Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Article abstract of DOI:10.1016/j.tet.2005.11.039

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chlo

Full text of DOI:10.1016/j.tet.2005.11.039

Tetrahedron 62 (2006) 1849–1863
Microwave-assisted synthesis and transformations of sterically
hindered 3-(5-tetrazolyl)pyridines
a,
b
*
Igor V. Bliznets, Sergey V. Shorshnev, Grigory G. Aleksandrov,
a
a
Sergey M. Lukyanov,
b
Aleksandr E. Stepanov and Andrei A. Vasil’ev
c
a
ChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
M.V. Lomonosov Moscow State Academy of Fine Chemical Technology, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
b
c
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, 119991 Moscow, Russian Federation
Received 3 August 2005; revised 31 October 2005; accepted 17 November 2005
Available online 13 December 2005
Abstract—Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using
microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-
chloromethyl derivatives. Intramolecular [3C2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form
a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise
to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-
naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were
alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields.
A majority of above-mentioned reactions was carried out under microwave irradiation.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
is alkyl or (FG)–CH (FGZfunctional group) (Scheme 1).
2
These compounds 3, 4 could be core structures for
some combinatorial libraries based on the nicotinic acid
derivatives such as nicotinonitriles.
For a long time 3-(5-tetrazolyl)pyridine 1 and its derivatives
have been of particular interest to the chemists because of the
1
–5
interesting pharmacological activity of these compounds
Scheme 1). For example, some 3-(5-tetrazolyl)pyridines,
1
We reported in our preliminary communication that the
3
(
corresponding nicotinonitriles 5a–c (Scheme 2) prepared by
substituted in the pyridine moiety, were described as
potential lipolysis inhibitors similar to nicotinic acid, but of
1
4
the literature method were used as starting materials for
syntheses under three different conditions: (a) NaN , AcOH,
2
,3,6
greater metabolic stability.
known as a bioisosteric substitute for the carboxylic group in
Indeed, tetrazole ring is well
3
1
n-BuOH; (b) NaN , ZnBr , H O;
toluene.
4,15
(c) Me SiN , Bu SnO,
3 3 2
However, only compound 3 (RZH) was
3
2
2
1
1,16
7
many biologically active molecules, since they both possess
2
,3,8
9
(see also review ). On the
obtained from nitrile 5a in moderate yield using trimethyl-
silyl azide and dibutyltin oxide (conditions c, 100 8C, 72 h).
All attempts to obtain the desired tetrazoles from nitriles
5b,c were ineffective under above-named conditions. It
should be noted that these results turned out not surprising
for us since many reactions of nitrile group are very
susceptible to sterical hindrances (e.g., Pinner reaction).
Poor yields of tetrazoles from ortho-substituted benzoni-
comparable acidity and size
other hand, related biphenyl derivatives 2 bearing a sterically
hindered ortho-tetrazole group have been described recently
1
0–12
as novel angiotensin II receptor antagonists.
In this context, it would be interesting to synthesize a
series of 3-(5-tetrazolyl)pyridines with substituents at
both positions adjacent to the tetrazole unit such as
2-alkyl-4-aryl-3-(5-tetrazolyl)pyridines 3 as well as other
similar compounds 4 where X is bulk aliphatic group, and Y
10,11
triles were also reported.
13
We have found that the sterically hindered 3-(5-tetra-
zolyl)pyridines 3, 4 can be successfully synthesized using
microwave technology (MW) (see footnote below in Section
Keywords: Nicotinic acid; Nicotinonitriles; Tetrazolyl derivatives; 1,3,4-
Oxadiazoles; Intramolecular cycloaddition; Fused tetrazoles; Microwave
irradiation.
4.3.5.3). At that time a synthesis of tetrazoles from some
simplest model nitriles under microwave irradiation was
*
Corresponding author. Tel.: C7 95 775 06 54; fax: C7 95 956 49 48;
e-mail: semiluk@chembridge.ru
1
described in only one paper. Another investigation on
7
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.039

1850
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
H
H
H
H
N
N
N
N
N
N
N N
N
N
R
N
N
N
N
N
N
R
X
Y
N
N
N
3
4
1
2
Scheme 1.
The optimal reaction conditions were initially determined
using the model nitriles 6a–f. We found that the yields of
target products 7a–f depended considerably on the ratio of
reactants, and the optimal molar ratio being ‘nitrile/
Bu SnO/TMSN Z1:0.3:4’. The results of the model
N
N
N
N
O
N
N
2
3
experiments are presented in Table 1. It is seen that the
yields of tetrazoles 7a–f decreased gradually along with the
growth of the carbocycle size. The unreacted nitriles 6a–f
can be isolated from the reaction mixtures; therefore, the
yields coincided practically with the conversion of the
starting reactants. The yields can be also improved upon by
a prolongation of microwave irradiation as well as by an
5
a
5b
5c
Scheme 2.
1
the same subject was reported concurrently and indepen-
8
1
3
dently of our preliminary communication. Now, we
describe in more detail not only the synthesis but also
transformations of 2,4-disubstituted 3-(5-tetrazolyl)pyri-
dines carried out under microwave irradiation.
increasing of Bu SnO content (entries 5, 8).
2
Table 1. Conditions and yields of model tetrazoles 7a–f
Entry 6,7 Ar
X
Time (h) Yield 7
%)
(
2
. Results and discussion
1
2
3
4
5
6
7
8
a
b
c
d
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
–(CH
–(CH
–(CH
–(CH
–(CH
–(CH
2
2
2
2
2
2
)
)
)
)
)
)
2
3
4
5
5
2
–
–
–
–
3
3
5
7
8
5
9
8
100
90
Initially, we investigated the reactions of nicotinonitriles
a–c as well as a series of model sterically hindered
aliphatic nitriles 6a–f (Scheme 3) under above-mentioned
conditions (a–c) using Milestone Ethos SYNTH and CEM
Discover microwave labstations. We quickly discovered
84
38
89
5
a
–
O(CH
2
)
2
–
83
63
85
p-CH OC H
3
3
p-CH OC
6
4
4
2 5
–(CH ) –
a
that an application of NaN was unsuitable for microwave-
3
f
6
H
–(CH
2
)
5
–
assisted reactions because of both toxic and explosion risk
(
a
Bu SnO (1 equiv) used.
2
conditions a, acid promoted HN liberation) as well as a
3
considerable hydrolysis of the starting nitriles to amides in
the presence of water (conditions b). At the same time the
reagent system TMSN /Bu SnO (conditions c) was found to
be best with respect to the reproducibility and ease of
handling. It should be noted that 1,4-dioxane was used
instead of toluene for this reagent system as the solvent
more suitable for microwave conditions.
These reaction conditions were applied in the preparation of
the 2,4-disubstituted 3-(5-tetrazolyl)pyridines 8a–m from
the corresponding nicotinonitriles 5a–m (Schemes 4 and 5).
All the experiments were carried out at 140 8C for 8 h (but
only for 4 h at 120 8C for 8m because of partial thermal
deprotection as well as at 110 8C for 8f owing to
resinification).
3
2
N
N
That the 3-(5-tetrazolyl)pyridines 8a–m obtained may serve
as core structures for combinatorial libraries, they should
containtwoormorefunctionalgroupsasderivatizationpoints.
These groups can be positioned in 4-aryl substituent (e.g.,
structures 8d–f) and/or in alkyl (cycloalkyl) group (e.g.,
structure 8m). To achieve more diversity and enhance the
synthetical potential of the system, it could be of interest to
introduceanaliphaticfunctionalgroupintothecorestructures.
One of these possibilities was a functionalization of the
Ar
CN
TMSN / Bu SnO
3 2
NH
Ar
N
X
1,4-dioxane
X
o
6a-f
MW, 140 C
7a-f
N
N
N
2-methyl group at pyridine nucleus. It seemed promising to
6a
6b
6c
transform the 2-methyl group prior to constructing a tetrazole
ring. Therefore, we have chosen a pathway for the
functionalization of nicotinonitriles 5. As we reported in our
O
N
N
N
1
9
preliminary communication this functionalisation involved
2
0
the well-known rearrangement of pyridine N-oxides 9a,h,l
under acylation conditions as a key step. The use of hydrogen
peroxide followed by trifluoroacetic anhydride gave rise to
labile trifluoroacetates 10a,h,l that were converted very
O
6e
6f
6d
Scheme 3. Synthesis of model tetrazoles 7a–f.

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1851
2
1
2
1
R
R
R
R
TMSN , Bu SnO
3
2
N
N
N
N
NH
1
,4-dioxane
N
N
o
Me
MW, 140 C
Me
5
a-m
8a-m
H
H
H
N N
N N
N N
1
0
10
1
0
3
N
N
N
15
N
N
N
4
11
12
9
8
1
1
9
8
11
9
16
1
3
7
3
4
4
7
4
3
7
12
12
13
2
8
13
2
2
1
N 1
O
14
N 1
5
N
1
5
5
14
6
1
5
6
6
8
c, 74 (25)
8
b, 52 (36)
8
a, 80 (15)
H
H
H
N N
N N
N N
O
N
N
Cl
N
N
Br
N
N
Si
3
3
4
O
+
4
3
4
N
2
2
2
N 1
O
5
N 1
5
N
1
5
6
6
6
8
f, 44 (29)
8
e, 78 (22)
8
d, 76 (20)
H
H
H
N
H
N
N
N N
N
N N
N
N
N
N
N
N
N
N
1
2
1
1
1
2
13
13
8
2
8
3
8
3
3
9
8
3
4
7
4
7
4
7
4
7
9
9
2
2
1
2
2
9
10
N
1
10
N
N
1
10
N
1
5
5
5
5
10
6
11
6
11
6
6
1
11
8
g, 78
8h, 61 (23)
8i, 58 (28)
8j, 47 (31)
H
H
H
N N
N N
N N
10
N
N
N
N
N
N
11
1
1
12
16
1
0
8
8
3
3
3
4
7
4
7
4
7
9
9
2
9
8
2
2
5
N
1
5
N
1
1
3
O 11
N
N 1
5
12
10
6
6
6
1
4
O
a
8
k, 63 (31)
8l, 25 (63)
15
8
m, 46
a
Scheme 4. 3-(5-Tetrazolyl)pyridines 8a–m, yields (%) and recovered starting nitriles (%, in brackets). 1 equiv of Bu
2
SnO used.
smoothly into alcohols 11a,h,l by treatment with methanol. It
should be noted that two isomeric alcohols 11h and 12 were
obtainedfromthepyridineN-oxide9hinyieldsof23and31%,
respectively (Scheme 5). Such introduction of a hydroxy
group into a 4-alkyl substituent at a pyridine ring has been
flexibility of the azidomethyl group is very important for this
intramolecular cycloaddition. Therefore, only the azido-
methylated intermediate 15h obtained from compound 11h
underwent smooth cyclization to give the tetracyclic product
16h. However, no reaction between the fixed cyano and azido
groups in azidomethylated isomer prepared from the
intermediate 12 occurred under various conditions (heating
in sealed tube for several days in toluene at 160 8C or
microwave irradiation for 4 h at 150 8C). This result is in
accordance with literature data concerning a significance of
positional relationship of a nitrile and an azido group for the
thermal intramolecular [3C2] cycloaddition. It was reported
that the tetrazoles formed under these conditions can be fused
only to five- or six-membered ring systems but not to seven-
2
1
reported previously. At last, this pathway was successfully
accomplished by straightforward conversion of the alcohol
1
1a into 2-hydroxymethyl-3-(5-tetrazolyl)pyridine 13 under
microwave irradiation (Scheme 5). It is of note that no
protection of hydroxyl group was required for this
transformation.
Further to this result we carried out an intramolecular
reaction between aromatic cyano and side azido
groups (Scheme 6). The corresponding 2-azidomethyl-3-
cyanopyridines 15a,h,l were prepared in two steps from the
2
2
membered cycles. Very few examples of the similar
intramolecular tetrazole formation were described in
2
3
literature. In the most of cases aliphatic and heteroatom-
2-hydroxymethyl derivatives 11a,h,l. Treatment of alcohols
11a,h,l with mesyl chloride gave rather the desired
2-chloromethylated intermediates 14a,h,l than mesylates.
1
5,22
substituted nitriles (cyanates, thiocyanates, cyanamides)
were used in such cycloaddition while only one example with
2
4
Then 2-azidomethyl-3-cyanopyridines 15a,h,l obtained
from chlorides were cyclized on heating in the toluene
solution at 130–140 8C. It is significant to note that a
aromatic nitrile was reported. To the best of our knowledge,
such intramolecular cycloaddition in a heterocyclic series
was unprecedented.

