vinylidenes (25) have been shown to be the intermediates of the reaction. The reaction does not take place when either the tetrazolyl group is N-substituted or the carbon atom separating the tetrazolyl and the carbonyl groups is disubstituted or these two groups are separated by two carbon atoms as in compound 17. The reaction offers a convenient method for the conversion of 2-cyanoacetyl derivatives into alk-2-ynoyl derivatives via intermediate tetrazolylacetyl derivatives. The 4-methoxyanilide 7o reacts differently, affording the fused heterocyclic compounds 19o and 20o.

Full text of DOI:10.1039/b005286h

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The reaction of 2-(tetrazol-5-yl)alkyl ketones and of 2-(tetrazol-
5-yl)alkanoic acid derivatives with lead tetraacetate. A novel
method of preparation of alk-2-ynyl ketones and alk-2-ynoic
acid derivatives†
1
József Fetter,*a Ildikó Nagy,a Le Thanh Giang,a Mária Kajtár-Peredy,b Antal Rockenbauer,c
László Koreczb and Gábor Czirad
a Department of Organic Chemistry, Budapest University of Technology and Economics,‡
H-1521 Budapest, Hungary
b Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences,
H-1525 Budapest, Hungary
c Department of Physics, Budapest University of Technology and Economics, H-1521 Budapest,
Hungary
d Gedeon Richter Chemical Works, Ltd., H-1475 Budapest 10, Hungary
Received (in Cambridge, UK) 3rd July 2000, Accepted 21st February 2001
First published as an Advance Article on the web 26th March 2001
The majority of tetrazolylacetyl derivatives 2 and 7, when treated with lead tetraacetate in dry 1,4-dioxane at room
or lower temperature, are oxidized with elimination of molecular nitrogen mainly to the corresponding alkynoyl
derivatives 4 and 8, respectively. Vinylidenes (25) have been shown to be the intermediates of the reaction. The
reaction does not take place when either the tetrazolyl group is N-substituted or the carbon atom separating the
tetrazolyl and the carbonyl groups is disubstituted or these two groups are separated by two carbon atoms as in
compound 17. The reaction offers a convenient method for the conversion of 2-cyanoacetyl derivatives into
alk-2-ynoyl derivatives via intermediate tetrazolylacetyl derivatives. The 4-methoxyanilide 7o reacts differently,
affording the fused heterocyclic compounds 19o and 20o.
another. Due to the presence of two chiral centers (C2Ј and
Introduction
C2Љ) compound 5a proved to be a diastereoisomeric mixture.
The long-range coupling between the 6-H and 2Ј-H protons
(≈0.5 Hz) and the NOE effects§ resulting from selective
saturation of the 6-H and 7-H resonances (see Experimental
section) as well as the carbon–proton long-range correlations
of C5, C8, C8a and the ketone carbonyl carbon (C5 with 7-H,
6-H, 2Ј-H and 3Ј-H2; C8 with 6-H and 7-H; C8a with 7-H
and 6-H; ketone carbonyl carbon with 7-H, 2Љ-H and 3Љ-H2)
clarified the manner of the connection of the two components
of the molecule.
Compounds of type 1 (m = 0, 1), when treated with lead tetra-
acetate (LTA) in boiling 1,4-dioxane, afford fused quinoxaline
and benzodiazepine derivatives 3 (m = 0, 1).1,2 In continuation
of these studies the reactions of compounds 2a and 2b, contain-
ing tetrazolylacetyl instead of the tetrazolylalkyl groups, with
LTA were now studied. Since these compounds reacted differ-
ently to compounds 1, viz. they afforded, by fragmentation
of the tetrazolyl group, the propiolyl derivatives 4a and 4b,
respectively, the study was extended to the simpler tetrazolyl-
methyl ketones 7a–7h (containing no lactam rings) as well as
to the tetrazolylacetic esters 7i and 7j and the related amides
7k–7p.
The formation of compounds 4a and 4b suggests that, in
contrast to the compounds 1 which are attacked by LTA at the
N-aryl substituent of the lactam ring, compounds 2a and 2b are
attacked by the same oxidant at their tetrazolylacetyl moieties,
and that the presence of the lactam ring is not a prerequisite of
the novel oxidative fragmentation reaction. In order to test
this hypothesis, the simpler tetrazolylmethyl ketones 7a–7h
(containing no lactam rings) were subjected to oxidation with
LTA (see Table 1). While 7a and 7b afforded the expected
products 8a and 8b, respectively, compound 7c did not react
and was not decomposed even at elevated temperatures. In
addition to compound 8b traces of compound 9b as well as of
Results
In contrast to the compounds 1, both compounds 2 underwent
fragmentation with loss of nitrogen, leading to the formation
of ethynyl ketones 4a and 4b, respectively, when treated with
LTA in anhydrous 1,4-dioxane at 0 ЊC or below. 4b was itself
readily isolated but 4a could be isolated only in the form of
its transformation product 5a or, on treatment of the reaction
mixture with diazomethane, in the form of compound 6a.
The cycloadduct 6b of compound 4b with diazomethane was
similarly obtained.
1
two further compounds which, according to their IR and H
NMR spectra, appear to possess structures 10b and 11b, were
obtained from compound 7b, their yields increasing (with
simultaneous significant decrease in the yield of compound 8b)
when the solvent 1,4-dioxane was replaced by acetic acid (see
Table 1). The reaction of compound 7d was totally different,
acetoxy derivative 12d and three dimeric compounds (13d–15d)
being the products isolated.
The 1H and 13C NMR spectra and the molecular com-
position (established by HRMS) of product 5a showed it to be
built up from one molecule of the starting 2a and a fragment of
† Electronic supplementary information (ESI) available: experimental
data for compounds 2, 7, 17, 30, 35–38 and 40–42. See http://
www.rsc.org/suppdata/p1/b0/b005286h/
§ NOEs are listed throughout this paper in the order of decreasing
intensity.
‡ Formerly Technical University Budapest.
DOI: 10.1039/b005286h
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139
This journal is © The Royal Society of Chemistry 2001
1131

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Table 1 Reaction of compounds 2a, 2b, 7a–7p and 17 with LTA in anhydrous 1,4-dioxane
Starting comp.
LTA (mol eq.)
Conditions
Products and yieldsa
2a
2b
7a
7b
7bc
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.0
1.1
1.2
1.1
1.1
3.1
1.3
4.1
0 ЊC, 30 min
0 or Ϫ20 ЊC, 30 min
0 ЊC, 30 min
5a (12%) or 6ab (41%)
4b (48%) or 6bb (50%)
8a (53%)
70–80 ЊC, 5 min
80 ЊC, 10 min
100 ЊC, 20 min
25 ЊC, 30 min
10–15 ЊC, 20 min
6–8 ЊC, 20 mind
10–15 ЊC, 10 min
10–15 ЊC, 20 min
100 ЊC, 30 min
70 ЊC, 30 min
100 ЊC, 20 min
80 ЊC, 10 min
100 ЊC, 1 h
8b (42%), 9b–11b (traces)
8b (19%), 9b (6%), 10b (10%)
No reaction. 55% 7c recovered
12d (13.5%), 13d (28%), 14d (16%), 15d (12%)
8e (83%)
8f (56%)
8g (45%) ϩ 16g (1.7%)
8h (69%)
18ib (7%)
8j (55%)
8k (18.5%)
8l (51%)
7m
7n
7o
7p
17
No reactione
100 ЊC, 2 h
100 ЊC, 3 h
100 ЊC, 1 h
100 ЊC, 1 day
8n (7%)
19o (11%), 20o (1.5%)
8p (25%)
Considerable decomposition; 15% 17 recovered
a Non-optimized yields. In several cases complex reaction mixtures containing considerable amounts of tarry products were obtained. As a con-
sequence, often considerable amounts of the products were lost during work-up and, possibly, often only part of the various products formed was
isolated. b Cycloadducts of the original products 4a, 4b and 8i, respectively, with diazomethane. c In acetic acid. d In THF. e 76% of the starting 7m
was recovered.
