Synthesis of fused tetrazole- and imidazole derivatives via iodocyclization

Article abstract of DOI:10.1016/S0040-4020(03)00818-4

The possibility to prepare fused tetrazole- and imidazole derivatives by iodocyclization in moderate to excellent yields is demonstrated. In some examples the cyclizations were not following Baldwin's rules entirely, i.e. exo-selectivity. Nucleophilic substitution of the formed iodides gave different results depending on the hardness of the nucleophile. Thus, elimination of the iodide could be a problem but a substitution reaction with ethyl potassium xanthate and a radical reaction using acrylonitrile were tolerated. In addition, we showed that it is possible to selectively use three iodo substituents individually in one of the fused imidazole derivatives.

Full text of DOI:10.1016/S0040-4020(03)00818-4

Tetrahedron 59 (2003) 6759–6769
Synthesis of fused tetrazole- and imidazole derivatives
via iodocyclization
a
Fredrik Ek, Lars-G o¨ ran Wistrand and Torbj o¨ rn Frejd
b
a,*
a
Organic Chemistry 1, Department of Chemistry, Lund University, P.O. Box 124, S-221 00 Lund, Sweden
Amersham Health R&D AB, Medeon-Malm o¨ , S-205 12 Malm o¨ , Sweden
b
Received 28 March 2003; revised 25 April 2003; accepted 25 April 2003
This paper is dedicated to Professor K. C. Nicolaou on occasion of receiving the 2003 Tetrahedron Prize
Abstract—The possibility to prepare fused tetrazole- and imidazole derivatives by iodocyclization in moderate to excellent yields is
demonstrated. In some examples the cyclizations were not following Baldwin’s rules entirely, i.e. exo-selectivity. Nucleophilic substitution
of the formed iodides gave different results depending on the hardness of the nucleophile. Thus, elimination of the iodide could be a problem
but a substitution reaction with ethyl potassium xanthate and a radical reaction using acrylonitrile were tolerated. In addition, we showed that
it is possible to selectively use three iodo substituents individually in one of the fused imidazole derivatives.
q 2003 Elsevier Ltd. All rights reserved.
1
. Introduction
to 3 and 4 and is extensively used in models for anxiety,
mediated by its unspecific interaction with a number of
receptors in the CNS. Mannose mimetics 5 and 6 have
12,13
been reported to be inhibitors of a-mannosidase.
1
0,11
The imidazole ring system is an important structural feature
1
,2
in biological systems, natural products and drugs. On the
other hand, the structurally similar tetrazole functional
group is much less abundant but the use is increasing due to
the excellent properties as a metabolically stable isosteric
Our interest in this area began during our development of a
new method for allylation of aromatic systems. We found
that tetrazole derivative 7 did not give the expected allylated
product 8 but continued to react with the in situ generated
3
replacement for the carboxylic acid moiety and as a cis-
4
–6
peptide bond mimetic.
precursors to other heterocycles and in high energy
Tetrazoles have also been used as
7
Br via a reaction resembling a bromolactonization, thus,
2
8
14
compounds. A few examples are shown in Figure 1,
forming the fused tetrazole derivative 9. To our surprise,
some of which are used as drugs. Losartan (1) is a
Angiotensin II antagonist and commonly used for treatment
of hypertension. Imidazoles can be found in important fused
heterocyclic compounds such as the benzodiazepine
antagonist Flumazenil (3). Tetrazole 4 has also been found
the halocyclization of olefin substituted tetrazoles had not
been reported in the literature. We also noted that available
methods for synthesis of this class of compounds had
limitations. A common procedure is the azide trapping of a
nitrilium cation in the Schmidt rearrangement of ketones,
but this method gives regioisomeric mixtures of fused
9
to posses binding affinity to benzodiazepine receptors.
Pentylentetrazole (PTZ 2) has the opposite effect compared
9
,15,16
tetrazoles.
Intramolecular approaches via an internal
Figure 1. Examples of tetrazole- and imidazole derivatives of pharmacological interest.
Keywords: tetrazoles; nucleophilic substitution; halocyclization.
*
Corresponding author. Tel.: þ46-46-222-8125; fax: þ46-46-222-4119; e-mail: torbjorn.frejd@orgk1.lu.se
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00818-4

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F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
Scheme 1. Allylation-bromocyclization.