1852
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
N
N
N
N
OCOCF3
OH
1
1
R
Me
O
1
1
ii
R
iii
R
Me
i
R
+
2
N
2
N
2
N
2
N
R
R
R
R
5a,h,l
9a,h,l
10a,h,l
11a,h,l
1
2
1
2
1
2
a: R = Ph, R = H; h: R R = -(CH ) -; l: R = t-Bu, R = H
2
4
N
N
N
OH
OH
Me ii, iii
+
+
N
N
N
O
9h
11h
12
H
N
N N
N
N
OH
OH
iv
N
N
11a
13
Scheme 5. Functionalization of methyl group in 2-methyl-3-cyanopyridines 5a,h,l. Reagents and conditions: (i) H
SnO, dioxane, MW, 140 8C.
2
O
2 3 2 2 2
, AcOH, 70 8C; (ii) (CF CO) O, CH Cl ,
4
0 8C; (iii) MeOH, rt; (iv) Me
3
SiN , Bu
3
2
N
N
N
N
+
N
N
N
N
N
Cl
1
1
1
R
i
R
ii
R
iii
11a,h,l
2
N
2
N
2
N
R
R
R
14a,h,l
15a,h,l
16a,h,l
1
2
1
2
1
2
a: R = Ph, R = H; h: R R = -(CH ) -; l: R = t-Bu, R = H
2
4
Scheme 6. Reaction pathway to tricyclic tetrazolylpyridine system 16a,h,l. Reagents and conditions: (i) MsCl, TEA, CH
PhMe, MW, 120–140 8C.
2 2 3
Cl , rt; (ii) NaN , DMSO, rt; (iii)
It should be noted that the compounds 16a,h,l
are the first representatives of novel heterocyclic (tetra-
zolo)azaisoindole system that were initially obtained in our
laboratory by refluxing of intermediates 15a,h,l in toluene
for 90–120 h. More recently we have found that this
intramolecular [3C2] cycloaddition can be carried out
under microwave irradiation, and the reaction occurred at
the same temperature (130–140 8C) for 2–4 h to afford the
products 16a,l in yields 80–99%.
The reaction of nicotinonitriles 5 with aldehydes in the
presence of potassium tert-butoxide was found as another
possibility to functionalize the 2-methyl substituent
(Scheme 7). The interaction resulted in 2-vinyl derivatives
1
9
H
N
N
N
N
N
N
N
N
2
N
N
R
1
2
1
2
TMSN3,
2
R
Me R CHO
R
R
1
R
R
1
R
Bu SnO
2
+
N
t-BuOK, THF
N
MW
N
N
63-94%
o
1
20-140 C
5a,l
17a,b
2-4 h
19a,b
18
p-TSA
1
1
5
a: R = Ph, 5l: R = t-Bu
1
2
1
2
1
7a, 18, 19a: R = Ph, R = t-Bu; 17b, 19b: R = t-Bu, R = Ph
Scheme 7. Reaction pathway to tricyclic tetrahydro(tetrazolo)naphthyridine system 19a,b.

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
7a,b that were then subjected to tetrazole ring formation
Table 2. Yields of alkylation products 20, 21
1853
1
1
from 3-cyano group. The reaction of intermediate 17a (R Z
Ph, R Zt-Bu) under microwave irradiation (140 8C, 2 h)
afforded a mixture of two products 18 and 19a in yields 22
Entry
7, 20, 21
X
Yield 20
(%)
Yield 21
(%)
2
1
2
3
4
5
a
b
c
d
e
–(CH
–(CH
–(CH
–(CH
–(CH
2
2
2
2
2
)
)
)
)
)
2
3
4
5
2
–
–
–
–
37
33
23
20
11
47
58
72
79
79
and 52%, respectively. The structure of the tricyclic product
1
9a was unequivocally confirmed by X-ray crystallo-
graphic analysis (Fig. 1) and manifested an intramolecular
N-alkylation of tetrazole moiety with olefinic fragment.
There are some reports in literature about similar
intermolecular N-alkylation in the presence of strong acids
2 2
O(CH ) –
The structures of the isomers 20a and 21a were determined
by the assignment of the H and C NMR spectra involving
2
5
1
13
(
to convert the olefins into carbocations). Indeed, we
1
13
H C HSQC, HMBC and H N HMBC experiments. The
1
15
succeeded to convert the 2-(3,3-dimethylbut-1-enyl)-3-(5-
tetrazolyl)-4-phenylpyridine 18 into the product 19a using
para-toluenesulfonic acid. The analogous reaction of the
position of benzyl group at N(1) atom in compound 20a
was established by the cross-peak in the proton-carbon
2D-HMBC spectrum between N-methylene protons and
C(5) atom of tetrazole ring (Scheme 9). Such cross-peak
1
2
isomeric 2-styryl derivative 17b (R Zt-Bu, R ZPh; MW,
1
6
40 8C, 4 h) gave the tricyclic product 19b directly in yield
8%. Therefore, we are inclined to believe that we found a
3
resulted from a coupling J of these atoms through three
bonds. Besides, two cross-peaks were found in the proton-
nitrogen 2D-HMBC spectrum resulted from the coupling
first example of an intramolecular N-alkylation of tetrazoles
with olefins under neutral conditions. Further, the obtained
2
constants J and J of N-methylene protons and the nitrogen
3
5
,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridines 19a,b are
the representatives of another novel heterocyclic system
that could serve not only as a core structure for
combinatorial libraries but also as an interesting subject
for further investigation.
nuclei N(1) and N(2) (Scheme 9).
Ph
N
N
3
N
4
2
N
N
3
4
5
2
N
5
1
N
CH2
1
N
Ph
Ph
CH2
Ph
2
1a
2
0a
Scheme 9. The proton-carbon and proton-nitrogen couplings in structures
0a and 21a.
2
As regards the compound 21a, no cross-peak between
N-methylene protons and C(5) atom of tetrazole ring
1
13
through four bonds was observed in the
HMBC spectrum. At the same time three cross-peaks were
H
C 2D-
Figure 1. X-ray crystal structure of compound 19a.
1
15
registered in the H N 2D-HMBC spectrum resulted from
a coupling of N-methylene protons with three nitrogen
nuclei N(1), N(2), and N(3) (Scheme 9). These facts indicate
the position of benzyl group at N(2) atom of tetrazole
moiety.
A diversity of above-mentioned potential combinatorial
libraries can be extended also by a modification of the
tetrazole fragment as such, for example, an alkylation in the
presence of bases. This alkylation can yield both 1-alkyl and
2
6
2
-alkyl substituted tetrazoles. To determine a behavior of
sterically hindered tetrazoles in this process, we carried out
N-alkylation of the model tetrazoles 7a–e using benzyl
bromide as test alkylating reagent (Scheme 8). The yields of
isomeric products 20, 21 are presented in Table 2.
Besides, it should be noted that the signal of the
1
N-methylene (i.e., benzylic) protons in H NMR spectrum
of compound 21a was characterized by a low-field chemical
shift (d 5.83 ppm) in comparison with that for compound
N
N
N
N
N
N
PhCH Br
NH
2
Ph
N
N
+
Ph
N
Ph
N
N
Ph
X
K CO , acetone
2
3
X
X
Ph
7a-e
2
0a-e
21a-e
Scheme 8. N-Alkylation of model tetrazoles 7a–e.

1854
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
Ph
H
N
N
N
N
N N
Ph
N
N
N
N
N
N
1
1
1
PhCH Br
R
R
2
R
+
acetone
2
N
2
N
2
N
R
R
K CO3
R
2
8a,g
23a,b
22a,b
1
2
1
2
8
a: R = Ph, R = H; 8g: R R = -(CH ) -
2
3
1
2
2
2
2a (44%), 23a (18%): R = Ph, R = H;
1
2
2b (31%), 23b (52%): R R = -(CH ) -
2
3
Scheme 10. N-Alkylation of 3-(5-tetrazolyl)pyridines 8a,g.
N
N
N
N
N
N
N
N
N
N
N
Ph
Ph
N
1
1
N
N
N
12
N
i
ii
1
0
3
7
4
+
9
8
2
Ph
1
N
N
N
5
N
1
3
6
1
6l
24 (33%)
25 (25%)
Ph
2
6 (26%)
Scheme 11. Alkylation of tricyclic compound 16l. Reagents and conditions: (i) PhCH
PhCH Br.
2
Br, acetone, 65 8C, 80 h, then aqueous NaHCO
3
; (ii) t-BuOK, THF, then
2
20a (d 5.38 ppm). Therefore, we distinguished other pairs of
isomers 20b–e and 21b–e using this feature of the
a bright red N-alkylation product 26. The structure 26 was
established with the help of H and C NMR spectra
involving HSQC and HMBC experiments.
1
13
1
corresponding H NMR spectra.
It is obvious from Table 2 that the N-alkylation of tetrazoles
occurred with good yields of products but a fraction of
Finally, tetrazoles can be recyclized into 1,3,4-oxadiazoles
2
7
by action of acylating reagents. We carried out an
acylation of 3-(5-tetrazolyl)pyridines 8a,b,c,g,i with a series
of carboxylic anhydrides and obtained the corresponding
3-(1,3,4-oxadiazol-2-yl)pyridines 27a–f in good to excellent
yields (Scheme 12) (Table 3). It should be emphasized that
this rearrangement under conventional conditions (refluxing
in toluene) turned out extremely slow (more than 100 h) and
resulted in complicated mixtures of products, and the target
2
-alkylated derivatives 21a–e increased as a carbocycle
enlarged. An analogous N-alkylation of the 3-(5-tetrazo-
lyl)pyridines 8a,g gave rise also to mixtures of isomeric
products 22a,b and 23a,b (Scheme 10). The structures of the
isomers 22a and 23a were also determined by the
1
13
1
assignment of the H and C NMR spectra involving H
1
3
1
15
C HSQC, HMBC and H N HMBC experiments. The
same proton-carbon and proton-nitrogen couplings were
registered in the corresponding spectra. It is noteworthy that
3
-(1,3,4-oxadiazol-2-yl)pyridines were isolated from these
mixtures in poor yields. However, an application of
microwave irradiation and acetonitrile as solvent allowed
reduction of the reaction time up to 1–4 h and dramatically
increase the yields. To our knowledge, it is a first example of
such recyclization under microwave irradiation.
1
the signals of benzylic protons in H NMR spectra of
2
-benzylated isomers 23a,b appeared again as the low-field
singlets while the same protons in 1-benzylated compounds
2a,b gave the pairs of high-field doublet signals.
2
The isomeric N-alkylated tetrazoles 20, 21 as well as 22, 23
can be effectively separated by column chromatography,
with the 2-alkyl derivatives migrating quicker than their
3
H
R
N
N
N
1
-isomers.
N
N
N
O
3
We have found that the tricyclic compound 16l can be also
subjected to alkylation (Scheme 11). A treatment with
benzyl bromide in the presence of potassium tert-butoxide
in THF resulted in a separable mixture of C-benzyl 24 and
C,C-dibenzyl derivative 25. Alternatively, refluxing of
tricyclic compound 16l with benzyl bromide in acetone
followed by treatment with aqueous NaHCO3 afforded
1
(R CO) O
2
1
R
R
2
N
acetonitrile
MW, 120 C, 1-4 h
2
N
R
o
R
8
a,b,c,g,i
27a-f
Scheme 12. Recyclization of 3-(5-tetrazolyl)pyridines 8 upon acylation.