The structure of compound 13d was determined by NMR
spectroscopy. The δH- and δC-values of the methine group (7.19
and 73.1, respectively) reflect, in addition to the substituent
effects of the carbonyl and tetrazolyl groups, the presence of
an adjacent oxygen atom (connecting the two moieties of the
O,C-dimer). The constitution of 13d derived on this basis was
corroborated by nuclear Overhauser enhancement (NOE)
measurements which, in addition, permitted us to derive the E
configuration for the olefinic bond.
data of the compound defined its structural fragments while the
connection of the fragments was established on the basis of 2D
long-range hetero-correlation spectra. Thus, the olefinic proton
correlations indicated the direct attachment of the benzoyl,
4-nitrophenyl and the substituted ethoxy groups to the olefinic
carbon atoms. By the correlations of the methine proton with
the second 4-nitrophenyl, the tetrazolyl and the acetoxy
groups the substitution pattern of the methine carbon atom
was defined. The structure and the substitution pattern of the
central chain were established on the basis of the long-range
correlations of the methylene groups with the other parts of the
molecule. No NOE was observed between the methine and
methylene groups, which suggested that the terminal methylene
group of the central chain is linked to N2 of the tetrazole ring.
In addition, ketone 17 in which the carbonyl group and the
tetrazole ring are separated by two methylene groups was also
prepared, and was found to be decomposed by LTA slowly at
100 ЊC.
1
The C,C-dimer 14d was shown by its H NMR spectrum to
be a 2 : 1 mixture of two stereoisomers, viz. of the meso and
racemic forms, but it is not known which is which. No attempts
were made to establish whether the unsaturated dimer 15d is the
E or Z isomer.
Ketones 7e–7h reacted with LTA in a similar fashion to
ketones 7a and 7b but, in the g series, a small amount of a
further product, 16g, was isolated.
The structure of compound 16g was derived from its 1H, 13
C
and hetero-correlation NMR spectra, and is supported by its
A comparison of the behavior of compounds 7a–7h and 17
toward LTA demonstrated that the necessary conditions for the
molecular composition determined by HRMS. The 1H and 13
C
1132
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139

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differently, the fused heterocyclic compounds 19o and 20o being
the isolated products.
Discussion
Formation of the acetoxylated product 12d (together with
formation of the dimeric products 13d–15d) on LTA treatment
of compound 7d is another example of the well known acetoxyl-
ation by LTA of saturated CHn groups activated by neigh-
boring carbonyl groups, viz. mainly of ketones containing
at least one α-hydrogen atom4–7 and of the related reactions
of phenols.8 Triacetoxy-λ4-plumbyl derivatives 21 formed by
rate-determining enolization5 of the ketone and reaction of
the resulting enol (or of the phenol8) with LTA are the key
intermediates of the reaction. The three electron-pair displace-
ments indicated in formula 21 then lead to the acetoxylated
product.4a,8
X
R1
R2
R3
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
Me
Me
H
Ph
PMP
4-NO2-C6H4
H
H
Me
H
H
H
H
H
H
H
1-Me
H
H
H
g
h
H
H
H
In the LTA oxidation of pentane-2,4-dione and ethyl aceto-
acetate (both containing doubly activated methylene groups)
formation of dimers has been observed in addition to that of
the acetoxylation products.7 The formation of dimeric products
13d–15d in addition to acetoxy derivative 12d in the LTA oxid-
ation of compound 7d appears to be in agreement with this
observation since the methylene group of the starting material
7d is also doubly activated by the benzoyl and the electron-
withdrawing aromatic tetrazol-5-yl group. Compound 13d
is the first O,C-dimer isolated from this type of LTA oxidation.
Dimer 15d is formed by dehydrogenation of part of the C,C-
dimer 14d.¶
In several cases formation of radicals accompanying the
acetoxylation was observed but these radicals were shown
not to be involved in the acetoxylation reaction.10 We also
have observed formation of radical 22d during oxidation of
compound 7d (cf. below).
i
EtO
BnO
Ph-NH
Ph
Me
Ph
Me
MMP-NH
PMP-NH
H
H
H
H
H
H
H
H
H
j
k
l
H
H
H
N
m
Me
H
H
N
n
o
Me
Me
H
H
H
H
p
H
H
H
PMP = 4-methoxyphenyl.
Ketones 2a, 2b, 7a, 7b and 7e–7h containing N-unsubstituted
tetrazol-5-yl groups are not acetoxylated by LTA but, instead,
their tetrazole rings undergo fragmentation with elimination of
nitrogen to afford ultimately ynones of type 8. The precursors
of the ynones are the vinylidenes [(2-oxoalkylidene)carbenes] 25
which afford the final products by 1,2-migration of either the
benzoyl or the R1 group (Scheme 1). The intermediacy of
the vinylidenes is established beyond doubt by the isolation
of the insertion product 9b (formed with acetic acid, the
co-product of the oxidation) and the hydration product 10b of
the latter. 9b is necessarily formed by reaction of acetic acid
with an intermediate in which the connectivity of the carbon
skeleton of the starting 7b is retained unchanged, obviously by
insertion of vinylidene 25 (R = Ph, R1 = Me) into the carboxyl
group of acetic acid. The sharp increase in the yields of
compounds 9b and 10b, together with the decrease in the yield
of compound 8b, when the solvent 1,4-dioxane was replaced
by acetic acid is also significant in this connection.
Further support for the intermediacy of the vinylidenes 25 is
furnished by the formation of compound 16g. Although the
mechanism of the reaction leading to this compound is not
known, it seems highly probable that the key step is formation
of an oxonium-ylide by reaction of vinylidene 25g with the
solvent 1,4-dioxane; the ylide is subsequently attacked by a
tetrazole N-atom.
The obvious precursors of the vinylidenes 25 are the tetra-
azafulvenes 24 which, however, could neither be isolated nor
detected. Related tetraazafulvenes 27 were assumed as the
intermediates of the pyrolysis of several 5-substituted tetrazoles
26, containing anionic leaving groups in position 1 of the 5-
substituent, leading to acetylenes 2811 (Scheme 2), but were also
not detected.
oxidative fragmentation reaction to take place are (i) the vicinal
position of the carbonyl group and the tetrazole ring, (ii) the
presence of one or two hydrogen atoms attached to the carbon
atom separating the carbonyl group from the tetrazole ring and
(iii) the absence of any N-substituent attached to the tetrazole
ring.
The tetrazoleacetic acid esters 7i and 7j as well as the related
amides 7k, 7l and 7n–7p also underwent the oxidative fragmen-
tation reaction when treated with LTA. Except for the case of
compound 7i where the product 8i was isolated in the form of
cycloadduct 18i (obtained by treatment of the reaction mixture
with diazomethane), the corresponding acetylene derivatives 8
were isolated. Amide 7m did not react, and amide 7o reacted
The tetraazafulvene intermediates 24 may be formed from
the starting compounds 2 and 7 via the triacetoxy-λ4-plumbyl
¶ For dehydrogenations with LTA, see ref. 9.
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139
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Scheme 1 Suggested mechanism for the reactions of compounds 2a, 2b, 7a, 7b and 7e–7h with LTA.