Table 1. Synthesis and iodocyclization of various tetrazole derivatives
a
b
Reactant
Yield (%)
Product (%)
Yield (%)
c
8
8
9 (10a)
0 (10b)
72 (11a and 12)
d
e
85 (11b and 13)
9
2
6 (10c)
8 (10d)
41 (11c)
98 (11d)
f
6
9
9 (10e)
0 (10f)
76 (11e)
g
98 (11f and 14)
8
6
3 (10g)
88 (11g)
h
3 (10h)
93 (11h)
a
Isolated yield of tetrazole derivatives 10a–h at 3 mmol scale if otherwise not stated.
Isolated yields of tetrazole derivatives 11a–h at 0.5 or 0.25 mmol (11d) scale. The regioisomeric and diastereoisomeric ratios were determined by H NMR
spectroscopy.
1:1 mixture of 11a and 12.
The reaction was performed at 10 mmol scale.
The reaction of 10a gave 85% of 11b containing 7% of 13. Recrystallization gave 55% yield of pure 11b.
Isolated as a mixture of distereoisomers (1.7:1).
The reaction of 10f gave 98% of 11f containing 15% of 14. Column chromatography gave 75% yield of pure 11f.
Isolated as a mixture of only two distereoisomers according to NOESY spectroscopy (selective trans attack). The distereoisomer in which the two bridgehead
protons are syn is formed to a larger extent (2:1).
b
1
c
d
e
f
g
h

F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
6761
[
of fused tetrazoles (exemplified by 5 and 6, Table 1).
2þ3] cycloaddition have also been reported in the synthesis
in a 1:1 mixture with 12. It has been reported that the
conditions used here would give a kinetically controlled
1
2,13,17,18
3
1
In a recent example, Demko and Sharpless presented a
procedure involving aminonitriles, cyanates and thio-
cyanates, although the method seems to be limited to the
formation of tetrazoles fused to 5- and 6-membered ring
product. By excluding NaHCO , which has been shown to
3
3
1
give thermodynamic control of the reaction, the product
from an endo-process was favored (3:2). Performing the
reaction using the standard procedure at 2308C did not
change the exo/endo selectivity. The cyclization of 10f also
gave the endo cyclization product (15%) despite that
formation of a 8-membered ring system is disfavored.
1
8
systems. Other methods involve azide ion addition to
1
9
imidoyl chlorides. A vast number of both intra- and
intermolecular methods have been developed for the
2,20–23
synthesis of fused imidazole derivatives (Scheme 1).
Not surprisingly, 10c did not give the corresponding product
11c using the standard procedure. Instead, we used syringe
pump technique, which gave a moderate yield of 11c.
In this paper we present the synthesis of fused tetrazole
derivatives via iodocyclization and some applications of the
formed products. An initial study towards the synthesis of
fused imidazole derivatives is also described.
3
2
Interestingly, only ,5% of the endo cyclized product could
be detected in the crude product while a corresponding
iodolactonization typically gives a 1:1 mixture of endo/exo
3
3
cyclization.
2
. Results and discussion
For reactions which showed some endo-selectivity (e.g.
10a,10b,10e and 10f) different methods were tested in order
to elucidate if other procedures could give better exo-
selectivity. However, exo-selectivity was improved only for
10e, which gave 10% endo-selectivity using the standard
procedure but gave 100% exo-selectivity using the biphasic
Two different methods were used in the synthesis of the
tetrazole derivatives 10a–h containing suitable olefinic
substituents (Scheme 2 and Table 1). In the first one, applied
in the synthesis of compound 10a–d, the olefin was already
in place and the tetrazole group was synthesized from the
corresponding unsaturated nitrile. We employed a recently
published method utilizing Et N/H SO /NaN in toluene
conditions NaHCO
/I in CHCl /H O.
3 2 3 2
3
2
4
3
2
4
which gave 10a–c in good to excellent yields. However,
this method failed in the synthesis of 10d probably due to
steric hindrance and sensitivity of the allyl functionality.