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1855
Table 3. Yields of 3-(1,3,4-oxadiazol-2-yl)pyridines 27a–f
The reactions were monitored by TLC (aluminium sheets,
silica gel 60 F254, Merck). Merck Kieselgel 60 (230–400
mesh) was used for a column chromatography.
1
R
2
R
3
R
8
27
Yield (%)
a
a
b
c
g
i
a
b
c
d
e
f
Ph
Ph
-o-C
o -- C
H
H
Me
CF
t-Bu
MeO(CH
i-Pr
6 4
4-Cl–C H
95
100
96
80
99
68
3
Materials. Starting nicotinonitriles 5 for 3-(5-tetrazolyl)-
6
H
H
4
4
2
–(CH )
2
–
–
1
4
–OCH
2
2
)
2
pyridines 8a–c, g–l have already been described. Nitriles
6a,b,d,f are commercially available, and compounds 6c and
6
–(CH
–(CH
2
)
)
3
5
–
–
3
0
2
6e were prepared according to literature procedures.
3-Methoxypropanoic, 2-methylpropanoic, and 4-chloro-
benzoic anhydrides were synthesized using known
procedures.
3
1
3. Conclusion
4
.2. General procedure for the preparation of model
In summary, we revealed some possibilities to convert a
series of readily available sterically hindered nitriles into the
corresponding tetrazole derivatives, including the fused
polycyclic systems, using microwave technology. Besides,
it was found that the 3-(5-tetrazolyl)pyridines can be
derivatized by alkylation and acylation reactions to give a
wide variety of nicotinic acid analogs that could constitute a
basis for a potential combinatorial library. This library
containing 222 compounds was tested by the computer
software PASS (prediction of activity spectra for sub-
(1-aryl-cycloalkyl)tetrazoles 7a–f
Dibutyltin oxide (0.75 g, 3 mmol) and trimethylsilyl azide
4.61 g, 5.31 mL, 40 mmol) were added to a solution of
(
nitrile 6 (10 mmol) in anhydrous 1,4-dioxane (10 mL). The
reaction mixture was subjected to microwave irradiation in
a tightly sealed Teflon vessel (70 mL) for 3–8 h at 140 8C
with stirring then cooled to room temperature. The solvent
was removed under reduced pressure (80 8C/20 Torr). The
residue was dissolved in diethyl ether (30 mL). The product
was extracted with 2 N aqueous solution of NaOH (3!
2
8
stances). This program illustrates the predicted activity
spectrum of a compound as probability of activity (P ) and
a
10 mL). The aqueous layer was acidified with 4 N HCl to
pH 1 and treated with ethyl acetate (4!10 mL). The organic
probability of inactivity (P ). For example, it was predicted
i
by the PASS that the tricyclic system 16 can possess an
antineurotoxic activity for in all the tested examples with Pa
more than 80% as well as all the 3-(5-tetrazolyl)pyridines 8
can be a 5-hydroxytriptamine release inhibitors with Pa
more than 70%. Our further investigations will be directed
to the synthesis of the compounds with the potential activity
predicted, and then to a pharmacological evaluation of the
latter.
extract was washed with brine (20 mL), dried over MgSO4,
and evaporated under reduced pressure (60 8C/20 Torr) to
give the target tetrazole 7a–f that was recrystallized from
ethyl acetate.
4.2.1. 5-(1-Phenylcyclopropyl)-2H-tetrazole (7a). Reac-
tion time: 3 h. Yield 100%; colorless needles, mp 176–
1
78 8C; H NMR (DMSO-d , d ppm): 1.43–1.50 (m, 2H,
1
CH ), 1.50–1.57 (m, 2H, CH ), 7.26–7.39 (m, 5H, Ph),
6
2
2
1
5.0–17.0 (br s, 1H, NH). C NMR (DMSO-d , d ppm):
3
1
6
4
. Experimental
16.3 (CH ), 20.4 (CH ), 127.3, 128.7, 140.2 (Ph), 160.1 (br
s, CN H). IR
2
2
(KBr) 3127, 2996, 2858, 2705, 2599, 2469,
max
4
4
.1. General
1875, 1566, 1429, 1267, 1044, 935, 701. Analysis found: C,
64.25; H, 5.48; N, 30.05%. Calcd for C H N (186.22): C,
64.50; H, 5.41; N, 30.09%.
10 10 4
Milestone Ethos SYNTH (reactors MPR 600/12S and
PRO-24) and CEM Discover microwave labstations (both
operating at 2450 MHz under continuous internal tempera-
ture control) were used for the experimental and scale-up
reactions. Melting points were determined by open glass
4.2.2. 5-(1-Phenylcyclobutyl)-2H-tetrazole (7b). Reaction
time: 3 h; yield 90%; white needles, mp 105–108 8C; H
1
NMR (DMSO-d
2.80 (m, 2H, CH
(m, 5H, Ph), 15.3–17.0 (br s, 1H, NH). C NMR
(DMSO-d , d ppm): 16.6 (CH ), 33.6 (CH ), 43.6 (PhC),
125.8, 126.8, 128.6, 144.8 (Ph), 162.3 (br s, CN H). IR nmax
, d ppm): 1.87–2.05 (m, 2H, CH
), 2.69–
6
2
1
capillary method and are uncorrected. H NMR spectra were
2
), 2.81–2.91 (m, 2H, CH ), 7.20–7.39
2
1
3
recorded on a Bruker Avance DRX 400 (400 MHz)
spectrometer equipped with a 5 mm inverse multinuclear
gradient probehead in DMSO-d6 or CDCl3. C NMR
6
2
2
1
3
4
spectra were recorded on the same instrument at 100 MHz
using DMSO-d as solvent. The assignments of signals in
(KBr) 3103, 2978, 2859, 2702, 2603, 2486, 1870, 1551,
1411, 1257, 1149, 1038, 745. Analysis found: C, 66.07; H,
6
1
13
H and C NMR spectra were performed using HSQC and
6.01; N, 27.94%. Calcd for C11
6.04; N, 27.98%.
H N (200.25): C, 65.98; H,
12 4
HMBC experiments. Mass spectra were run by electron
impact at 70 eV on a Kratos MS-30 spectrometer or by
chemical ionization (LCMS) on an 1100 LCMSD (Agilent
Technologies) instrument with ELSD (PL-ELS-1000)
detector. IR spectra were measured on an EQUINOX 55
Bruker spectrometer. Elemental analyses were carried out in
CARLO-ERBA 1106 and 1500 automatic elemental
analyzers. Single-crystal X-ray diffraction data were
measured using an Enraf-Nonius Cad-4 diffractometer
4.2.3. 5-(1-Phenylcyclopentyl)-2H-tetrazole (7c).
Reaction time: 5 h; yield 84%; colorless needles, mp 151–
1
153 8C; H NMR (DMSO-d , d ppm): 1.47–1.61 (m, 2H,
6
CH ), 1.69–1.82 (m, 2H, CH ), 2.14–2.26 (m, 2H, CH ),
2
2
2
2.64–2.75 (m, 2H, CH ), 7.18–7.35 (m, 5H, Ph), 15.5–16.6
2
1
(br s, 1H, NH). C NMR (DMSO-d , d ppm): 22.8 (CH ),
3
6
2
37.6 (CH ), 49.6 (PhC), 126.4, 126.8, 128.6, 144.2 (Ph),
2
(
0
graphite-monochromated lMo Ka radiation, lZ
161.4 (br s, CN H). IR n
4
2602, 2490, 1876, 1551, 1493, 1412, 1259, 1039, 749.
(KBr) 3097, 2974, 2876, 2699,
max
2
9
˚
.71073 A) and processed using the SHELX97 package.

1856
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
Analysis found: C, 67.24; H, 6.57; N, 26.09%. Calcd for
C H N (214.27): C, 67.27; H, 6.59; N, 26.15%.
ppm): 0.25 (s, 6H, Si(CH ) ), 0.98 (s, 9H, SiC(CH ) ), 2.74
3 2 3 3
(s, 3H, Me), 7.04 (d, 2Harom, JZ8.8 Hz, Ar), 7.46 (d, 1H,
JZ5.1 Hz, 5-H), 7.59 (d, 2Harom, JZ8.8 Hz, Ar), 8.68 (d,
1H, JZ5.1 Hz, 6-H). IR nmax (film) 2224 (C^N).
1
2 14 4
4.2.4. 5-(1-Phenylcyclohexyl)-2H-tetrazole (7d). Reaction
time: 8 h; yield 38% (89% with 1 equiv of Bu SnO); white
2
1
crystals, mp 156–157 8C; H NMR (DMSO-d , d ppm):
4.3.3. 4-(4-Chloro-3-nitrophenyl)-2-methylnicotinoni-
trile (5f). Obtained from 1-(4-chloro-3-nitrophenyl)etha-
6
1
1
.20–1.40 (m, 3H, CH , 4-H), 1.49–1.58 (m, 1H, 4-H),
2
.59–1.70 (m, 2H, CH ), 2.01–2.13 (m, 2H, CH ), 2.53–2.63
2
none; yield 46%; dark yellow crystals, mp 188–190 8C
(decomp.); H NMR (DMSO-d , d ppm): 2.77 (s, 3H, Me),
2
1
(
Ph), 15.5–16.5 (br s, 1H, NH). C NMR (DMSO-d , d
m, 2H, CH ), 7.17–7.24 (m, 3H, Ph), 7.27–7.35 (m, 2H,
2
6
1
3
7.60 (d, 1H, JZ5.1 Hz, 5-H), 8.00–8.04 (m, 2Harom, Ar),
8.39–8.42 (m, 1Harom, Ar), 8.81 (d, 1H, JZ5.1 Hz, 6-H). IR
nmax (film) 2223 (C^N).
6
ppm): 22.5 (CH ), 24.8 (CH ), 35.4 (CH ), 41.9 (PhC),
2
2
2
1
25.7, 126.7, 128.6, 145.5 (Ph), 160.3 (br s, CN H). IR nmax
4
(
KBr) 3094, 2944, 2857, 2738, 2600, 1812, 1544, 1496,
1
6
6
448, 1257, 1155, 1040, 893, 747, 700. Analysis found: C,
8.54; H, 7.01; N, 24.68%. Calcd for C H N (228.30): C,
8.39; H, 7.06; N, 24.54%.
4.3.4. tert-Butyl 5-cyano-6-methyl-3,4-dihydro-2,7-
naphthyridine-2(1H)-carboxylate (5m). Obtained from
tert-butyl 4-oxopiperidine-1-carboxylate; yield 66%; pale
1
3 16 4
1
yellow crystals, mp 133–134 8C; H NMR (DMSO-d , d
6
4.2.5. 5-(4-Phenyltetrahydro-2H-pyran-4-yl)-2H-tetra-
zole (7e). Reaction time: 5 h; yield 83%; white crystals,
ppm): 1.43 (s, 9H, t-Bu), 2.63 (s, 3H, Me), 2.88 (t, 2H, JZ
5.9 Hz, 5-CH ), 3.62 (t, 2H, JZ5.9 Hz, 6-CH ), 4.55 (s, 2H,
2
2
1
mp 141–142 8C; H NMR (DMSO-d , d ppm): 2.21–2.33
13
6
8-CH ), 8.54 (s, 1H, 1-H). C NMR (DMSO-d , d ppm):
2
6
(
CH ), 3.79–3.88 (m, 2H, CH ), 7.21–7.29 (m, 3H, Ph),
7
m, 2H, CH ), 2.58–2.68 (m, 2H, CH ), 3.26–3.37 (m, 2H,
23.1, 26.9, 28.0, 40.2, 42.3, 79.5, 108.2, 115.7, 127.8, 147.4,
150.2, 153.9, 158.7. IR nmax (KBr) 2975, 2870, 2230
(C^N), 1695 (C]O), 1470, 1420, 1250, 1170, 1120, 920,
2
2
2
2
1
3
.30–7.38 (m, 2H, Ph), 15.5–16.8 (br s, 1H, NH). C NMR
C
C
(
DMSO-d , d ppm): 35.2 (CH ), 39.7 (PhC), 63.9 (OCH ),
6
765. Mass (m/z): 273 (2) [M] , 216 (16) [MKC H ] , 200
4 9
2
2
C
C
1
25.6, 127.1, 128.8, 144.5 (Ph), 160.3 (br s, CN H). IR nmax
4
(13) [MKC H O] , 172 (24) [MKC H OCO] , 144 (21),
4 9 4 9
C
(
1
KBr) 3106, 2980, 2962, 2865, 2788, 2608, 1545, 1499,
463, 1397, 1245, 1147, 1106, 1040, 1032, 838, 739, 691.
56 (100) [C H ] , 55 (37). Analysis found: C, 65.98; H,
4 8
6.94; N, 15.31%. Calcd for C H N O (273.34): C, 65.91;
15 19 3 2
Analysis found: C, 62.65; H, 6.18; N, 24.11%. Calcd for
C H N O (230.27): C, 62.59; H, 6.13; N, 24.33%.
H, 7.01; N, 15.37%.
1
2 14 4
4
.3.5. General procedure for the preparation of 3-(5-
4
.2.6. 5-[1-(4-Methoxyphenyl)cyclohexyl]-2H-tetrazole
7f). Reaction time: 8 h; yield 63% (85% with 1 equiv of
tetrazolyl)pyridines 8a–m. Dibutyltin oxide (0.75 g,
3 mmol) and trimethylsilyl azide (4.61 g, 5.31 mL,
40 mmol) were added to a solution of nitrile 5 (10 mmol)
in anhydrous 1,4-dioxane (10 mL). The reaction mixture
was subjected to microwave irradiation in a tightly sealed
Teflon vessel (70 mL) for 8 h at 140 8C with stirring then
cooled to room temperature. The solvent was removed
under reduced pressure (60 8C/15 Torr). The residue was
dissolved in methanol (20 mL). Silica gel (5 g) was added to
the solution, which was then evaporated to dryness. The
solid residue was loaded on a top of a chromatography
column packed with silica gel, and then eluted with
chloroform and later with a gradient system with methanol
in chloroform (0/30% v/v). The fractions obtained were
concentrated under reduced pressure to give the target
products, which were recrystallized from ethyl acetate.
(
Bu SnO); white crystals, mp 188–190 8C; H NMR
1
2
(
DMSO-d , d ppm): 1.18–1.39 (m, 3H, CH , 4-H), 1.47–
6 2
1
2
6
9
.56 (m, 1H, 4-H), 1.57–1.68 (m, 2H, CH ), 1.97–2.10 (m,
2
H, CH ), 2.49–2.60 (m, 2H, CH ), 3.70 (s, 3H, OCH ),
2
2
3
0 0
, JZ9 Hz, 3 -H, 5 -H), 7.12 (d, 2Harom, JZ
13
.86 (d, 2H
0
arom
0
Hz, 2 -H, 6 -H), 15.5–16.5 (br s, 1H, NH). C NMR
(
DMSO-d , d ppm): 22.5 (CH ), 24.9 (CH ), 35.5 (CH ),
6 2 2 2
4
1
1.1 (PhC), 55.1 (OCH ), 113.9, 126.9, 137.4, 157.9 (Ph),
3
60.8 (br s, CN H). IR n
4
(KBr) 3100, 2959, 2858, 2606,
max
1
7
517, 1302, 1265, 1038, 807. Analysis found: C, 65.15; H,
.04; N, 21.55%. Calcd for C H N O (258.33): C, 65.09;
H, 7.02; N, 21.69%.
1
4 18 4
4
.3. Preparation of the 3-(5-tetrazolyl)pyridines 8a–m
1
13
Starting nicotinonitriles 5d–f,m for 3-(5-tetrazolyl)pyri-
dines 8d–f,m were prepared according to literature
procedure.
Atom numbering for H and C NMR spectra below see in
Scheme 4.
1
4
4
.3.5.1. 2-Methyl-4-phenyl-3-(2H-tetrazol-5-yl)-
pyridine, monohydrate (8a). Yield 80%; white crystals,
4.3.1. 4-(4-Bromophenyl)-2-methylnicotinonitrile (5d).
Obtained from 4-bromoacetophenone; yield 79%; creamy
1
mp 94–95 8C; H NMR (DMSO-d , d ppm): 2.30 (s, 3H,
6
1
crystals, mp 138–140 8C; H NMR (DMSO-d , d ppm): 2.76
6
Me), 7.06–7.13 (m, 2H, Ph), 7.28–7.35 (m, 3H, Ph), 7.44 (d,
1H, JZ5.1 Hz, 5-H), 8.72 (d, 1H, JZ5.1 Hz, 6-H).
1
3
(
s, 3H, Me), 7.50 (d, 1H, JZ5.1 Hz, 5-H), 7.61 (d, 2Harom,
C
NMR (DMSO-d , d ppm): 22.9 (CH ), 119.0 (3-C), 122.2
0
0
JZ8.6 Hz, 2 -H, 6 -H, Ar), 7.79 (d, 2Harom, JZ8.6 Hz,
3
2
6
3
0
0
216 (C^N).
-H, 5 -H, Ar), 8.75 (d, 1H, JZ5.1 Hz, 6-H). IR nmax (film)
(5-C), 128.3 (9-C, 13-C), 128.5 (10-C, 12-C), 128.6 (11-C),
137.1 (8-C), 149.9 (4-C), 151.0 (6-C), 152.8 (CN H), 157.6
4
(2-C). IR nmax (film) 3070, 2460, 1940, 1595, 1440, 1240,
1160, 1100, 1060, 1010, 985, 855, 760, 710. Mass (m/z): 237
4
.3.2. 4-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-2-
methylnicotinonitrile (5e). Obtained from 1-(4{[tert-
C
(29) [M] , 236 (76) [MKH] , 208 (38) [MKHN ] , 194
C
C
2
C
(100) [MKHN ] , 181 (64), 180 (45), 166 (32), 152 (35),
139 (31), 127 (33), 115 (20), 77 (41), 51 (38). Analysis
butyl(dimethyl)silyl]oxy}phenyl)ethanone; yield 32%;
amber crystals, mp 68–69 8C; H NMR (DMSO-d , d
3
1
6