31b and 31d were detected by ESR. The ESR spectra of both
secondary radicals exhibited similar six-line patterns (31b:
g = 2.0059, aN = 13.52 G, aH = 1.99 G; 31d: g = 2.0065, aN =
13.19 G, aH = 1.61 G). The small nitrogen splittings for both
secondary radicals are in accordance with the ‘alkoxy’ char-
acter 31 of the radicals, rather than with the isomeric structures
32.12
The mechanisms of the LTA oxidation of tetrazolylacetic
esters 7i and 7j as well as of 2-(tetrazol-5-yl)alkanamides 7k, 7l,
7n and 7p are thought to be analogous to those of ketones 2a,
2b, 7a, 7b and 7e–7h. This implies that compounds 7i–7l, 7n and
7p should be able to enolize to a significant extent, while simple
esters and amides, as shown by their insensitivity to LTA, are
not. This difference is due to the presence of the tetrazolyl
groups and, as a result, of doubly activated aliphatic CH2 or
CH groups in compounds 7i–7l, 7n and 7p. The insensitivity
of compound 7m towards LTA appears also to be consistent
with the enolization mechanism. The extra C-methyl group in
compound 7m should reduce the propensity to enolization** (cf.
the influence of simple alkyl groups on keto–enol equilibria13).
From N-PMP amide 7o products of a different type (19o
and 20o) were obtained. The central diazepine ring of these
compounds is similar to those of compounds 3. This suggests
similar modes of formation for these compounds (Scheme 3),
in particular that the site of attack of LTA is, in contrast to
the case of all other compounds 7 studied, not the enolized
COCHR group but, instead, the N-aryl substituent. That
among all substrates containing N-aryl substituents (2a, 2b,
7k–7o) this mode of reaction has been observed only with com-
pound 7o appears to be reasonable since the N-PMP group is
one of the most easily oxidizable N-aryl groups. However, due
to the low yields of compounds 19o and 20o, the possibility
derivatives 23 (analogous to and similarly formed as the com-
pounds 21) as a result of the five electron-pair displacements
indicated.||
The necessary conditions stated above for the oxidative
transformations discussed to take place are consistent with the
mechanism shown in Scheme 1.
An alternative mode of transformation of the triacetoxy-λ4-
plumbyl derivatives 23 into the tetraazafulvenes 24 and thence
into acetylenes 4 and 8 could in principle take place via
electron-pair displacements similar to those shown for 21 and
leading to the formation of acetoxy derivative 29, followed by
elimination of acetic acid. On the basis of the observations that
the related compound 30 is stable to sodium acetate (2 mol
equivalents) in boiling acetic acid at least for 2 h and is trans-
formed into the acetylene 8a (34%) only by sodium methoxide
(1 mol equivalent) on boiling for 4 h in methanol, this pathway
appears to be unlikely.
Similarly to the LTA oxidation of compound 7d, formation
of a radical 22b accompanying the oxidation of compound 2b
was observed. None of the two enoxyl radicals 22 was stable
enough for ESR detection but both could be trapped by N-(tert-
butyl)-α-phenylnitrone, and the resulting secondary radicals
** On the other hand, introduction of a (substituted) phenyl group (as
in ketones 7e–7g) at the saturated carbon atom adjacent to the carbonyl
group does not prevent the oxidative fragmentation reaction. This,
again, appears to be consistent with the enolization mechanism.
|| We are grateful to a referee for suggesting this mechanism for the
formation of the tetraazafulvene intermediates 24.
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J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139

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Scheme 2 Pyrolysis of some 5-substituted tetrazoles 26.11
may not be ruled out at present that part of compound 7o is
attacked by LTA competitively also at the enolized COCHMe
group, affording therefore products (lost during work-up of
the reaction mixture) analogous to those resulting from com-
pounds 7k, 7l and 7n. Two alternative mechanisms are shown
for the reaction 7o → 19o ϩ 20o in Scheme 3,†† the two
mechanisms differing in the timing of the second one-electron
oxidation and the closure of the third ring.
Starting compounds
Compounds 2a, 2b and, except for compounds 7d,14 7i,15 7j16
and 7k,17 all compounds 7 as well as compounds 17 and 30 were
new.
The synthesis of compounds 2a and 2b is summarized in
Scheme 4. Except for the known compound 7d and compound
30, all other ketonic compounds were obtained by cycloaddi-
tion of the corresponding cyano ketones 42a–c, 42e–h and 43
with aluminium triazide18 as shown, together with the syn-
theses of compounds 7d and 30 (that of the former being
different from the reported14 synthesis) as well as of the inter-
mediates 42 in Scheme 5.
Scheme 3 Suggested alternative mechanisms for the formation of
compounds 19o and 20o.
separations 20 × 20 cm glass plates coated with Kieselgel
PF254 ϩ 366 (Merck; thickness of adsorbent layer 2.0 mm) were
used (home-made ones, except where otherwise noted). The
solvents are given in parentheses. Dichloromethane is abbrev-
iated as DCM. The purity of the products was checked, in
combination with IR spectroscopy, by TLC on DC-Alufolien
60 F254 (Merck); the individual compounds were detected
by UV irradiation or by using iodine or 5% ethanolic molyb-
dophosphoric acid as the reagent. MgSO4 was used as the
drying agent. Evaporations to dryness as well as the removal of
volatile components of reaction mixtures by distillation were
carried out at reduced pressure (≈2.5 kPa, unless otherwise
stated).
All new crystalline compounds described in the present paper
were colorless. Mps were determined on a Kofler hot-stage mp
apparatus and are uncorrected. IR spectra were recorded on
a Specord-75 (Zeiss, Jena) spectrometer. 1H and 13C NMR spec-
tra were obtained with Varian VRX-400 and Unity INOVA-400
spectrometers, using tetramethylsilane as the internal reference.
J-Values are given in Hz. The ESR spectra were taken at room
temperature (291 K) on an upgraded JEOL JES-FE3X spec-
trometer with 100 kHz field modulation, using a manganese()-
doped MgO powder for the calibration of g-measurements. A
Lake Shore Model 647 Magnet Power Supply and a Stanford
Model SR830 DSP Lock-in Amplifier were applied. The field
was measured by a temperature-stabilized Hall probe with
an accuracy of 10Ϫ5 T. The spectrometer was controlled by a
Pentium 100 computer. Exact molecular mass determinations
were made at 70 eV with a Finnigan-MAT 95 SQ instrument of
reversed geometry equipped with a direct-inlet system using
PFK (perfluorokerosene) as the reference.
The known anilide 7k17 was synthesized by a new method,
viz. by anilinolysis of compound 7i. Reaction of the latter with
N-methylaniline similarly afforded compound 7l. Compounds
7m–7o were obtained by reaction of 2-cyanopropionic acid,
after activation of its carboxy group, with N-methylaniline,
m- and p-anisidine, respectively, and cycloaddition of the
resulting cyano anilides 42m–o (X, R1 and R2 as in the corre-
sponding compounds 7). Piperidine derivative 7p was obtained
by cycloaddition of the known cyano amide 42p22 with
aluminium triazide.
For details concerning the methods of preparation, yields,
mps and spectra of the starting compounds and their inter-
mediates, see the Electronic supplementary information.
Experimental
General
All reactions were monitored by TLC (DC-Alufolien 60 F254
,
Merck) and allowed to go to completion. Separations of
product mixtures by flash column chromatography (CC) were
carried out using Kieselgel G (Merck) as the adsorbent unless
otherwise stated (pressure differences between the two ends
of the columns 10–25 kPa). For preparative TLC (PLC)
†† The timing of the acetoxylation step is not known. However, since
the only compound 7 which underwent acetoxylation with LTA was
compound 7d containing an N-substituted tetrazole ring, acetoxylation
in the case under discussion may be assumed to take place after closure
of the new ring, probably at the stage of 19o.