Instead, we applied a method in which catalytic amounts of
dibutyltin oxide together with trimethylsilyl azide were used
Various degrees of diasteroselectivity have been reported in
3
0,31
the iodolactonization reactions.
and 10h gave poor diastereoselectivity using the standard
Both compound 10e
1
procedure according to analysis of the crude products by H
NMR spectroscopy (1.7:1 and 2:1, respectively).
2
5
as reagents, although the yield was poor (28%).
After the synthesis of the fused tetrazoles we turned our
attention towards the imidazole derivatives. It was not
possible to use the method for the synthesis of 10a–h to
generate imidazole derivatives 15a–c (Table 2). Instead,
15a–c were synthesized with an efficient one-pot procedure
In the second method for synthesis of olefinic tetrazoles we
started with the tetrazole and then attached the olefinic part.
This was made by directed ortho metalation of aryl-
tetrazoles using sec-BuLi and TMEDA at 2358C followed
by the addition of an appropriate olefinic reagent. As seen
in Table 1 (10e–h), the yields were often high and the crude
products were sufficiently pure to be used directly in the
iodocyclization step.
2
6
34
developed by Demuth Jr. et al. in which 2-phenylimida-
zole or 2-o-tolyl-1H-imidazole were treated sequentially
with n-BuLi/SEMCl(N-protection)/n-BuLi/TMSCl(C-5
protection)/n-BuLi/RBr or RCHO (Scheme 3 and Table 2).
The protective groups were then removed by TBAF to give
15a–c in moderate to good yields considering the number of
transformations involved in the sequence. In case of
compound 15a, the hydroxy group was benzylated using
NaH/BnBr before the final deprotection.
Several literature methods for iodocyclization of unsatu-
rated carboxylic acids were tested for the formation of the
2
7 – 29
fused tetrazole derivatives.
obtained using NaHCO , I in dry CH CN at 08C under
The best result was
3
2
3
3
0
argone in the dark. As seen in Table 1, good to excellent
yields of the products were isolated, which were often pure
after work-up. However, it should be mentioned that some
of the compounds deteriorated if not carefully handled and
they should be stored in the refrigerator. Initially, this
method was used in the synthesis of compound 11a–h but
we noticed that some of the reactions gave results, which
deviated from the expected halocyclizations. The formation
of 4- to 7-membered-ring lactones via halocyclization of
v-unsaturated carboxylic acids has been reported to proceed
exclusively via exo-cyclization in accordance with
The large pK
derivatives motivated the change of base to K
difference between tetrazole- and imidazole
CO .
3
a
2
However, applying the standard conditions for iodocycliza-
tion on 15a using the stronger base gave, in addition to 16a,
also the tri-iodinated compound 16b as a 1:1 mixture.
Analogously, 15b and 15c gave mixtures of mono and tri-
iodinated products. The commercial bis(collidine)iodine
hexafluorophosphate was also tested in the reaction and we
found that it gave cyclization without iodination of the
imidazole ring (Table 2). Thus, imidazole derivatives
16a,16c and 16e were synthesized in good yields. However,
the extended reaction times, the large excess of reagent
required and the questionable appearance of the reagent
(brown powder) prompted reinvestigation with freshly
synthesized pure reagent. Consequently, we prepared
bis(collidine)iodine hexafluorophosphate (white crystals)
2
7,28
Baldwin’s rules.
4
We could confirm this by using pent-
-enoic acid, which gave only the exo-cyclized product.
However, some of the tested unsaturated tetrazoles gave
considerable amounts of the products resulting from an
endo-process. For example, when 10a was subjected to the
standard reaction conditions, the expected 11a was formed

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F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
and used it in the reaction with 15a. To our surprise we now
observed iodination of the imidazole ring and the reaction
was completed in less than 3 h. The endo/exo selectivity was
poor, however, resulting in a mixture of mono and tri-
3
5
iodinated products as 7 and 8 membered ring systems.
exo-Cyclization occurred as the major reaction when NIS
was used as cyclization agent as demonstrated for 15a and
1
5b which gave 16b and 16d, respectively. In the case of
5b less than 5% of the endo cyclization product could be
1
detected.
Scheme 2. Synthesis of olefinic tetrazole derivatives.