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1857
found: C, 61.11; H, 4.97; N, 27.46%. Calcd for C H N C
1
ppm): 1.97–2.08 (m, 2H, 9-CH ), 2.44 (s, 3H, Me), 2.84 (t,
2
3
11
5
H O (255.29): C, 61.17; H, 5.13; N, 27.43%.
2
2H, JZ7.6 Hz, 8-CH ), 2.95 (t, 2H, JZ7.5 Hz, 10-CH ),
2
2
1
.48 (s, 1H, 6-H). C NMR (DMSO-d , d ppm): 22.3
3
8
(CH
6
4.3.5.2. 2-Methyl-1-(2H-tetrazol-5-yl)-5,6-dihydro-
benzo[f]isoquinoline (8b). Yield 52%; creamy crystals,
3
), 24.6 (9-CH
2
), 29.8 (8-CH
2
), 32.2 (10-CH
2
), 118.2
H),
155.1 (4-C). Mass (m/z): 201 (37) [M] , 173 (48) [MK
(3-C), 138.3 (5-C), 144.8 (6-C), 153.4 (2-C), 153.5 (CN
4
1
mp 269–270 8C (decomp.); H NMR (DMSO-d , d ppm):
C
6
C
C
C
2
1
7
.26 (s, 3H, Me), 2.82 (br s, 4H, CH –CH ), 6.20–6.31 (m,
2
H, Ph), 6.93–7.04 (m, 1H, Ph), 7.20–7.31 (m, 1H, Ph),
.33–7.42 (m, 1H, Ph), 8.61 (s, 1H, 6-H). C NMR
N
2
] , 172 (44) [MKHN ] , 158 (62) [MKHN ] , 157
2 3
2
C
(63) [MKHN –H] , 128 (58), 116 (22), 103 (18), 89 (15),
3
1
3
53 (37), 51 (46), 50 (100), 43 (48). Analysis found: C, 59.61;
H, 5.68; N, 34.68%. Calcd for C10
H, 5.51; N, 34.80%.
(
DMSO-d , d ppm): 22.7 (CH ), 25.3 (15-C), 28.4 (14-C),
6
H N (201.23): C, 59.69;
11 5
3
1
1
16.0 (3-C), 126.2 (10-C), 126.6 (12-C), 128.6 (11-C),
29.5 (9-C), 130.5 (8-C), 131.4 (5-C), 140.4 (13-C), 141.9
(
(
4-C), 149.7 (6-C), 153.8 (CN H), 156.4 (2-C). IR n
4
4.3.5.8. 3-Methyl-4-(2H-tetrazol-5-yl)-5,6,7,8-tetrahy-
droisoquinoline (8h). Yield 61%; pale yellow crystals, mp
, d ppm): 1.59–1.75 (m,
max
film) 2940, 2360, 1960, 1590, 1430, 1390, 1230, 1195,
105, 1095, 1005, 890, 850, 750. Mass (m/z): 263 (14)
1
220–222 8C; H NMR (DMSO-d
1
[
6
C
M] , 234 (13) [MKHN ] , 220 (100) [MKHN ] , 207
C
C
4H, 9-CH
8-CH ), 2.71–2.78 (m, 2H, 11-CH
NMR (DMSO-d
22.2 (CH ), 25.6 (8-CH
30.6 (5-C), 146.0 (4-C), 150.9 (6-C), 152.5 (CN H), 153.4
, 10-CH
), 2.15 (s, 3H, CH
), 2.26–2.34 (m, 2H,
2
3
2
2
3
1
3
(18), 190 (14), 165 (19), 77 (10). Analysis found: C, 68.49;
H, 4.94; N, 26.61%. Calcd for C H N (263.30): C, 68.43;
H, 4.98; N, 26.60%.
2
2
), 8.45 (s, 1H, 6-H).
C
, d ppm): 21.6 (10-CH
), 26.3 (11-CH
2
), 21.7 (9-CH
), 120.2 (3-C),
),
2
1
5 13 5
6
2
3
2
1
4
C
C
(
2-C). Mass (m/z): 215 (65) [M] , 187 (52) [MKN ] , 186
2
4
meno[3,4-c]pyridine (8c). The title compound was
described in preliminary communication.
.3.5.4. 4-(4-Bromophenyl)-2-methyl-3-(2H-tetrazol-
5
2
(
1
.3.5.3.
2-Methyl-1-(2H-tetrazol-5-yl)-5H-chro-
C C
42) [MKHN ] , 172 (100) [MKHN ] , 171 (94) [MK
(
HN –H] , 159 (71), 158 (34), 157 (47), 144 (73), 131 (17),
2
3
C
†
13
3
1
(
15 (30), 104 (24), 91 (41), 77 (62), 65 (38), 63 (54), 59
51), 51 (58). Analysis found: C, 61.37; H, 6.09; N, 32.54%.
Calcd for C H N (215.26): C, 61.38; H, 6.09; N, 32.53%.
4
-yl)pyridine (8d). Yield 76%; pale grey crystals, mp
11 13 5
1
12–215 8C (decomp.); H NMR (DMSO-d , d ppm): 2.31
6
0
0
4.3.5.9. 3-Methyl-4-(2H-tetrazol-5-yl)-6,7,8,9-tetrahy-
dro-5H-cyclohepta[c]pyridine (8i). Yield 58%; brown
s, 3H, Me), 7.01 (d, 2H, JZ8.4 Hz, 2 -H, 6 -H, Ar), 7.45 (d,
H, JZ5.1 Hz, 5-H), 7.52 (d, 2H, JZ8.3 Hz, 3 -H, 5 -H,
0 0
1
crystals, mp 224–226 8C (decomp.); H NMR (DMSO-d ,
Ar), 8.72 (d, 1H, JZ5.1 Hz, 6-H), 15.5–17.3 (br s, 1H, NH).
Analysis found: C, 49.19; H, 3.11; Br, 25.25; N, 22.11%.
Calcd for C H BrN (316.16): C, 49.39; H, 3.19; Br,
6
d ppm): 1.35–1.45 (m, 2H, 9-CH ), 1.53–1.62 (m, 2H, 11-
2
CH ), 1.69–1.79 (m, 2H, 10-CH ), 2.05 (s, 3H, CH ), 2.27–
2
2
3
1
3
10
5
2
1
.35 (m, 2H, 8-CH ), 2.75–2.82 (m, 2H, 12-CH ), 8.26 (s,
2 2
2
5.27; N, 22.15%.
1
H, 6-H). C NMR (DMSO-d , d ppm): 22.7 (CH ), 26.5
3
6
3
(
9-CH ), 27.7 (11-CH ), 31.0 (10-CH ), 31.6 (8-CH ), 31.8
2 2 2 2
4.3.5.5. 4-(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)-
-methyl-3-(2H-tetrazol-5-yl)pyridine (8e). CHCl /THF
(12-CH ), 122.6 (3-C), 136.0 (5-C), 148.6 (6-C), 151.6 (4-
C), 154.7 (2-C), 154.8 (CN H). Mass (m/z): 229 (41) [M] ,
200 (28) [MKHN ] , 186 (100) [MKHN ] , 172 (79),
2 3
2
2
system was used for purification; yield 78%; pale yellow
3
C
4
C
C
1
crystals, mp 207–210 8C (decomp.); H NMR (DMSO-d , d
6
1
59 (33), 145 (37), 144 (75), 132 (18), 115 (20), 101 (15), 91
ppm): 0.16 (s, 6H, Si(CH ) ), 0.92 (s, 9H, SiC(CH ) ), 2.28
3
2
3 3
0 0
(38), 77 (32), 59 (41), 57 (38), 43 (31). Analysis found: C,
62.88; H, 6.56; N, 30.45%. Calcd for C H N (229.29): C,
6
(
s, 3H, Me), 6.77 (d, 2H, JZ8.8 Hz, 3 -H, 5 -H, Ar), 6.97 (d,
0 0
H, JZ8.8 Hz, 2 -H, 6 -H, Ar), 7.42 (d, 1H, JZ5.1 Hz, 5-
1
2 15 5
2
2.86; H, 6.59; N, 30.54%.
H), 8.67 (d, 1H, JZ5.1 Hz, 6-H). Analysis found: C, 62.42;
H, 7.01; N, 18.69%. Calcd for C H N OSi (367.53): C,
6
1
9 25 5
4.3.5.10. 3,5-Dimethyl-4-(2H-tetrazol-5-yl)-5,6,7,8-
tetrahydroisoquinoline (8j). Yield 47%; white powder,
2.09; H, 6.86; N, 19.06%.
1
mp 172–174 8C; H NMR (DMSO-d , d ppm): 0.77 (d, 3H,
6
4.3.5.6. 4-(4-Chloro-3-nitrophenyl)-2-methyl-3-(2H-
tetrazol-5-yl)pyridine (8f). Yield 44%; pale yellow
JZ7.3 Hz, 12-CH ), 1.55–1.85 (m, 4H, 9-CH , 10-CH ),
3
2
2
1
crystals, mp 107–110 8C; H NMR (DMSO-d , d ppm):
2.10 (s, 3H, 7-CH ), 2.63–2.89 (m, 3H, 8-H, 11-CH ), 8.36
3
2
6
13
0
(s, 1H, 6-H). C NMR (DMSO-d , d ppm): 16.6 (10-CH ),
6 2
2
7
.36 (s, 3H, Me), 7.31 (dd, 1H, JZ8.4, 2.2 Hz, 6 -H, Ar),
0
21.2 (12-CH ), 22.2 (7-CH ), 25.4 (11-CH ), 28.7 (9-CH ),
3 3 2 2
28.8 (8-CH), 119.9 (3-C), 129.7 (5-C), 150.9 (4-C), 151.3
.53 (d, 1H, JZ5.1 Hz, 5-H), 7.71 (d, 1H, JZ8.4 Hz, 5 -H,
0
.1 Hz, 6-H). Analysis found: C, 49.49; H, 3.02; N, 26.93%.
Ar), 7.86 (d, 1H, JZ2.2 Hz, 2 -H, Ar), 8.76 (d, 1H, JZ
5
Calcd for C H ClN O (316.71): C, 49.30; H, 2.86; N,
(
[
(
6-C), 152.7 (CN H), 153.8 (2-C). Mass (m/z): 229 (39)
4
C
M] , 200 (12) [MKHN ] , 186 (100) [MKHN ] , 185
C
C
2
3
1
3
9
6
2
C
38) [MKHN –H] , 172 (38), 156 (24), 144 (34), 130 (16),
3
2
6.54%.
1
(
14 (16), 102 (16), 91 (25), 76 (21), 59 (84), 57 (64), 43
42), 42 (35). Analysis found: C, 62.99; H, 6.53; N, 30.46%.
Calcd for C H N (229.29): C, 62.86; H, 6.59; N, 30.54%.
4.3.5.7. 3-Methyl-4-(2H-tetrazol-5-yl)-6,7-dihydro-
H-cyclopenta[c]pyridine (8g). Yield 78%; pale brown
1
2 15 5
5
crystals, mp 225–227 8C (decomp.); H NMR (DMSO-d , d
1
6
4.3.5.11. 4-Isopropyl-2-methyl-3-(2H-tetrazol-5-
yl)pyridine (8k). Yield 63%; light brown crystals, mp
†
The authors apologise for inaccuracy in structure 6c in the communi-
1
160–163 8C (decomp.); H NMR (DMSO-d , d ppm): 1.08
13
6
cation where oxygen atom was depicted as connected with pyridine
ring. This oxygen atom has to be connected with phenyl ring; the correct
structure is 8c in this paper (Scheme 4).
(
d, 6H, JZ6.8 Hz, 9-CH , 10-CH ), 2.15 (s, 3H, 7-CH ),
3 3 3
2.38 (m, 1H, JZ6.8 Hz, 8-CH), 7.40 (d, 1H, JZ5.2 Hz,