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139
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Scheme 4 Synthesis of compounds 2a and 2b. MMP means 3-methoxyphenyl. All chiral compounds shown are racemic.
Scheme 5 Synthesis of compounds 7a–h, 17 and 30. X, R1 and R2 in all compounds shown are as in the corresponding compounds 7. All chiral
compounds shown are racemic. Reagents: (i) NaN3, AlCl3, THF.
LTA oxidation of compounds 2a, 2b, 7a–7p and 17
filtered off and washed with EtOAc. The combined filtrate and
washings were cooled to Ϫ5 to 0 ЊC. Ethereal diazomethane
(1.5 mmol) was slowly added and the mixture was stirred for 30
min with the temperature being kept at 0 ЊC throughout. At this
point the cycloaddition was shown by TLC to be complete. The
excess of diazomethane was destroyed by adding acetic acid
and the mixture was evaporated to dryness.
The yields of the products obtained and the reaction con-
ditions are compiled in Table 1 (see above); mps, HRMS and
spectral data are listed below with the individual compounds.
General method. LTA (1.1 mmol) was added to a suspension
of a title compound (1 mmol) in dry 1,4-dioxane (15 cm3) at
room temperature. The mixtures were stirred for 15 min, and
the progress of the reactions was monitored by TLC. If no
reaction took place at room temperature, the mixture was
gradually heated (if necessary, to its bp), in order to initiate
the reaction. The mixtures were heated and stirred until the
evolution of nitrogen ceased and the reactions were shown by
TLC to be complete. Work-up of the reaction mixtures was
carried out by one of methods A–C described below.
Method A. Kieselgel 60 G (Merck) was added to the
mixture [or, if a precipitate of PbII acetate was formed during
the reaction, to its filtrate combined with the EtOAc washings].
The mixture was then evaporated to dryness. The residue was
worked up by flash CC.
Method B. The reaction mixture was filtered through a
Kieselgel 60 G column (10 g) and the products were eluted
either with EtOAc, a 7 : 2 DCM–EtOAc mixture or DCM. The
eluate was evaporated to dryness. The residue was taken up
in DCM (30–50 cm3) and washed with 3% aq. NaHCO3. The
organic layer was dried and evaporated to dryness. The residue
was taken up in DCM and worked up (B1) by PLC or (B2) by
CC (DCM–hexane 1 : 2, followed by DCM–hexane 1 : 1 and
DCM–MeOH, 10 : 0.5).
5-[1-(3-Methoxyphenyl)-4-oxoazetidin-2-yl]-8-[1-(3-methoxy-
phenyl)-4-oxoazetidin-2-ylcarbonyl]tetrazolo[1,5-a]pyridine 5a.
A 1 : 1 mixture of two diastereoisomers; work-up: Method B1
(solvent used for TLC DCM–acetone, 10 : 0.5), mp 155 ЊC;
HRMS (FAB), Found: (M ϩ H)ϩ, 499.1747. C26H23N6O5
requires m/z, 499.1730; νmax/cmϪ1 (KBr) 1760 (CO), 1750 (CO),
1680 (CO); δH ‡‡ (CDCl3) 3.01 (1H, dd, J 15.0, 3.0, 3Љ-HA),
3.16 ϩ 3.17 (together 1H,
2 dd, J
15.4, 2.7, 3Ј-HA),
3.776 ϩ 3.781 (together 3H, 2 s, MeO, MMPЉ), 3.795 ϩ 3.799
(together 3H, 2 s, MeO, MMPЈ), 3.85 ϩ 3.86 (together 1H,
2 dd, J 15.0, 6.5, 3Љ-HB), 3.99 (1H, dd, J 15.4, 6.0, 3Ј-HB),
5.94 ϩ 5.95 (together 1H, 2 dd, J 6.0, 2.7, 2Ј-H), 6.23 ϩ 6.24
‡‡ Primed characters are used for the left-hand side, doubly primed
characters for the right-hand side, and unprimed characters for the
central part of the molecular formula of compound 5a oriented as
shown above.
Method C. The reaction mixture was cooled to 0 ЊC. Meth-
anolic NaOMe (2.2 mmol) was added, and the precipitate was
1136
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139

View Article Online
(together 1H, 2 dd, J 6.5, 3.0, 2Љ-H), 6.65 (1H, ddd, J 8.2, 2.5,
1.0, 4-H, MMPЉ), 6.71 (1H, ddd, J 8.2, 2.3, 1.0, 4-H, MMPЈ),
6.76 (1H, ddd, J 8.0, 2.1, 1.0, 6-H, MMPЉ), 6.78 ϩ 6.79
(together 1H, 2 ddd, J 8.0, 2.1, 1.0, 6-H, MMPЈ), 7.00 (1H, dd,
J 2.5, 2.1, 2-H, MMPЉ), 7.02 (1H, dd, J 2.3, 2.1, 2-H, MMPЈ),
7.18 (1H, dd, J 8.2, 8.0, 5-H, MMPЉ), 7.23 (1H, dd, J 8.2, 8.0,
5-H, MMPЈ), 7.36 (1H, dd, J 7.4, ≈0.5, 6-H), 8.47 ϩ 8.48
(together 1H, 2 d, J 7.4, 7-H); NOE: 7.36 (6-H)→8.47 (7-H),
7.02 (2-H, MMPЈ), 6.79 (6-H, MMPЈ), 5.94 (2Ј-H), 3.16
(3Ј-HA); 8.47 (7-H)→7.36 (6-H), 7.00 (2-H, MMPЉ), 6.76 (6-H,
MMPЉ), 6.23 (2Љ-H), 3.01 (3Љ-HA); δC ‡‡ (CDCl3) 42.4 (two lines
within less than 0.1 ppm; C3Љ), 45.05 (C3Ј), 49.0 (two lines
within less than 0.1 ppm; C2Ј), 55.4 ϩ 55.5 (2 × MeO), 56.7
(two lines within less than 0.1 ppm; C2Љ), 103.1 (C2, MMPЉ),
103.2 (two lines within less than 0.1 ppm; C2, MMPЈ), 108.6
(two lines within less than 0.1 ppm; C6, MMPЈ), 108.9 (C6,
MMPЉ), 110.1 (C4, MMPЉ), 110.5 (two lines within less than
0.1 ppm; C4, MMPЈ), 113.4 (C6), 121.4 (two lines within less
than 0.1 ppm; C8), 130.0 (C5, MMPЉ), 130.6 (C5, MMPЈ),
135.6 (C7), 137.8 (C1, MMPЈ), 138.6 (C1, MMPЉ), 142.0 (C5),
147.3 (C8a), 160.3 (C3, MMPЉ), 160.6 (C3, MMPЈ), 162.2
(C4Љ), 162.5 (C4Ј), 190.7 (two lines within less than 0.1 ppm;
CO).
Compound 9b. Oil; HRMS (FAB), Found: (M ϩ H)ϩ,
205.0870. C12H13O3 requires m/z, 205.0865; νmax/cmϪ1 (film) 1760
(ester), 1630 (CO), 1200 (ester), 1120 (ester); δH (CDCl3) 2.01
(3H, d, J 1.4, ᎐CMe), 2.25 (3H, s, OAc), 7.43 (2H, m, 3-H ϩ
᎐
5-H, Ph), 7.52 (1H, m, 4-H, Ph), 7.64 (2H, m, 2-H ϩ 6-H, Ph),
7.87 (1H, q, J 1.4, CH᎐CMe); DIFNOE: 2.01→7.87, 7.64;
᎐
7.87→7.64, 2.01, 2.25.