The possibility to introduce an amine functionality is of
great importance due to its frequent appearance in drug
molecules. Iodides can be easily transformed into nitriles or
azides, which are common starting materials for the
synthesis of amines. However, applying standard substi-
tution conditions for the formation of nitriles using KCN on
Table 2. Synthesis and iodocyclization of various imidazole derivatives
a
Reactant
Yield (%)
Product (%)
Yield (%)
11b gave the eliminated product 17 as seen in Scheme 4.
Also the use of NaN resulted predominately in elimination
b,c
3
4
4 (15a)
63 (16a)
(4:1 elimination:substitution). On the other hand, the softer
nucleophile potassium ethyl xanthate gave 18 as the sole
product. It is of course possible to use the elimination
product in subsequent reactions but it is clearly a limitation
to the synthetic applications of the iodides. However, the
convenient access to xanthate derivatives broadens the
scope of the fused tetrazoles due to additional chemistry
d,e
15a
65 (16b)
3
6
possible with this functional group. Zard and coworkers
have developed interesting radical chemistry based on
3
7
xanthates for the synthesis of tetrazole derivatives.
However, it would also be advantageous if the iodides
could be used directly in radical reactions, thus, avoiding an
additional substitution. We were delighted to see that the
radical addition using the methodology developed by Stork
et al. gave nitrile 19 in 55% yield (Scheme 4). This
reaction shows that the elimination problem can be
circumvented. Thus, free radical chemistry appears to be
more promising as a method of further derivation.
b,f
3
2 (15b)
61 (16c)
3
8
d
15b
71 (16d)
We were also interested in chemoselective manipulation of
the three iodides in 16b and 16d. As expected it was
possible to transform 16d into ethyl xantate 20 in good yield
without affecting the iodides in the imidazole ring
b
2
8 (15c)
85 (16e)
(Scheme 5). However, a more delicate problem was to
a
achieve selectivity between the two remaining iodides. It
has been demonstrated that protective groups at N-1 capable
of coordinating metal reagents can direct metalation to the
Isolated yields of imidazole derivatives 15a–c. The reactions were
performed at 4 mmol (15a) or 1.5 mmol scale. The regioisomeric and
diastereoisomeric ratios were determined by H NMR spectroscopy.
The reaction was performed using commercial bis(collidine)iodine
hexafluorophosphate.
1
b
39
5-position in 4,5-dihaloimidazole derivatives. Also with a
c
d
e
f
non-coordinative substituent, such as a vinyl group, the
metal–halogen exchange preferably takes place in the
Isolated as a mixture of diastereoisomers (1.4:1).
The reaction was performed using NIS in DMF.
Isolated as a mixture of diastereoisomers (1:1).
The yield of 5-iodomethyl-6,7-dihydro-imidazo[2,3-a][2]benzazepine
40
5-position. Yet, to our knowledge ethyl xanthates have not
been used as directing groups in metal–halogen exchange
reactions. We were also concerned that the metal reagent
would react with the xanthate group since it is known that
they are sensitive to nucleophiles. However, adding
1
was determined to be 87% by H NMR spectroscopy using anisole as
internal standard. 16c was isolated due to elimination of HI during
purification.
Scheme 3. Synthesis of olefinic imidazole derivatives.

F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
6763
0
.070 mm). Thin-layer chromatography was performed on
Merck precoated TLC plates with Silica gel 60 F-254,
.25 mm. After elution, the TLC plates were visualized with
0
UV light and sprayed with a solution of KMnO (10 g),
4
K CO (50 g), NaOH (20 mL, 5%) and H O (900 mL)
2
3
2
followed by heating. Chemicals were reagent grade. All
reagents were used as received if not otherwise noted. The
allylic bromides were distilled prior to use. Pent-4-
4
1
42
enenitrile,
4
nitrile
non-8-enenitrile,
and 2-o-tolyl-1H-imidazole were synthesized
2-allyl-5-nitrobenzo-
45
3,44
according to literature procedures. Bis(collidine)iodine(I)
hexafluorophosphate was either purchased from Aldrich (lot
number 10921KI, referred to as commercial quality) and
used as received or synthesized according to a literature
4
6
procedure.