1858
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1
3
5
ppm): 22.7 (9-CH , 10-CH ), 22.8 (7-CH ), 30.2 (8-CH),
1
-H), 8.57 (d, 1H, JZ5.2 Hz, 6-H). C NMR (DMSO-d , d
4.4.1.3. 3-(Hydroxymethyl)-5,6,7,8-tetrahydroisoqui-
noline-4-carbonitrile (11h). Yield 23%; pale yellow
6
3
3
3
1
crystals, mp 69–72 8C; H NMR (DMSO-d , d ppm):
18.5 (5-C), 119.7 (3-C), 150.8 (6-C), 152.6 (CN H), 156.7
4
6
C
2-C), 157.6 (4-C). Mass (m/z): 203 (34) [M] , 174 (17)
(
1.71–1.84 (m, 4H, 6-CH , 7-CH ), 2.72–2.77 (m, 2H, 5-
2
2
C C
MKHN ] , 160 (100) [MKHN ] , 159 (51) [MKHN –
[
CH ), 2.83–2.88 (m, 2H, 8-CH ), 4.61 (d, 2H, JZ5.8 Hz,
2
3
3
2
2
C
H] , 145 (78), 131 (29), 118 (34), 91 (32), 77 (53), 65 (56),
3 (31), 59 (50), 57 (35), 51 (58). Analysis found: C, 59.11;
H, 6.41; N, 34.41%. Calcd for C H N (203.25): C, 59.10;
CH OH), 5.50 (t, 1H, JZ5.8 Hz, OH), 8.46 (s, 1H, 1-H). IR
2
6
nmax (film) 3217 (OH), 2224 (C^N).
1
0 13 5
H, 6.45; N, 34.46%.
4.4.1.4. 5-Hydroxy-3-methyl-5,6,7,8-tetrahydroiso-
quinoline-4-carbonitrile (12). Yield 31%; pale yellow
1
crystals, mp 138–140 8C; H NMR (DMSO-d , d ppm):
4.3.5.12. 4-tert-Butyl-2-methyl-3-(2H-tetrazol-5-
yl)pyridine (8l). Yield 25%; pale yellow crystals, mp
6
1
3
.65–1.93 (m, 4H, CH ), 2.53–2.62 (m, 1H, CH ), 2.63 (s,
2 2
1
65–167 8C (decomp.); H NMR (DMSO-d , d ppm): 1.05
H, CH ), 2.72–2.83 (m, 1H, CH ), 4.72–4.77 (m, 1H,
3
1
2
6
CHOH), 5.56 (d, 1H, JZ5.9 Hz, OH), 8.46 (s, 1H, 1-H). IR
nmax (film) 3187 (OH), 2228 (C^N).
(
s, 9H, t-Bu), 1.98 (s, 3H, CH ), 7.47 (d, 1H, JZ5.4 Hz, 5-
3
13
H), 8.55 (d, 1H, JZ5.4 Hz, 6-H). C NMR (DMSO-d , d
6
ppm): 22.8 (7-CH ), 30.6 (9-CH , 10-CH , 11-CH ), 36.1
(
3
3
3
3
4.4.1.5. 4-tert-Butyl-2-(hydroxymethyl)nicotinonitrile
11l). yield 86%; pale yellow crystals, mp 66–68 8C; H
8-C), 119.3 (3-C), 119.6 (5-C), 150.8 (6-C), 154.2 (CN H),
4
1
C
57.8 (2-C), 159.0 (4-C). Mass (m/z): 217 (43) [M] , 202
(
NMR (DMSO-d , d ppm): 1.47 (s, 9H, (CH ) ), 4.71 (d, 2H,
1
C C
14) [MKNH] , 189 (17) [MKN ] , 174 (55) [MK
(
HN ] , 160 (61) [MKt-Bu] , 159 (100), 145 (43), 132
6
3 3
2
C
C
JZ5.6 Hz, CH ), 5.46 (t, 1H, JZ5.6 Hz, OH), 7.49 (d, 1H,
2
3
(
6
29), 118 (14), 91 (21), 77 (36), 57 (31). Analysis found: C,
1.19; H, 7.03; N, 32.58%. Calcd for C H N (217.28): C,
11 15 5
JZ5.4 Hz, 5-H), 8.69 (d, 1H, JZ5.4 Hz, 6-H). IR nmax
(
film) 3226 (OH), 2221 (C^N).
6
0.81; H, 6.96; N, 32.23%.
4
.4.1.6. [4-Phenyl-3-(2H-tetrazol-5-yl)pyridine-2-
yl]methanol (13). Dibutyltin oxide (0.046 g, 0.18 mmol)
and trimethylsilyl azide (0.33 mL, 2.5 mmol) were added to
a solution of nitrile 11a (0.20 g, 0.95 mmol) in anhydrous
1,4-dioxane (5 mL). The reaction mixture was subjected to
microwave irradiation in a tightly sealed glass vessel for 2 h
at 120 8C with stirring then cooled to room temperature. The
solvent was removed under reduced pressure (80 8C/
4.3.5.13. tert-Butyl-6-methyl-5-(2H-tetrazol-5-yl)-3,4-
dihydro-2,7-naphthyridine-2(1H)-carboxylate (8m).
Reaction time 4 h at 120 8C; yield 46%; pale yellow
crystals, mp 187–190 8C (decomp.); H NMR (DMSO-d , d
1
6
ppm): 1.42 (s, 9H, t-Bu), 2.24 (s, 3H, Me), 2.45 (t, 2H, JZ
5
1
2
4
.7 Hz, 8-CH ), 3.49 (t, 2H, JZ5.7 Hz, 9-CH ), 4.60 (s, 2H,
2 2
13
0-CH ), 8.49 (s, 1H, 6-H). C NMR (DMSO-d , d ppm):
2
6
2
0 Torr). The residue was treated with methanol (5 mL),
2.5 (7-CH ), 26.1 (13-CH , 14-CH , 15-CH ), 28.1 (8-C),
3
3
3
3
and the mixture was evaporated to dryness. The residue was
mixed with acetonitrile (10 mL). The precipitate was
filtered off and recrystallized from methanol to give the
0.7 (10-C), 42.7 (9-C), 79.4 (12-C), 120.0 (3-C), 127.7 (5-
C), 143.9 (4-C), 148.7 (6-C), 152.3 (CN H), 153.9 (11-C),
4
1
54.6 (2-C). IR nmax (film) 2970, 2925, 2340, 1920, 1680
C]O), 1600, 1455, 1420, 1285, 1250, 1165, 1105, 1045,
titled product 13 (0.13 g, 51%) as white powder, mp 240–
242 8C; H NMR (DMSO-d , d ppm): 3.01–3.60 (br s, 1H,
(
1
C
80, 910, 780. Mass (m/z): 316 (2) [M] , 259 (24) [MK
6
9
C H ] , 243 (10) [MKC H O] , 216 (24) [MKC H –
C
C
OH), 4.44 (s, 2H, CH ), 7.05–7.12 (m, 2H, Ph), 7.28–7.36
2
(m, 3H, Ph), 7.53 (d, 1H, JZ5.1 Hz, 5-H), 8.78 (d, 1H, JZ
4
9
4
9
4 9
C
HN ] , 200 (12), 187 (27), 172 (45), 142 (28), 55 (100).
3
5.1 Hz, 6-H). Analysis found: C, 60.80; H, 4.50; N, 27.35%.
Calcd for C H N OC0.2H O (256.87): C, 60.79; H, 4.47;
N, 27.26%.
Analysis found: C, 56.98; H, 6.41; N, 26.51%. Calcd for
C H N O (316.37): C, 56.95; H, 6.37; N, 26.56%.
1
3
11
5
2
1
5 20 6 2
0
0
4.4. Preparation of the 5H-tetrazolo[1 ,5 :1,5]-
pyrrolo[3,4-b]pyridines 15a,h,l
4.4.1.7. 3-(Chloromethyl)-5,6,7,8-tetrahydroisoquino-
line-4-carbonitrile (14h). Yield 55%; pale yellow glassy
1
mass; H NMR (DMSO-d , d ppm): 1.71–1.85 (m, 4H,
6
4
.4.1. Functionalization of 2-methyl group. General
procedure for a conversion 5a,h,l/9a,h,l/10a,h,l/
11a,h,l was described in preliminary communication (for
compound 5a).
2
4
CH ), 2.74–2.80 (m, 2H, CH ), 2.85–2.92 (m, 2H, CH ),
2 2 2
.84 (s, 2H, CH Cl), 8.53 (s, 1H, 6-H).
2
1
9
4.4.1.8. 4-tert-Butyl-2-(chloromethyl)nicotinonitrile
14l). Yield 100%; pale yellow glassy mass; H NMR
1
(
4.4.1.1. 3-Methyl-5,6,7,8-tetrahydroisoquinoline-4-
carbonitrile 2-oxide (9h). Yield 94%; pale yellow crystals,
(
7
DMSO-d , d ppm): 1.48 (s, 9H, (CH ) ), 5.74 (s, 2H, CH ),
6
.64 (d, 1H, JZ5.5 Hz, 5-H), 8.79 (d, 1H, JZ5.5 Hz, 6-H).
3 3
2
1
mp 135–138 8C; H NMR (DMSO-d , d ppm): 2.62–2.96
6
(
2
m, 4H, 6-CH , 7-CH ), 2.49 (s, 3H, CH ), 2.62–2.69 (m,
2 2 3
H, 5-CH ), 2.74–2.80 (m, 2H, 8-CH ), 8.35 (s, 1H, 1-H).
2 2
4.4.1.9. 3-(Azidomethyl)-5,6,7,8-tetrahydroisoquino-
line-4-carbonitrile (15h). Yield 91%; pale yellow crystals,
1
mp 88–90 8C; H NMR (DMSO-d , d ppm): 1.71–1.85 (m,
IR nmax (film) 2229 (C^N).
6
4
CH
H, 2CH ), 2.74–2.80 (m, 2H, CH ), 2.85–2.91 (m, 2H,
2
2
4.4.1.2. 4-tert-Butyl-2-methylnicotinonitrile 1-oxide
9l). Yield 50%; pale yellow crystals, mp 147–149 8C; H
2
), 4.63 (s, 2H, CH
2
N
3
), 8.55 (s, 1H, 6-H). IR nmax (film)
1
(
NMR (DMSO-d , d ppm): 1.44 (s, 9H, (CH ) ), 2.58 (s, 3H,
2102 (N ), 2224 (C^N).
3
6
3 3
CH ), 7.39 (d, 1H, JZ7.1 Hz, 5-H), 8.44 (d, 1H, JZ7.1 Hz,
4.4.1.10. 2-(Azidomethyl)-4-tert-butylnicotinonitrile
(15l). Yield 65%; pale yellow crystals, mp 65–67 8C; H
3
1
6
-H). IR nmax (film) 2227 (C^N).