Compound 10b. Oil; νmax/cmϪ1 (film) 3470br (OH), 1730
(ester), 1680 (CO, 1250 (ester), 1050 (ester); δH (CDCl3) 1.60
(3H, s, Me), 1.99 (3H, s, OAc), 4.11br (1H, OH), 4.36 ϩ 4.57
(together 2H, 2 d, J 11.7, CH2OAc), 7.46 (2H, m, 3-H ϩ 5-H,
Ph), 7.58 (1H, m, 4-H, Ph), 8.00 (2H, m, 2-H ϩ 6-H, Ph);
δC (CDCl3) 20.6 (MeCO2), 23.7 (Me), 69.9 (CH2O), 78.4
(C–OH), 128.6 ϩ 129.3 ϩ 133.2 ϩ 134.3 (Ph), 170.7 (COO),
202.0 (CO).
Compound 11b. Oil; νmax/cmϪ1 (film) 3450 (OH), 1760sh ϩ
1750 ϩ 1740sh (COOs), 1675 (CO); δH (CDCl3) 1.61 (3H, s,
Me), 2.07 (3H, s, OAc), 4.1 (1H, br, OH), 4.51 ϩ 4.60 (together
2H, 2 d, J 11.4, CH2O), 4.52 ϩ 4.55 (together 2H, 2 d, J 16.0,
COCH2OAc), 7.48 ϩ 7.59 ϩ 8.00 (together 5H, 3 m, Ph);
δC (CDCl3), 20.3 (MeCO2), 23.6 (Me), 60.6 (COCH2OAc),
70.4 (CCH2OAc), 78.3 (COCOH), 128.7 (C3 ϩ C5, Ph),
129.4 (C2 ϩ C6, Ph), 133.3 (C4, Ph), 134.0 (C1, Ph), 167.5
(OCOCH2), 170.4 (MeCO2), 201.6 (PhCO).
1-(3-Methoxyphenyl)-4-[pyrazol-3(5)-ylcarbonyl]azetidin-2-
one 6a. Work-up: Method C, mp 139–142 ЊC; HRMS, Found:
1-Benzoyl-1-(1-methyltetrazol-5-yl)methyl acetate 12d, (E)-
(1-methyltetrazol-5-yl)-[2-(1-methyltetrazol-5-yl)-1-phenylvinyl-
oxy]methyl phenyl ketone 13d, 2,3-bis(1-methyltetrazol-5-yl)-
1,4-diphenylbutane-1,4-dione 14d (as a mixture of the racemic
and meso forms), and 2,3-bis(1-methyltetrazol-5-yl)-1,4-
diphenylbut-2-ene-1,4-dione 15d. Work-up: the filtrate of the
reaction mixture, combined with the EtOAc washings, was
evaporated to dryness and the residue was dissolved in EtOAc.
On storage for 12 h in a refrigerator, compound 15d separated
in the form of colorless crystals. The filtrate was evaporated to
dryness, and the residue was taken up in a small amount of
DCM and worked up by PLC (solvent: DCM–acetone, 7 : 2) to
yield compounds 12d, 14d and 13d in order of increasing
M
ϩ, 271.0950. C14H13N3O3 requires M, 271.0957; νmax/cmϪ1
᝽
(KBr) 3220br (NH), 1760 (CO), 1680 (CO); δH (CDCl3) 3.11 ϩ
3.50 (together 2H, ABM, J 15.2, 2.8, 5.5, 3-H2), 3.76 (3H, s,
MeO), 5.53 (1H, ABM, J 2.8, 5.5, 4-H), 6.63 (1H, m, 4-H,
MMP), 6.78 (1H, m, 6-H, MMP), 6.95 [1H, d, J 2.5, 5(3)-H,
pyrazole], 7.02 (1H, m, 2-H, MMP), 7.17 (1H, m, 5-H, MMP),
7.67 (1H, d, J 2.5, 4-H, pyrazole), 11.0 (1H, br s, NH).
1-(3-Methoxyphenyl)-5-propiolylpyrrolidin-2-one 4b. Work-
up: Method A (solvent used in CC: DCM–acetone, 10 : 0.1),
mp 114 ЊC; HRMS, Found: M ϩ, 243.0886. C14H13NO3
᝽
requires M, 243.0895; νmax/cmϪ1 (KBr) 3200 (᎐CH), 2100
᎐
᎐
polarity.
᎐
(C᎐C), 1700 (CO), 1680 (CO); δ (CDCl3) 2.25 ϩ 2.46–2.80
(together 4H, 2 m, 3-H ϩ 4-H ), 3.36 (1H, s, ᎐CH), 3.80 (3H, s,
᎐
H
ϩ
Compound 12d. Oil, HRMS, Found:
M
᝽
,
260.0906.
᎐
᎐
2
2
C12H12N4O3 requires M, 260.0909; νmax/cmϪ1 (film) 1760 (ester),
1700 (CO), 1200 (ester), 1070 (ester); δH (CDCl3) 2.27 (3H, s,
OAc), 4.14 (3H, s, NMe), 7.47 (1H, s, COCHO), 7.48 (2H, m,
3-H ϩ 5-H, Ph), 7.62 (1H, m, 4-H, Ph), 8.09 (2H, m, 2-H ϩ
6-H, Ph); δC (CDCl3) 20.2 (MeCOO), 35.1 (NMe), 68.0
(COCHO), 129.1 ϩ 129.2 (C2 ϩ C6 and C3 ϩ C5, Ph), 132.8
(C1, Ph), 135.0 (C4, Ph), 148.9 (C5, tetrazole), 168.7 (MeCOO),
189.0 (PhCO).
MeO), 4.83 (1H, dd, J 9.5, 3.3, 5-H), 6.74 (1H, ddd, J 1.0, 2.5,
8.5, 4-H, MMP), 6.92 (1H, ddd, J 1.0, 2.0, 8.2, 6-H, MMP),
7.20 (1H, dd, J 2.0, 2.5, 2-H, MMP), 7.25 (1H, dd, J 8.2, 8.5,
5-H, MMP).
1-(3-Methoxyphenyl)-5-[pyrazol-3(5)-ylcarbonyl]pyrrolidin-2-
one 6b. Work-up: Method C;§§ mp 164–165 ЊC (from EtOH);
HRMS (FAB), Found: (M ϩ H)ϩ, 286.1206. C15H16N3O3
requires m/z, 286.1192; νmax/cmϪ1 (KBr) 3200br (NH), 1700sh
(CO), 1680 (CO); δH (CDCl3) 2.15 ϩ 2.54–2.82 (together 4H,
2 m, 3-H2 ϩ 4-H2), 3.72 (3H, s, MeO), 5.90 (1H, m, 5-H), 6.67
(1H, ddd, J 8.2, 2.5, 0.8, 4-H, MMP), 6.88 [1H, d, J 2.5, 5(3)-H,
pyrazole], 6.98 (1H, ddd, J 8.0, 2.0, 0.8, 6-H, MMP), 7.17 (1H,
dd, J 8.2, 8.0, 5-H, MMP), 7.25 (1H, dd, J 2.5, 2.0, 2-H, MMP),
7.57 (1H, d, 2.5, 4-H, pyrazole), 10.3 (br, 1H, NH).