2-bromopropane and magnesium.
i-PrMgBr was freshly prepared from
3.1.1. 5-But-3-enyl-1H-tetrazole (10a). A mixture of
concentrated H SO (191 mg, 1.95 mmol), triethylamine
Scheme 4. Substitutions using hard and soft nucleophiles and radical
reaction of 11b.
2
4
(0.54 mL, 3.9 mmol), sodium azide (253 mg, 3.9 mmol) and
Scheme 5. Synthesis and regioselective deiodination of 20.
i-PrMgBr to 20 in THF at 2408C gave selectively metal–
halogen exchange of the iodide in position 3. Subsequent
addition of saturated aqueous NH Cl to the reaction mixture
4
pent-4-enenitrile (244 mg, 3 mmol) in toluene (10 mL) was
stirred for 18 h at 1008C. The reaction mixture was cooled to
room temperature and then extracted three times with
gave 21, which was confirmed by NOESY spectroscopy.
H O. The combined aqueous phases were acidified with
2
concentrated HCl and extracted three times with EtOAc.
The combined organic phases were dried over Na SO and
the solvent was removed at reduced pressure to yield
331 mg (89%) of 10a as pale yellow oil which crystallized
1
in the refrigerator: mp 41–428C. H NMR (CDCl3,
In conclusion, we have demonstrated the possibility to
prepare fused tetrazole- and imidazole derivatives by
iodocyclization in moderate to excellent yields. The
cyclization of some of the substrates did not follow
Baldwin’s cyclization rules entirely i.e. exo-selectivity.
However, we were in some of these cases able to improve
the exo-selectivity by using different reaction conditions.
Nucleophilic substitution of the formed iodides gave
different results depending on the hardness of the nucleo-
phile. Thus, elimination of the iodide could be a problem but
substitution was possible with the soft nucleophile ethyl
potassium xanthate. Additionally, radical addition to
acrylonitrile was performed. Finally, we have demonstrated
that it is possible to selectively use two of the three iodo
substituents in 16d for specific reactions.
2
4
400 MHz) d 12.75–12.25 (br s, 1H), 5.84 (ddt, 1H,
J¼17.0, 10.3, 6.6 Hz), 5.11–5.05 (dd, 1H, J¼17.1,
1.5 Hz), 5.05 (d, 1H, J¼10.3 Hz), 3.25 (t, 2H, J¼7.5 Hz),
1
3
2.65 (br q, 2H, J¼7.2 Hz); C NMR (CDCl , 100 MHz) d
3
þ
156.4, 135.5, 117.3, 31.5, 23.1. Anal. HRMS (EI ) calcd for
C H N (M): 124.0749. Found: 124.0744.
5
8 4
3.1.2. 5-Pent-4-enyl-1H-tetrazole (10b). The reaction was
performed according to the synthesis of 10a using hex-5-
enenitrile (10 mmol scale) as starting material which gave
1
1.10 g (80%) of 10b as a pale yellow oil. H NMR (CDCl ,
3
4
00 MHz) d 12.50–12.00 (br s, 1H), 5.76 (ddt, 1H, J¼17.1,
1
0.3, 6.6 Hz), 5.05–4.96 (m, 2H), 3.15 (t, 2H, J¼7.7 Hz),
1
3
3. Experimental
2.18 (br q, 2H, J¼7.1 Hz), 2.01 (quint, 2H, J¼7.5 Hz); C
NMR (CDCl , 100 MHz) d 156.9, 136.9, 116.3, 33.0, 26.8,
3
þ
3
.1. General
22.9. Anal. HRMS (EI ) calcd for C
Found: 138.0899.
H N (M): 138.0905.