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1859
NMR (DMSO-d , d ppm): 1.47 (s, 9H, (CH ) ), 4.74 (s, 2H,
6
NMR (DMSO-d , d ppm): 0.90 (s, 9H, (CH ) ), 3.51 (dd,
6 3 3
3 3
CH ), 7.57 (d, 1H, JZ5.5 Hz, 5-H), 8.77 (d, 1H, JZ5.5 Hz,
1H, JZ17.4, 1.7 Hz, CH ), 3.80 (dd, 1H, JZ17.4, 8.1 Hz,
2
2
6
-H). IR nmax (film) 2111 (N ), 2220 (C^N).
CH ), 4.93 (dd, 1H, JZ8.1, 1.7 Hz, CH), 7.32–7.40 (m, 3H,
3
2
Ph), 7.44–7.51 (m, 2H, Ph), 7.48 (d, 1H, JZ5.2 Hz, 5-H),
8.67 (d, 1H, JZ5.2 Hz, 6-H). Analysis found: C, 70.68; H,
6.14; N, 22.79%. Calcd for C18H N (305.39): C, 70.80; H,
19 5
4
.4.2. Intramolecular [3C2] cycloaddition. All the
compounds 16a,h,l were described in preliminary
1
9
communication.
6.27; N, 22.93%. Crystallographic data for compound 19a:
C H N , monoclinic, space group P2(1)/n, aZ
1
8
19
5
˚
3
4.5. Preparation of the 5,6-dihydrotetrazolo[5,1-f]-1,6-
naphthyridines 19a,b
9.1730(18), bZ9.4000(19), cZ18.803(4) A, aZ908, bZ
˚
93.32(3)8, gZ908, volume 1618.6(6) A , TZ293(2) K,
3
K1
ZZ4, D Z1.253 Mg/m , mZ0.078 mm , qmaxZ25.238,
c
4
.5.1. 2-[(1E)-3,3-Dimethylbut-1-en-1-yl]-4-phenylnico-
tinonitrile (17a). Potassium tert-butoxide (0.34 g,
mmol) was added to a solution of 2-methyl-4-phenylni-
3101 reflections measured and 2885 unique (RintZ0.0401)
2
reflections, full matrix least-squares refinement on F , R
1
3
(obsd)Z0.0474, and wR (all data)Z0.1333. Crystallo-
2
cotinonitrile (0.5 g, 2.57 mmol) in anhydrous THF (5 mL).
Trimethylacetic aldehyde (0.29 mL, 2.7 mmol) was added
dropwise to this bright red reaction mixture that was then
stirred at room temperature for 2 h. The mixture was diluted
with water (5 mL) and treated with ethyl acetate (4!
graphic data (excluding structure factors) for the structure in
this paper in the form of a CIF have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 276729. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: C44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
10 mL). The extract was dried over MgSO and concen-
4
trated under reduced pressure (60 8C/10 Torr). The residue
was chromatographed (silica gel, hexane/ethyl acetate 4:1)
to give the product 17a (0.63 g, 94%) as white powder, mp
4.5.4. 2-[(1E)-3,3-Dimethylbut-1-en-1-yl]4-phenyl-3-
(2H-tetrazol-5-yl)pyridine (18). The title compound was
also isolated from the reaction mixture (0.05 g, 22%) as
1
73–175 8C; H NMR (DMSO-d , d ppm): 1.16 (s, 9H,
1
6
(
CH ) ), 6.79 (d, 1H, JZ15.4 Hz, CH]CH), 7.27 (d, 1H,
3
3
1
JZ15.4 Hz, CH]CH), 7.49 (d, 1H, JZ5.1 Hz, 5-H), 7.54–
white powder, mp 165–167 8C; H NMR (DMSO-d
6
, d
7
.61 (m, 3H, Ph), 7.62–7.69 (m, 2H, Ph), 8.79 (d, 1H, JZ
.1 Hz, 6-H). Analysis found: C, 82.29; H, 6.97; N, 10.59%.
ppm): 0.96 (s, 9H, (CH ) ), 5.88 (d, 1H, JZ15.5 Hz,
CH]CH), 6.97 (d, 1H, JZ15.5 Hz, CH]CH), 7.06–7.12
(m, 2H, Ph), 7.22–7.28 (m, 3H, Ph), 7.34 (d, 1H, JZ5.0 Hz,
3 3
5
Calcd for C H N (262.36): C, 82.41; H, 6.92; N, 10.68%.
1
8 18 2
5-H), 8.67 (d, 1H, JZ5.0 Hz, 6-H). Analysis found: C,
4
(
.5.2. 4-tert-Butyl-2-[(E)-2-phenylvinyl]nicotinonitrile
17b). Potassium tert-butoxide (0.77 g, 6.88 mmol) was
added to a solution of 4-tert-butyl-2-methylnicotinonitrile
1.0 g, 6.25 mmol) in anhydrous THF (10 mL) at 0 8C. The
70.84; H, 6.27; N, 22.78%. Calcd for C18
70.80; H, 6.27; N, 22.93%.
H N (305.39): C,
19 5
(
4.5.5. 10-tert-Butyl-5-phenyl-5,6-dihydrotetrazolo[5,1-f]-
1,6-naphthyridine (19b). Dibutyltin oxide (0.23 g,
0.9 mmol) and trimethylsilyl azide (0.4 mL, 3 mmol) were
added to a solution of nitrile 17b (0.20 g, 0.76 mmol) in
anhydrous 1,4-dioxane (2 mL). The reaction mixture was
subjected to microwave irradiation in a tightly sealed glass
vessel for 4 h at 140 8C with stirring then cooled to room
temperature. The solvent was removed to dryness. The
residue was treated with methanol (5 mL), and the mixture
was evaporated to dryness. The residue was chromato-
graphed (silica gel, hexane/ethyl acetate 2:1) to give the
bright red reaction mixture was stirred at 0 8C for 15 min,
and benzaldehyde (0.67 mL, 6.6 mmol) was added drop-
wise. The mixture was stirred at 0 8C for 10 min then at
room temperature for 1 h. The mixture was diluted with
water (10 mL) and treated with diethyl ether (4!20 mL).
The extract was washed with brine, dried over MgSO and
4
concentrated under reduced pressure. The residue was
chromatographed (silica gel, chloroform) to give the
product 17b (1.03 g, 63%) as white crystals, mp 130–
1
7
1
31 8C; H NMR (DMSO-d , d ppm): 1.47 (s, 9H, (CH ) ),
3 3
6
.36–7.49 (m, 3H, Ph), 7.41 (d, 1H, JZ5.1 Hz, 5-H), 7.58
titled product 19b (0.16 g, 68%) as pale yellow crystals, mp
1
(
d, 1H, JZ15.5 Hz, CH]CH), 7.66–7.72 (m, 2H, Ph), 7.97
d, 1H, JZ15.5 Hz, CH]CH), 8.73 (d, 1H, JZ5.1 Hz, 6-
175–177 8C; H NMR (DMSO-d
(CH
6
, d ppm): 1.56 (s, 9H,
), 3.93 (dd, 1H,
), 4.93 (t, 1H, JZ5.6 Hz, CH), 7.07–
7.12 (m, 2H, Ph), 7.27–7.37 (m, 3H, Ph), 7.53 (d, 1H, JZ
.5 Hz, 5-H), 8.53 (d, 1H, JZ5.5 Hz, 6-H). Analysis found:
(
H). Analysis found: C, 82.56; H, 7.12; N, 10.49%. Calcd for
) ), 3.73 (dd, 1H, JZ16.4, 5.6 Hz, CH
3 3 2
JZ16.4, 5.6 Hz, CH
2
C H N (262.36): C, 82.41; H, 6.92; N, 10.68%.
18 18 2
5
4.5.3. 5-tert-Butyl-10-phenyl-5,6-dihydrotetrazolo[5,1-f]-
1,6-naphthyridine (19a). Dibutyltin oxide (0.068 g,
0.25 mmol) and trimethylsilyl azide (0.4 mL, 3 mmol)
C, 70.84; H, 6.31; N, 22.94%. Calcd for C18
C, 70.80; H, 6.27; N, 22.93%.
H N (305.39):
19 5
were added to a solution of nitrile 17a (0.20 g,
.76 mmol) in anhydrous 1,4-dioxane (2 mL). The reaction
4.6. General procedure for alkylation of model tetrazoles
7a–f
0
mixture was subjected to microwave irradiation in a tightly
sealed glass vessel for 2 h at 140 8C with stirring then cooled
to room temperature. The solvent was removed to dryness.
The residue was treated with methanol (5 mL), and the
mixture was evaporated to dryness. The residue was
chromatographed (silica gel, hexane then hexane/ethyl
Freshly calcined K CO (0.15 g, 1.08 mmol) was added to a
2
3
solution of the tetrazole (1.08 mmol) in acetone (2 mL). The
mixture was refluxed under stirring for 2 h, and then benzyl
bromide (0.13 mL, 1.13 mmol) was added to the reaction
mixture. The latter was refluxed for 6 h then cooled to room
temperature, diluted with acetone (10 mL) and filtered. The
filtrate was evaporated to dryness. The residue was
acetate in gradient 2:1–1:100) to give the titled product
1
1
9a (0.12 g, 52%) as white crystals, mp 174–176 8C; H