Compound 13d. Oil, HRMS (FAB), Found: (M ϩ H)ϩ,
403.1647. C20H19N8O2 requires m/z, 403.1631; νmax/cmϪ1 1700
(CO); δH ¶¶ (CDCl3) 4.00 (3H, s, NЈMe), 4.25 (3H, s, NMe), 5.85
(1H, s, ᎐CH), 7.19 (1H, s, COCH), 7.34 (2H, m, 3-H ϩ 5-H,
᎐
Ph), 7.4–7.5 (3H, m, 3-H ϩ 4-H ϩ 5-H, PhЈ), 7.52 (1H, m,
4-H, Ph), 7.53 (2H, m, 2-H ϩ 6-H, PhЈ), 7.75 (2H, m, 2-H ϩ
6-H, Ph); NOE 4.00 (NЈ-Me)→5.85 (᎐CH); 4.25 (NMe)→7.19
᎐
(COCH), 7.75 (2-H ϩ 6-H, Ph), 7.53 (2-H ϩ 6-H, PhЈ), 5.85
(᎐CH); 5.85 (᎐CH)→4.00 (NЈMe), 7.53 (2-H ϩ 6-H, PhЈ); 7.19
(COCH)→7.75 (2-H ϩ 6-H, Ph), 4.25 (NMe), 7.53 (2-H ϩ
᎐
᎐
Ethynyl phenyl ketone 8a. Work-up: Method A (solvent used
in CC: DCM–hexane, 1 : 1), mp 47–48 ЊC (lit.,23 49–50 ЊC); the
IR and 1H NMR spectra were identical with those reported.24
6-H, PhЈ), 5.85 (᎐CH); δ ¶¶ (CDCl ) 33.6 (NЈMe), 35.4 (NMe),
᎐
C
3
73.1 (COCH), 93.1 (᎐CH), 127.9 (C2 ϩ C6, PhЈ), 128.7
᎐
(C2 ϩ C6, Ph), 129.0 (C3 ϩ C5, Ph), 129.3 (C3 ϩ C5, PhЈ),
131.1 (C4, PhЈ), 132.6 (C1, PhЈ), 132.8 (C1, Ph), 134.8 (C4, Ph),
149.5 (C5, tetrazole), 149.8 (C5, tetrazoleЈ), 161.2 (PhC=), 181.8
Phenyl propyn-1-yl ketone 8b, 2-benzoylprop-1-enyl acetate
9b, 2-benzoyl-2-hydroxypropyl acetate 10b and 2-benzoyl-2-
hydroxypropyl acetoxyacetate 11b. Work-up: Method B1 (solv-
ent used in TLC: DCM).
(PhC᎐O).
᎐
Compound 14d. A 2 : 1 mixture of stereoisomers A and B,
1
mp 187–196 ЊC; HRMS (FAB), Found: (M ϩ H)ϩ, 403.1651.
Compound 8b. Oil, the IR and H NMR spectra were essen-
tially identical with those reported.25
¶¶ Primed characters are used for the lower and unprimed characters
for the upper half of the molecular formula of compound 13d oriented
as shown above.
§§ In addition, compound 6b was obtained in 79% yield from isolated
compound 4b.
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139
1137

View Article Online
C20H19N8O2 requires m/z, 403.1631; νmax/cmϪ1 (KBr) 1690 (CO);
stereoisomer A, δH (CDCl3) 4.03 (6H, s, 2 × NMe), 6.34 (2H, s,
2 × COCH), 7.50 (4H, m, 3-H ϩ 5-H, 2 × Ph), 7.62 (2H, m,
4-H, 2 × Ph), 7.97 (4H, m, 2-H ϩ 6-H, 2 × Ph); NOE: 6.34
(COCH)→7.97 (2-H ϩ 6-H, Ph), 4.03 (NMe); δC (CDCl3) 34.4
(NMe), 43.9 (COCH), 128.7 (C2 ϩ C6, Ph), 129.3 (C3 ϩ C5,
Ph), 134.7 (two lines within less than 0.1 ppm; C4, Ph and
m, 3-H ϩ 5-H, PNPЈ); NOE 7.28 (7Ј-H)→7.61 (2-H ϩ 6-H,
Ph), 4.12 (5Ј-H2); 7.14 (CHOAc)→7.68 (2-H ϩ 6-H, PNPЈ), 2.17
(OAc); δC (CDCl3)††† 20.8 (OOCMe), 53.0 (C1Ј), 68.3 (C2Ј),
68.4 (CHOAc), 69.9 (C4Ј), 74.3 (C5Ј), 119.4 (C8Ј), 123.2
(C3 ϩ C5, PNP), 124.0 (C3 ϩ C5, PNPЈ), 128.4 (two lines
within less than 0.1 ppm; C2 ϩ C6, PNPЈ and C3 ϩ C5, Ph),
129.2 (C2 ϩ C6, Ph), 130.9 (C2 ϩ C6, PNP), 131.9 (C4, Ph),
138.9 (C1, Ph), 140.6 (C1, PNP), 143.2 (C1, PNPЈ), 146.5 (C4,
PNP), 148.2 (C4, PNPЈ), 162.3 (C7Ј), 164.3 (C5, tetrazole),
169.4 (OOCMe), 194.7 (C9Ј).
C1, Ph), 150.4 (C5, tetrazole), 192.0 (C᎐O); stereoisomer B,
᎐
δH (CDCl3) 4.29 (6H, s, 2 × NMe), 6.20 (2H, s, 2 × COCH),
7.44 (4H, m, 3-H ϩ 5-H, 2 × Ph), 7.58 (2H, m, 4-H, 2 × Ph),
7.80 (4H, m, 2-H ϩ 6-H, 2 × Ph); NOE: 6.20 (COCH)→7.80
(2-H ϩ 6-H, Ph), 4.29 (NMe); δC (CDCl3) 34.4 (NMe), 44.3
(COCH), 128.3 (C2 ϩ C6, Ph), 129.3 (C3 ϩ C5, Ph), 134.7 (C4,
Cyclohexyl ethynyl ketone 8h. Work-up: Method B1 (solvent
used in TLC: DCM), oil; νmax/cmϪ1 (film) 3250 (᎐C–H), 2090
᎐
᎐
29
᎐
Ph), 134.9 (C1, Ph), 151.2 (C5, tetrazole), 192.8 (C᎐O).
(C᎐C), 1680 (C᎐O), identical with the reported spectrum;
᎐
᎐
᎐
ϩ
Compound 15d. Mp 230–236 ЊC; HRMS, Found: M
,
δH (CDCl3) 1.15–1.50 (5H, m, 2-H to 5-H cyclohexyl, axial),
1.60–2.05 (5H, m, 2-H to 5-H, cyclohexyl, equatorial), 2.43
(1H, tt, Jaa 11.0, Jae 3.6, 1-H, cyclohexyl, axial), 3.21 (1H, s,
᝽
400.1383. C20H16N8O2 requires M, 400.1396; νmax/cmϪ1 (KBr)
1680 (CO); δH (CDCl3 ϩ DMSO-d6) 3.97 (6H, s, 2 × NMe),
7.55 (4H, m, 3-H ϩ 5-H, 2 × Ph), 7.68 (2H, m, 4-H, 2 × Ph),
7.95 (4H, m, 2-H ϩ 6-H, 2 × Ph); δC (CDCl3 ϩ DMSO-d6) 35.2
(NMe),129.4(C2 ϩ C6,Ph),||||129.5(C3 ϩ C5,Ph),||||134.4(C1,
29
᎐
᎐CH), essentially identical with the reported spectrum.
᎐
Ethyl pyrazole-3(5)-carboxylate 18i. Work-up: Method C, mp
152–154 ЊC (lit.,30 154–157 ЊC); νmax/cmϪ1 (KBr) 3240 (NH),
Ph), 135.3 (C4, Ph), 136.9 ( C᎐), 149.3 (C5, tetrazole), 189.7
᎐
(C᎐O).