1860
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
chromatographed (silica gel, hexane/ethyl acetate in
gradient 4:1 to 3:1) to give the isomeric products.
1349, 1319, 1189, 1070, 1028, 745, 725, 696. Analysis
found: C, 74.89; H, 6.45; N, 18.50%. Calcd for C H N
9 20 4
1
(304.40): C, 74.97; H, 6.62; N, 18.41%.
4
.6.1. 1-Benzyl-5-(1-phenylcyclopropyl)-1H-tetrazole
1
(20a). Yield 37%; pale yellow oil; H NMR (DMSO-d , d
6
ppm): 1.42–1.48 (m, 2H, CH ), 1.48–1.53 (m, 2H, CH ),
4.6.7. 1-Benzyl-5-(1-phenylcyclohexyl)-1H-tetrazole
(20d). Yield 20%; white crystals, mp 102–103 8C; H
NMR (DMSO-d , d ppm): 1.27–1.40 (m, 1H, 4-H), 1.41–
6
1
2
2
5
2
.38 (s, 2H, PhCH ), 6.92–6.97 (m, 2H, Ph), 7.05–7.10 (m,
2
1
3
H, Ph), 7.20–7.33 (m, 6H, Ph). C NMR (DMSO-d , d
6
1.60 (m, 5H, CH , 4-H), 1.97–2.10 (m, 2H, CH ), 2.41–2.50
2
2
ppm): 15.1 (CH ), 18.6 (PhC), 50.3 (PhCH ), 126.7, 127.0,
2
2
(m, 2H, CH ), 5.10 (s, 2H, PhCH ), 6.72–6.78 (m, 2H, Ph),
2 2
1
(
27.8, 128.2, 128.6, 128.8, 133.8, 139.3 (Ph), 157.2
CN H). IR n (film) 3444, 3061, 3031, 1602, 1523,
7
.17–7.21 (m, 2H, Ph), 7.21–7.31 (m, 4H, Ph), 7.31–7.39
(m, 2H, Ph). IR nmax (film) 3063, 3010, 2947, 2926, 2862,
596, 1492, 1443, 1399, 1278, 1235, 1112, 895, 743, 723,
4
max
1
7
7
451, 1333, 1175, 1030, 931, 725, 700. Analysis found: C,
3.75; H, 5.69; N, 20.11%. Calcd for C H N (276.34): C,
3.89; H, 5.84; N, 20.27%.
1
1
7
16
4
700. Analysis found: C, 75.51; H, 7.07; N, 17.68%. Calcd
for C H N (318.43): C, 75.44; H, 6.96; N, 17.59%.
2
0 22 4
4
.6.2. 2-Benzyl-5-(1-phenylcyclopropyl)-2H-tetrazole
21a). Yield 47%; pale yellow oil; H NMR (DMSO-d , d
4
(
.6.8. 2-Benzyl-5-(1-phenylcyclohexyl)-2H-tetrazole
21d). Yield 79%; white crystals, mp 92–93 8C; H NMR
1
(
ppm): 1.37–1.41 (m, 2H, CH ), 1.47–1.52 (m, 2H, CH ),
5
1
6
2
2
(DMSO-d , d ppm): 1.17–1.39 (m, 3H, CH , 4-H), 1.46–
6
1
3
2
.83 (s, 2H, PhCH ), 7.22–7.41 (m, 10H, Ph). C NMR
2
1
2
7
.56 (m, 1H, 4-H), 1.56–1.66 (m, 2H, CH ), 1.96–2.09 (m,
2
(
DMSO-d , d ppm): 16.2 (CH ), 22.1 (PhC), 55.8 (PhCH ),
6 2 2
H, CH ), 2.54–2.65 (m, 2H, CH ), 5.91 (s, 2H, PhCH ),
2
2
2
1
26.8, 128.1, 128.3, 128.8, 129.1, 134.2, 140.9 (Ph), 169.9
(film) 3421, 3060, 3031, 1602, 1503, 1454,
335, 1212, 1057, 1026, 935, 755, 723, 698. Analysis found:
.13–7.19 (m, 1H, Ph), 7.20–7.31 (m, 6H, Ph), 7.31–7.42
(
CN H). IR n
4
max
(m, 3H, Ph). IR nmax (film) 3060, 2940, 2861, 1580, 1495,
1
1
6
452, 1346, 1318, 1185, 1133, 1067, 1026, 895, 743, 724,
92. Analysis found: C, 75.57; H, 6.91; N, 17.69%. Calcd
C, 73.85; H, 5.97; N, 20.28%. Calcd for C H N (276.34):
1
C, 73.89; H, 5.84; N, 20.27%.
7 16 4
for C H N (318.43): C, 75.44; H, 6.96; N, 17.59%.
20 22 4
4
.6.3. 1-Benzyl-5-(1-phenylcyclobutyl)-1H-tetrazole
1
4.6.9. 1-Benzyl-5-(4-phenyltetrahydro-2H-pyran-4-yl)-
(20b). Yield 33%; white crystals, mp 108–110 8C;
NMR (DMSO-d , d ppm): 1.88–2.06 (m, 2H, CH ), 2.66–
H
1
1
2
4
2
H-tetrazole (20e). Yield 11%; white crystals, mp 113–
15 8C; H NMR (CDCl , d ppm): 2.19–2.30 (m, 2H, CH ),
6
2
1
3
2
2
PhCH ), 6.72–6.77 (m, 2H, Ph), 7.16–7.39 (m, 8H, Ph). IR
nmax (film) 3420, 3031, 2993, 2947, 2866, 1699, 1493, 1445,
.77 (m, 2H, CH ), 2.82–2.93 (m, 2H, CH ), 5.16 (s, 2H,
2 2
.37–2.45 (m, 2H, CH ), 3.66–3.81 (m, 4H, CH OCH ),
2
2
2
2
.95 (s, 2H, PhCH ), 6.79–6.85 (m, 2H, Ph), 7.12–7.18 (m,
2
H, Ph), 7.22–7.28 (m, 3H, Ph), 7.28–7.40 (m, 3H, Ph). IR
1
7
7
410, 1306, 1230, 1107, 829, 723, 699. Analysis found: C,
4.18; H, 6.15; N, 18.98%. Calcd for C H N (290.37): C,
4.46; H, 6.25; N, 19.29%.
nmax (film) 3032, 2956, 2889, 2866, 1597, 1493, 1447, 1412,
296, 1242, 1201, 1135, 1098, 1025, 922, 749, 721, 697.
1
8 18 4
1
Analysis found: C, 71.37; H, 6.22; N, 17.29%. Calcd for
C H N O (320.40): C, 71.23; H, 6.29; N, 17.49%.
1
9 20 4
4
.6.4. 2-Benzyl-5-(1-phenylcyclobutyl)-2H-tetrazole
1
(21b). Yield 58%; white crystals, mp 104–106 8C;
NMR (DMSO-d , d ppm): 1.86–2.04 (m, 2H, CH ), 2.65–
2
PhCH ), 7.16–7.22 (m, 1H, Ph), 7.24–7.41 (m, 9H, Ph). IR
H
4
2
9
2
.6.10. 2-Benzyl-5-(4-phenyltetrahydro-2H-pyran-4-yl)-
H-tetrazole (21e). Yield 79%; white crystals, mp
6
2
.76 (m, 2H, CH ), 2.79–2.88 (m, 2H, CH ), 5.87 (s, 2H,
2 2
1
2–94 8C; H NMR (DMSO-d , d ppm): 2.17–2.27 (m,
6
2
H, CH ), 2.59–2.67 (m, 2H, CH ), 3.23–3.29 (m, 2H,
2
nmax (film) 3445, 3022, 2978, 2939, 2863, 1599, 1550, 1486,
445, 1320, 1196, 1147, 1077, 1020, 745, 722, 696.
2
CH ), 3.77–3.85 (m, 2H, CH ), 5.92 (s, 2H, PhCH ), 7.17–
2
1
2
2
7.23 (m, 1H, Ph), 7.25–7.31 (m, 6H, Ph), 7.31–7.41 (m, 3H,
Ph). IR nmax (film) 3064, 3035, 2958, 2923, 2845, 2769,
Analysis found: C, 74.48; H, 6.31; N, 19.17%. Calcd for
C H N (290.37): C, 74.46; H, 6.25; N, 19.29%.
1
8 18 4
1
7
597, 1462, 1389, 1352, 1246, 1142, 1102, 1037, 933, 742,
21, 692. Analysis found: C, 71.20; H, 6.38; N, 17.52%.
4
.6.5. 1-Benzyl-5-(1-phenylcyclopentyl)-1H-tetrazole
1
Calcd for C H N O (320.40): C, 71.23; H, 6.29; N,
19 20 4
1
(
20c). Yield 23%; white crystals, mp 85–87 8C; H NMR
DMSO-d , d ppm): 1.62–1.78 (m, 4H, CH ), 2.25–2.35 (m,
7.49%.
(
6
2
2
H, CH ), 2.41–2.53 (m, 2H, CH ), 5.14 (s, 2H, PhCH ),
2 2 2
6
(
.70–6.77 (m, 2H, Ph), 7.17–7.30 (m, 6H, Ph), 7.30–7.40
m, 2H, Ph). IR nmax (film) 3059, 2967, 2873, 1493, 1445,
4.7. General procedure for alkylation of 3-(5-tetra-
zolyl)pyridines 8a,g
1
7
7
409, 1240, 1090, 1030, 748, 726, 703. Analysis found: C,
5.01; H, 6.54; N, 18.48%. Calcd for C H N (304.40): C,
4.97; H, 6.62; N, 18.41%.
1
9
20
4
Freshly calcined K CO (0.23 g, 1.68 mmol) was added to a
2
3
solution of the 3-(5-tetrazolyl)pyridine (0.84 mmol) in
acetone (2 mL). The mixture was heated in sealed tube at
70 8C under stirring for 2 h, and then benzyl bromide
(0.10 mL, 0.84 mmol) was added to the reaction mixture.
The latter was refluxed for 4 h then cooled to room
temperature, diluted with acetone (10 mL) and filtered.
The filtrate was evaporated to dryness. The residue was
chromatographed (silica gel, hexane/ethyl acetate in
gradient 3:1–1:1) to give the isomeric products.
4
.6.6. 2-Benzyl-5-(1-phenylcyclopentyl)-2H-tetrazole
1
(21c). Yield 72%; white crystals, mp 109–110 8C;
NMR (DMSO-d , d ppm): 1.44–1.57 (m, 2H, CH ), 1.67–
H
6
2
1
2
7
3
.81 (m, 2H, CH ), 2.09–2.21 (m, 2H, CH ), 2.65–2.76 (m,
2 2
H, CH ), 5.87 (s, 2H, PhCH ), 7.14–7.20 (m, 1H, Ph),
2
2
.23–7.33 (m, 6H, Ph), 7.33–7.41 (m, 3H, Ph). IR nmax (film)
058, 3021, 2961, 2915, 2873, 1598, 1484, 1459, 1382,

S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
1861
4.7.1. 3-(1-Benzyl-1H-tetrazol-5-yl)-2-methyl-4-phenyl-
pyridine (22a). Yield 44%; white crystals, mp 155–
Bu), 3.65 (dd, 1H, JZ14.2, 4.5 Hz, CH ), 3.87 (dd, 1H, JZ
2
14.2, 4.5 Hz, CHH ), 5.72 (t, 1H, JZ4.5 Hz, CH), 6.61–
2
1
57 8C; H NMR (CDCl , d ppm): 2.98 (s, 3H, Me), 4.42
1
6.65 (m, 2H, Ph), 6.93–7.05 (m, 3H, Ph), 7.36 (d, 1H, JZ
5.4 Hz, 5-H), 8.64 (d, 1H, JZ5.4 Hz, 6-H). Analysis found:
C, 75.61; H, 6.28; N, 17.70%. Calcd for C H N (305.39):
3
(
PhCH ), 6.27–6.77 (m, 2H, Ph), 7.14–7.20 (m, 4H, Ph),
d, 1H, JZ14.8 Hz, PhCH ), 5.12 (d, 1H, JZ14.8 Hz,
2
2
18 19 5
7
.21–7.25 (m, 1H, Ph), 7.29–7.39 (m, 3H, Ph), 7.34 (d, 1H,
C, 70.80; H, 6.27; N, 23.00%.
1
3
JZ5.5 Hz, 5-H), 8.71 (d, 1H, JZ5.5 Hz, 6-H). C NMR
(
1
1
CDCl , d ppm): 22.7 (CH ), 51.1 (PhCH ), 118.0, 121.5,
0
0
3
3
2
4.8.2. 5,5-Dibenzyl-9-tert-butyl-5H-tetrazolo[1 ,5 :1,5]-
pyrrolo[3,4-b]pyridine (25). The title compound was
also isolated (0.1 g, 25%) as white crystals, mp 195–197 8C;
27.8, 128.3, 128.9, 129.0, 129.1, 132.5, 136.5, 150.0,
51.5, 152.1 (Ph), 159.2 (CN H). Analysis found: C, 73.38;
4
H, 5.19; N, 21.43%. Calcd for C H N (327.39): C, 73.37;
2
H, 5.23; N, 21.39%.
1
0
17
5
H NMR (DMSO-d , d ppm): 1.12 (s, 9H, t-Bu), 3.85 (dd,
6
H, JZ17.1, 13.8 Hz, 2CH ), 6.43–6.48 (m, 4H, Ph), 6.86–
4
2
6
.98 (m, 6H, Ph), 7.38 (d, 1H, JZ5.4 Hz, 5-H), 8.81 (d, 1H,
4.7.2. 3-(2-Benzyl-2H-tetrazol-5-yl)-2-methyl-4-phenyl-
pyridine (23a). Yield 18%; light brown oil; H NMR
JZ5.4 Hz, 6-H). Analysis found: C, 75.70; H, 6.59; N,
17.70%. Calcd for C H N (395.51): C, 75.92; H, 6.37; N,
17.71%.
1
25 25 5
(
CDCl , d ppm): 2.45 (s, 3H, Me), 5.72 (s, 2H, PhCH ),
3 2
7
.01–7.06 (m, 2H, Ph), 7.10–7.16 (m, 4H, Ph), 7.18–7.22
(
m, 1H, Ph), 7.24 (d, 1H, JZ5.1 Hz, 5-H), 7.29–7.37 (m,
0
0
1
3
4.8.3. 6-Benzyl-9-tert-butyl-6H-tetrazolo[1 ,5 :1,5]-
pyrrolo[3,4-b]pyridine (26). Benzyl bromide (0.024 mL,
0
0
3
ppm): 23.3 (CH ), 56.7 (PhCH ), 122.0, 122.1, 127.8, 128.0,
1
1
5
5
H, Ph), 8.64 (d, 1H, JZ5.1 Hz, 6-H). C NMR (CDCl , d
3
3
2
.2 mmol) was added to a solution of compound 16l (0.04 g,
.2 mmol) in anhydrous acetone (1 mL). The mixture was
heated in sealed tube at 65 8C for 80 h then cooled and
diluted with anhydrous ether (1 mL). The precipitate formed
was filtered off, washed with cold ether (2 mL) and dried to
give an intermediate pyridinium bromide (0.02 g, 29%) as
28.1, 128.5, 129.8, 130.0, 133.3, 138.1, 149.6, 151.2 (Ph),
58.5 (CN H), 163.1 (Ph). Analysis found: C, 73.02; H,
4
.08; N, 21.28%. Calcd for C H N (327.39): C, 73.37; H,
0 17 5
2
.23; N, 21.39%.
4.7.3. 4-(1-Benzyl-1H-tetrazol-5-yl)-3-methyl-6,7-dihy-
dro-5H-cyclopenta[c]pyridine (22b). Yield 31%; grey
1
white crystals, mp 175–180 8C (decomp.); H NMR
(DMSO-d
1
crystals, mp 102–104 8C; H NMR (DMSO-d , d ppm):
6
, d ppm): 1.62 (s, 9H, t-Bu), 6.01 (s, 2H, CH
),
2
6
6
6
.25 (s, 2H, CH ), 7.30–7.62 (m, 5H, Ph), 8.29 (d, 1H, JZ
.7 Hz, 5-H), 9.20 (d, 1H, JZ6.7 Hz, 6-H). The salt
obtained was treated with saturated aqueous solution of
NaHCO (1 mL), and the product was extracted with ethyl
2
1
1
.79–2.10 (m, 3H, CH ), 1.99 (s, 3H, Me), 2.36–2.46 (m,
2
H, CH ), 2.83–2.97 (m, 2H, CH ), 5.48 (d, 1H, JZ15.2 Hz,
2
2
PhCH ), 5.57 (d, 1H, JZ15.2 Hz, PhCH ), 6.96–7.02 (m,
2
2
3
2
H, Ph), 7.24–7.33 (m, 3H, Ph), 8.50 (s, 1H, 6-H). IR nmax
film) 3034, 2962, 2864, 1578, 1495, 1452, 1404, 1240,
115, 988, 937, 727, 702. Analysis found: C, 70.19; H, 5.88;
N, 23.93%. Calcd for C H N (291.36): C, 70.08; H, 5.88;
acetate (4!1 mL). The extract was evaporated to give the
title product (26) (0.015 g, 26% for two steps) as deep red
(
1
1
crystals, mp 170–175 8C (decomp.); H NMR (CDCl , d
3
1
7 17 5
ppm): 1.72 (s, 9H, t-Bu), 5.28 (s, 2H, CH ), 6.69 (d, 1H, JZ
.8 Hz, 5-H), 7.27–7.31 (m, 2H, Ph), 7.32 (s, 1H, 7-CH),
.38–7.45 (m, 3H, Ph), 7.64 (d, 1H, JZ6.8 Hz, 6-H). C
NMR (CDCl , d ppm): 28.6 (9-C, 10-C, 11-C), 36.6 (8-C),
58.5 (13-C), 84.8 (7-C), 103.9 (5-C), 104.3 (3-C), 127.9
Ph), 129.2 (Ph), 129.5 (Ph), 132.4 (Ph), 134.1 (4-C), 137.1
6-C), 161.3 (2-C), 174.0 (12-C) (atom numbering see
Scheme 11). Analysis found: C, 70.42; H, 6.78; N, 22.59%.
Calcd for C H N C0.1 mol Et O (312.79): C, 70.65; H,
2
N, 24.04%.
6
7
1
3
4
.7.4. 4-(2-Benzyl-2H-tetrazol-5-yl)-3-methyl-6,7-dihy-
dro-5H-cyclopenta[c]pyridine (23b). Yield 52%; brown
3
1
oil; H NMR (DMSO-d , d ppm): 1.97–2.06 (m, 2H, CH ),
6
2
(
(
2
PhCH ), 7.34–7.44 (m, 5H, Ph), 8.42 (s, 1H, 6-H). IR n
.54 (s, 3H, Me), 2.89–2.96 (m, 4H, CH ), 6.04 (s, 2H,
2
2
max
(
film) 3420, 3033, 2957, 1720, 1581, 1498, 1456, 1437,
1
8
19
5
2
1
6
5
152, 1030, 939, 723, 692. Analysis found: C, 69.83; H,
.03; N, 23.74%. Calcd for C H N (291.36): C, 70.08; H,
6.44; N, 22.39%.
1
7 17 5
.88; N, 24.04%.
4.9. Preparation of 3-(1,3,4-oxadiazol-2-yl)pyridines
27a–f
0
0
4.8. Alkylation of the 5H-tetrazolo[1 ,5 :1,5]pyrrolo[3,4-
b]pyridine 16l
4
.9.1. 2-Methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-4-phe-
0
0
4
.8.1. 5-Benzyl-9-tert-butyl-5H-tetrazolo[1 ,5 :1,5]-
pyrrolo[3,4-b]pyridine (24). Potassium tert-butoxide
0.112 g, 1.0 mmol) was added to a solution of compound
6l (0.20 g, 1.0 mmol) in anhydrous THF (2 mL) at
nylpyridine (27a). Acetic anhydride (0.12 mL, 1.26 mmol)
was added to a solution of compound 8a (0.2 g, 0.84 mmol)
in anhydrous acetonitrile (2 mL). The solution was
subjected to microwave irradiation in sealed reactor at
120 8C for 1 h. The reaction mixture was evaporated to
dryness, the residue was chromatographed (silica gel,
hexane/ethyl acetate in gradient 2:1–1:1) to give the target
product 27a (0.2 g, 95%) as white crystals, mp 104–105 8C;
(
1
K10 8C. The ice-cold mixture was stirred for 30 min, and
benzyl bromide (0.12 mL, 1.0 mmol) was added to the
mixture under stirring. The mixture was then stirred at
K10 8C for 3 h and treated with water (2 mL). The product
was extracted with ethyl acetate (3!4 mL), the extract was
dried over MgSO4 and evaporated. The residue was
chromatographed (silica gel, hexane/ethyl acetate 3:1) to
1
H NMR (DMSO-d , d ppm): 2.41 (s, 3H, CH ), 2.48 (s, 3H,
6
3
CH ), 7.16–7.23 (m, 2H, Ph), 7.35–7.42 (m, 3H, Ph), 7.45
3
(d, 1H, JZ5.1 Hz, 5-H), 8.72 (d, 1H, JZ5.1 Hz, 6-H).
Analysis found: C, 71.76; H, 5.15; N, 16.69%. Calcd for
C H N O (251.29): C, 71.70; H, 5.21; N, 16.72%.
give the titled product 24 (0.1 g, 33%) as pale yellow solid,
mp 113–114 8C; H NMR (CDCl , d ppm): 1.43 (s, 9H, t-
1
3
15 13 3

1862
S. M. Lukyanov et al. / Tetrahedron 62 (2006) 1849–1863
4
.9.2. 2-Methyl-4-phenyl-3-[5-(trifluoromethyl)-1,3,4-
oxadiazol-2-yl]pyridine (27b). Trifluoroacetic anhydride
0.23 mL, 1.68 mmol) was added to a solution of compound
a (0.2 g, 0.84 mmol) in anhydrous acetonitrile (2 mL). The
4.9.5. 4-(5-Isopropyl-1,3,4-oxadiazol-2-yl)-3-methyl-6,7-
dihydro-5H-cyclopenta[c]pyridine (27e). 2-Methylpropa-
noic anhydride (0.25 mL, 1.5 mmol) was added to a solution
of compound 8g (0.20 g, 1.0 mmol) in anhydrous aceto-
nitrile (2 mL). The mixture was subjected to microwave
irradiation in sealed reactor at 120 8C for 2 h. The reaction
mixture was evaporated to dryness, and the residue was
chromatographed (silica gel, hexane/ethyl acetate in
(
8
mixture was stirred at room temperature for 2 h and then
concentrated under reduced pressure to dryness. The residue
was treated with saturated aqueous solution of NaHCO3
(
5
3 mL), the mixture was extracted with ethyl acetate (4!
mL). The extract was dried over MgSO and evaporated.
The residue was chromatographed (silica gel, hexane/ethyl
gradient 7:3–1:100) to give the target product 27e (0.24 g,
99%) as dark brown oil; H NMR (CDCl , d ppm): 1.46 (d,
4
1
3
acetate in gradient 2:1–1:1) to give the target product 27b
(
6H, JZ7.1 Hz, CH(CH ) ), 2.16 (m, 2H, JZ7.6 Hz, CH ),
3
2
2
1
0.32 g, 100%) as white solid, mp 109–110 8C; H NMR
DMSO-d , d ppm): 2.65 (s, 3H, CH ), 7.15–7.22 (m, 2H,
2.80 (s, 3H, Me), 3.00 (t, 2H, JZ7.6 Hz, CH ), 3.18 (t, 2H,
2
(
JZ7.6 Hz, CH ), 3.30 (m, 1H, JZ7.1 Hz, CH(CH ) ), 8.45
6
3
2
3 2
Ph), 7.37–7.45 (m, 3H, Ph), 7.52 (d, 1H, JZ5.1 Hz, 5-H),
(s, 1H, 6-H). Analysis found: C, 69.04; H, 6.95; N, 17.27%.
Calcd for C H N O (243.31): C, 69.11; H, 7.04; N,
17.27%.
8
.80 (d, 1H, JZ5.1 Hz, 6-H). Analysis found: C, 58.98; H,
1
4 17 3
3
.24; F, 18.53; N, 13.71%. Calcd for C H F N O
1
5
10
3
3
(
305.26): C, 59.02; H, 3.30; F, 18.67; N, 13.77%.
4
.9.6. 4-[5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-3-
methyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine
27f). 4-Chlorobenzoic anhydride (0.31 g, 1.05 mmol) was
4
.9.3. 1-(5-tert-Butyl-1,3,4-oxadiazol-2-yl)-2-methyl-5,6-
dihydrobenzo[f]isoquinoline (27c). 2,2-Dimethylpropa-
noic anhydride (0.16 g, 0.84 mmol) was added to a
suspension of compound 8b (0.2 g, 0.76 mmol) in anhy-
drous acetonitrile (2 mL). The mixture was subjected to
microwave irradiation in sealed reactor at 120 8C for 2 h.
Additional 2,2-dimethylpropanoic anhydride (0.16 g,
(
added to a suspension of compound 8i (0.2 g, 0.87 mmol) in
anhydrous acetonitrile (2 mL). The mixture was subjected
to microwave irradiation in sealed reactor at 120 8C for 3 h.
The reaction mixture was evaporated to dryness, and the
residue was treated with saturated aqueous solution of
0
at the same temperature for 2 h again. The reaction mixture
.84 mmol) was added to the mixture that then irradiated
NaHCO (5 mL). The mixture was extracted with ethyl
3
acetate (4!5 mL). The extract was dried over MgSO and
4
was poured into saturated aqueous solution of NaHCO3
evaporated to dryness. The residue was chromatographed
(silica gel, hexane/ethyl acetate in gradient 2:1–1:100) to
give the target product 27f (0.2 g, 68%) as light yellow
(
(
5 mL), and the mixture was extracted with ethyl acetate
4!5 mL). The extract was washed with brine (10 mL),
1
crystals, mp 105–107 8C; H NMR (CDCl , d ppm): 1.60
dried over MgSO and evaporated to dryness. The residue
4
3
was chromatographed (silica gel, hexane/ethyl acetate in
gradient 2:1–1:1) to give the target product 27c (0.23 g,
9
(
2
2
m, 4H, (CH ) ), 1.82–1.91 (m, 2H, CH ), 2.49 (s, 3H, Me),
2 2 2
.64–2.70 (m, 2H, CH ), 2.83–2.90 (m, 2H, CH ), 7.52 (d,
2 2
H, JZ8.6 Hz, Ph), 8.04 (d, 2H, JZ8.6 Hz, Ph), 8.38 (s, 1H,
1
6%) as light creamy crystals, mp 110–111 8C; H NMR
(
DMSO-d , d ppm): 1.31 (s, 9H, (CH ) ), 2.45 (s, 3H, CH ),
6 3 3 3
6-H). Analysis found: C, 67.18; H, 5.37; Cl, 10.46; N,
12.24%. Calcd for C H ClN O (339.83): C, 67.16; H,
5
2
7
.77–2.88 (m, 4H, CH ), 6.46 (m, 1H, Ph), 7.12 (m, 1H, Ph),
2
.31 (m, 1H, Ph), 7.39 (m, 1H, Ph), 8.63 (s, 1H, 6-H).
1
9
18
3
.34; Cl, 10.43; N, 12.37%.
Analysis found: C, 75.11; H, 6.64; N, 13.14%. Calcd for
C H N O (319.41): C, 75.21; H, 6.63; N, 13.16%.
2
0 21 3
4
.9.4. 1-[5-(2-Methoxyethyl)-1,3,4-oxadiazol-2-yl]-2-
methyl-5H-chromeno[3,4-c]pyridine (27d). 3-Methoxy-
propanoic anhydride (0.16 g, 0.84 mmol) was added to a
suspension of compound 8c (0.2 g, 0.75 mmol) in anhy-
drous acetonitrile (2 mL). The mixture was subjected to
microwave irradiation in sealed reactor at 120 8C for 2 h.
Additional 3-methoxypropanoic anhydride (0.08 g,
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.42 mmol) was added to the mixture that then irradiated
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at the same temperature for 1 h again. The reaction mixture
was poured into saturated aqueous solution of NaHCO3
(
(
5 mL), and the mixture was extracted with ethyl acetate
4!5 mL). The extract was washed with brine (10 mL),
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4
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8
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0%) as light yellow crystals, mp 89–91 8C; H NMR
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