᎐
1690 (C᎐O), identical with the spectrum reported.31
᎐
Phenyl phenylethynyl ketone 8e. Work-up: Method B2, mp
Benzyl propiolate 8j. Work-up: Method B2 (only solvent used
44 ЊC (lit.,26 46.5–48 ЊC); νmax/cmϪ1 (KBr) 2200 (C᎐C), 1645
for CC: DCM–hexane, 1 : 2), oil; νmax/cmϪ1 (film) 3280 (᎐C–H),
᎐
᎐
᎐
᎐
(CO), identical with the reported spectrum;27 δH (CDCl3)***
᎐
2110 (C᎐C), 1710 (C᎐O), 1220 (ester); δ (CDCl3) 2.83 (1H, s,
᎐
᎐
H
᎐
7.48 (2H, m, 3-H ϩ 5-H, PhЉ), 7.49 (1H, m, 4-H, PhЉ), 7.69 (2H,
m, 2-H ϩ 6-H, PhЉ), 7.52 (2H, m, 3-H ϩ 5-H, PhЈ), 7.63 (1H, m,
4-H, PhЈ), 8.23 (2H, m, 2-H ϩ 6-H, PhЈ), essentially identical
᎐CH), 5.20 (2H, s, OCH ), 7.30–7.40 (5H, m, Ph), essentially
᎐
2
identical with the CCl4 spectrum described in ref. 32.
with the reported spectrum;27 δ (CDCl )*** 86.9 (COC᎐), 93.1
᎐
Propiolanilide 8k. Work-up: Method A (solvent used for CC:
DCM), mp 85–86 ЊC (lit.,33 82–83 ЊC); νmax/cmϪ1 (KBr) 3260
᎐
C
3
᎐
(᎐CPhЉ), 120.2 (C1, PhЉ), 128.7 (two lines within less than 0.1
ppm; C3 ϩ C5, PhЈ and PhЉ), 129.6 (C2 ϩ C6, PhЈ), 130.8 (C4,
PhЉ), 133.1 (C2 ϩ C6, PhЉ), 134.1 (C4, PhЈ), 137.0 (C1, PhЈ),
᎐
᎐
᎐
(᎐C–H), 2100 (C᎐C), 1620 (Amide I), essentially identical with
᎐
᎐
the spectrum reported.33
178.0 (C᎐O).
᎐
N-Methylpropiolanilide 8l. Work-up: Method B1 (solvent
used for TLC: DCM–acetone, 7 : 1); mp 83–85 ЊC (lit.,34 78–
(4-Methoxyphenyl)ethynyl phenyl ketone 8f. Work-up:
79 ЊC); νmax/cmϪ1 3330 (᎐C–H), 2120 (C᎐C), 1630 (Amide I),
Method B1 (solvent used in TLC: DCM–acetone, 10 : 0.1); mp
᎐
᎐
᎐
᎐
81–85 ЊC (lit.,28 81–82 ЊC); νmax/cmϪ1 (KBr) 2195 (C᎐C), 1625
᎐
᎐
identical with the spectrum reported for a CHCl3 solution.34
(CO), identical with the reported spectrum;28 δH (CDCl3) 3.85
(3H, s, MeO), 6.93 ϩ 7.64 (4H, AAЈBBЈ, PMP), 7.51 (2H, m,
3-H ϩ 5-H, Ph), 7.61 (1H, m, 4-H, Ph), 8.22 (2H, m, 2-H ϩ
6-H, Ph).
N-(3-Methoxyphenyl)but-2-ynamide 8n. Work-up: Method A
(solvent used for CC: DCM); mp 79–83 ЊC; HRMS, Found:
M
ϩ, 189.0788. C11H11NO2 requires M, 189.0790; νmax/cmϪ1
᝽
᎐
3200–2800br (NH), 2210 (C᎐C), 1620 (Amide I); δ (CDCl3)
1.98 (3H, s, ᎐CMe), 3.79 (3H, s, OMe), 6.67 (1H, br dd, J 2.0,
᎐
H
(4-Nitrophenyl)ethynyl phenyl ketone 8g. Work-up: Method
B1 (solvent used in TLC: DCM–acetone, 10 : 0.5), the least
polar component of the mixture; mp 152–154 ЊC (lit.,28 148–
᎐
᎐
8.0, 4-H, MMP), 7.00 (1H, br dd, J 2.0, 8.0, 6-H, MMP), 7.20
(1H, t, J 8.0, 5-H, MMP), 7.25 (1H, t, J 2.0, 2-H, MMP), 7.56
148.5 ЊC); νmax/cmϪ1 (KBr) 2200 (C᎐C), 1650 (CO) identical
᎐
᎐
᎐
(1H, br s, NH); δC (CDCl ) 3.7 (᎐CMe), 55.3 (OMe), 75.4
᎐
3
with the reported spectrum;28 δH (CDCl3) 7.55 (2H, m, 3-H ϩ
᎐
᎐
(COC᎐), 84.5 (᎐CMe), 105.7 (C2, MMP), 110.5 (C4, MMP),
᎐
᎐
5-H, Ph), 7.67 (1H, m, 4-H, Ph), 8.20 (2H, m, 2-H ϩ 6-H, Ph),
7.84 ϩ 8.29 (4H, AAЈBBЈ, J 8.8, nitrophenyl).
112.0 (C6, MMP), 129.7 (C5, MMP), 138.6 (C1, MMP), 151.1
(C3, MMP), 160.1 (C᎐O).
᎐
(E)-{2-[8-Benzoyl-8-(4-nitrophenyl)-3,6-dioxanon-7-en-1-yl]-
tetrazol-5-yl}-(4-nitrophenyl)methyl acetate 16g. From a mix-
ture of the other compounds accompanying compound 8g as a
highly polar component by two successive PLC separations,
using a Merck coated glassplate (20 × 20 cm; thickness of
adsorbent layer 2.5 mm) for the second separation; oil, HRMS,
9-Methoxy-4-methyl-4H-tetrazolo[1,5-a][1,5]benzodiazepin-
5(6H)-one 19o and 4-acetoxy-9-methoxy-4-methyl-4H-tetrazolo-
[1,5-a][1,5]benzodiazepin-5(6H)-one 20o. Work-up: Method
B1 (solvent used for TLC: DCM–acetone, 7 : 1). The resulting
crude compound 19o was taken up in DCM (1 ml) and sub-
jected to purification by TLC (solvent: DCM–EtOAc, 7 : 1).
Found: M ϩ, 602.1734. C29H26N6O3 requires M, 602.1761;
ϩ
,
᝽
Compound 19o. Mp 260–262 ЊC; HRMS, Found: M
᝽
245.0917. C11H11N5O2 requires M, 245.0913; νmax/cmϪ1 (KBr)
3190br (NH), 1680 (Amide I); δH (CDCl3 ϩ DMSO-d6) 1.68
(3H, d, J 7.0, Me), 3.77 (1H, q, J 7.0, 4-H), 3.89 (3H, s, MeO),
7.12 (1H, dd, J 9.0, 2.8, 8-H), 7.32 (1H, d, J 9.0, 7-H), 7.39 (1H,
d, J 2.8, 10-H), 10.50 (1H, br, NH).
δH (CDCl3)††† 2.17 (3H, s, OAc), 3.67 ϩ 4.12 (2 × 2H, 2 m,
4Ј-H2 ϩ 5Ј-H2, respectively), 4.03 (2H, t, J 5.4, 2Ј-H2), 4.74 (2H,
m, 1Ј-H2), 7.14 (1H, s, CHOAc), 7.28 (1H, s, 7Ј-H), 7.40 (2H, m,
3-H ϩ 5-H, Ph), 7.50 (1H, m, 4-H, Ph), 7.52 (2H, m, 2-H ϩ
6-H, PNP), 7.61 (2H, m, 2-H ϩ 6-H, Ph), 7.68 (2H, m,
2-H ϩ 6-H, PNPЈ), 8.18 (2H, m, 3-H ϩ 5-H, PNP), 8.20 (2H,
Compound 20o. Mp 198–205 ЊC (from Et2O); HRMS,
Found: M ϩ, 303.0957. C13H13N5O4 requires M, 303.0968; νmax
/
᝽
cmϪ1 (KBr) 3200br (NH), 1756 (ester), 1688 (Amide I), 1224
(ester), 1068 (ester); δH (CDCl3) 1.63 (3H, s, OAc), 2.26 (3H, s,
Me), 3.92 (3H, s, MeO), 7.09 (1H, dd, 8-H), 7.18 (1H, d, 7-H),
7.50 (1H, d, 10-H), 8.10 (1H, br s, NH); NOE: 8.10→7.18;
3.92→7.50, 7.09; δC (CDCl3) 18.2 (Me), 19.9 (MeCO2), 56.1
|||| The reverse assignation is equally possible.
*** Primed characters are used for the phenyl group adjacent to the
carbonyl group, doubly primed characters for the phenyl group adjacent
to the triple bond.
††† The 4-nitrophenyl groups on the left- and right-hand side of the
formula are denoted by PNP and PNPЈ, respectively.
1138
J. Chem. Soc., Perkin Trans. 1, 2001, 1131–1139

View Article Online
3 J. Elguero, R. Jacquier and H. C. N. Tien Duc, Bull. Soc. Chim. Fr.,
1966, 3727.
4 (a) R. Criegee, Angew. Chem., 1958, 70, 173; (b) G. W. Rotermund,
in Methoden der Organischen Chemie (“Houben-Weyl”), ed. E.
Müller, Thieme, Stuttgart, 4th edn., 1975, vol. IV/1b, pp. 207,
223 et seq., 242.
5 K. Ichikawa and Y. Yamaguchi, J. Chem. Soc. Jpn., 1952, 73,
415.
6 W. Cocker and J. C. P. Schwarz, Chem. Ind., 1951, 390.
7 G. W. K. Cavill and D. H. Solomon, J. Chem. Soc., 1955, 4426.
8 M. J. Harrison and R. O. C. Norman, J. Chem. Soc. (C), 1970, 728
and earlier references cited.
(MeO), 75.1 (C4), 107.1 (C10), 117.6 (C8), 121.9 (C6a), 123.0
(C7), 126.5 (C10a), 151.9 (C3a), 157.6 (C9), 165.7 (C5), 168.1
(MeCO2).
N-Propinoylpiperidine 8p.‡‡‡ Work-up: Method B1 (solvent
ϩ
used for TLC: DCM–acetone, 10 : 2); oil; HRMS, Found: M
,
᝽
137.0836. C8H11NO requires M, 137.0841; νmax/cmϪ1 (film) 3200
(᎐C–H), 2100 (C᎐C), 1625br (Amide I); δ (CDCl3) 1.50–1.75
(6H, m, 3-H ϩ 4-H ϩ 5-H ), 3.09 (1H, s, ᎐CH), 3.58 ϩ 3.71
᎐
᎐
᎐
᎐
H
᎐
᎐
2
2
2
(4H, 2 t, 2-H2 ϩ 6-H2).
9 Ref. 4b, pp. 274–276.
ESR measurements
10 E. Hecker and R. Lattrell, Justus Liebigs Ann. Chem., 1963, 662, 48.
11 H. Behringer and M. Matner, Tetrahedron Lett., 1966, 1663.
12 E. G. Janzen and B. J. Blackburn, J. Am. Chem. Soc., 1968, 90, 5909;
E. G. Janzen and B. J. Blackburn, J. Am. Chem. Soc., 1969, 91, 4481.
13 Ch. K. Ingold, Structure and Mechanism in Organic Chemistry, Bell,
London, 1953, p. 555.
14 (a) R. B. Woodward and R. A. Olofson, Tetrahedron Suppl. 7, 1966,
415; (b) R. T. Chakrasali, H. Ila and H. Junjappa, Synthesis, 1988,
453.
15 W. G. Finnegan, R. A. Henry and R. Lofquist, J. Am. Chem. Soc.,
1958, 80, 3908.
16 K. H. Boltze, O. Brendler, H. Jacobi and W. Opitz, Arzneim.-
Forsch., 1980, 30, 1314.
The solvent THF used was pretreated by refluxing for ca. 3 h
over LiAlH4. THF solutions (0.1 cm3) of N-(tert-butyl)-α-
phenylnitrone (0.1 g cmϪ3) were added to saturated THF solu-
tions (1 cm3) of compounds 2b and 7d, and the mixtures were
thoroughly homogenized. After the spectrometer was set to
measuring conditions, suspensions of LTA in THF were added
dropwise to the solutions placed into the spectrometer at
Ϫ20 ЊC and room temperature, respectively, whereby mixing
took place due to gravitational forces. The measurements were
carried out in air. In the absence of the nitrone no ESR signals
were detected.
17 J. Diago-Meseguer, A. L. Palomo-Coll, J. R. Fernandez-Lizarbe
and A. Zugaza-Bilbao, Synthesis, 1980, 547.
18 C. Arnold, Jr. and D. N. Thatcher, J. Org. Chem., 1969, 34,
1141.
Acknowledgements
19 M. Augustin, W. Jahreis and D. Rudolf, Synthesis, 1977, 472.
20 A. Dornow and H. Grabhöfer, Chem. Ber., 1958, 91, 1824.
21 A. Miyashita, Y. Suzuki, Y. Okamura and T. Higashino, Chem.
Pharm. Bull., 1996, 44, 252.
22 J. Speziale and P. C. Hamm, J. Am. Chem. Soc., 1956, 78, 5580.
23 R. R. France and W. Faulconer, J. Org. Chem., 1971, 36, 2048.
24 M. Noro, T. Masuda, A. S. Ichimura, N. Koga and H. Iwamura,
J. Am. Chem. Soc., 1994, 116, 6179.
We thank Miss K. Ófalvi for the IR spectra. J. F., I. N. and
L. T. G. are grateful to OTKA (Hungarian Scientific Research
Fund, Grant No. T 029035) and to the Hungarian Ministry
of Education (Grant No. FKFP 0028/1999) for financial
assistance. L. T. G. also thanks the Technical University
Budapest for a scholarship.
25 J. Suffet and D. Toussaint, J. Org. Chem., 1995, 60, 3550.
26 M. S. Newman and B. C. Ream, J. Org. Chem., 1966, 31, 3861.
27 J. B. Hendrickson and S. Hussain, Synthesis, 1989, 217.
28 W. F. Winecoff and D. W. Boykin, Jr., J. Org. Chem., 1973, 38,
2544.
‡‡‡ This compound had been obtained by a different route before34 but
no physical or spectral data were disclosed.
29 R. D. Dillard and D. E. Pavey, J. Org. Chem., 1971, 36, 749.
30 E. Schweizer and C. S. Labaw, J. Org. Chem., 1973, 38, 3069.
31 Y. Nakano, M. Hamaguchi and T. Nagai, J. Chem. Res. (M), 1991,
1701.
32 L. Balas, B. Jaisseaume and B. Langwort, Tetrahedron Lett., 1989,
30, 4525.
33 S. Puertas, R. Brieva, F. Rebolledo and V. Gotor, Tetrahedron, 1993,
49, 4007.
34 B. Kanner and U. K. Pandit, Tetrahedron, 1982, 38, 3597.
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