6 10 4
HPLC analyses were performed on a HiChrom column
(
grade)/H O; flow rate 1 mL/min. NMR spectra were
Kromasil 100-5C18, 150£4.6 mm); eluent: CH CN (HPLC
3.1.3. 5-Oct-7-enyl-1H-tetrazole (10c). The reaction was
performed according to the synthesis of 10a using non-8-
enenitrile (3 mmol scale) as starting material which gave
3
2
recorded on a 400 MHz instrument using CDCl3 or
acetone-d as internal standard. Elemental analyses were
520 mg (96%) of 10c as pale yellow oil, which crystallized
1
6
made by A. Kolbe, Mikroanalytisches Laboratorium,
Germany. Chromatographic separations were performed
on Matrex Amicon normal phase silica gel 60 (0.035–
in the refrigerator: mp 46–478C. H NMR (CDCl
3
,
400 MHz) d 11.20–10.90 (br s, 1H), 5.76 (ddt, 1H,
J¼17.0, 10.3, 6.6 Hz), 4.95 (ddd, 1H, J¼17.1, 3.6,

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F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
1
2
1
1
.6 Hz), 4.90 (br d, 1H, J¼10.3 Hz), 3.12 (t, 2H, J¼7.7 Hz),
starting from 5-(2-methylphenyl)tetrazole (3.0 mmol scale)
4
7
.01 (br q, 2H, J¼6.8 Hz), 1.89 (quint, 2H, J¼7.5 Hz),
and using allyl bromide as electrophile. The crude product
was recrystallized from heptane/EtOAc to give 540 mg
1
3
.45–1.29 (m, 6H); C NMR (CDCl , 100 MHz) d 157.0,
3
1
38.9, 114.6, 33.8, 29.0, 28.7, 28.7, 27.8, 23.6. Anal. HRMS
(90%) of 10f as white crystals: mp 112–1138C; H NMR
(CDCl , 400 MHz) d 11.75–11.25 (br s, 1H), 7.61 (dd, 1H,
þ
81.1451.
(
1
CI ) calcd For C H N (MþH): 181.1453. Found:
9
17
4
3
J¼7.7, 1.0 Hz), 7.45 (dt, 1H, J¼7.6, 1.3 Hz), 7.36 (br d, 1H,
J¼7.7 Hz), 7.27 (dt, 1H, J¼7.6, 1.2 Hz), 5.71 (ddt, 1H,
J¼17.1, 10.3, 6.6 Hz), 4.97–4.88 (m, 2H), 2.93 (br t, 2H,
3
.1.4. 5-(2-Allyl-5-nitrophenyl)tetrazole (10d). Dibutyltin
1
3
oxide (109 mg, 0.45 mmol) was added to a mixture of
-allyl-5-nitrobenzonitrile (568 mg, 3.0 mmol), TMSN3
1.95 mL, 14.5 mmol) and dry toluene (5 mL). The mixture
J¼7.7 Hz), 2.28 (br q, 2H, J¼7.4 Hz); C NMR (CDCl ,
3
2
(
100 MHz) d 156.3, 141.8, 137.6, 131.5, 130.9, 130.0, 126.8,
122.9, 115.8, 35.2, 33.2. Anal. HRMS (EI ) calcd for
C H ClNO (M): 200.1062. Found: 200.1061.
þ
was heated at 1108C for 23 h before cooling to room
temperature followed by the removal of the solvent at
reduced pressure. The residue was dissolved in methanol
and the solvent was removed at reduced pressure in order to
cleave off the TMS-group. Saturated aqueous NaHCO and
3
EtOAc were added to the residue and the organic phase was
extracted twice with saturated aqueous NaHCO followed
9
8
2
3.1.7. 5-(2-(3-Methyl-but-3-enyl)phenyl)tetrazole (10g).
The reaction was performed according to the synthesis of
10e starting from 5-(2-methylphenyl)tetrazole (3.0 mmol
scale) and using methallyl bromide as electrophile. The
crude product was recrystallized from heptane/EtOAc to
3
by acidification of the combined water phases with aqueous
concentrated HCl until pH,3. The aqueous phase was
extracted three times with EtOAc and the combined organic
phases were dried (Na SO ). The solvent was then removed
give 535 mg (83%) of 10g as white crystals: mp 94–958C;
1
H NMR (CDCl , 400 MHz) d 7.61 (m, 1H), 7.50–7.35 (m,
3
2H), 7.31–7.22 (m, 1H), 4.68 (m, 1H), 4.59 (m, 1H), 3.00
1
3
(m, 2H), 2.21 (m, 2H), 1.65 (br quint, 3H, J¼4.5 Hz);
C
NMR (CDCl , 100 MHz) d 156.2, 144.9, 142.0, 131.3,
2
4
at reduced pressure, which gave 195 mg (28%) of 10d as
1
3
pale yellow crystals: mp 157–1588C; H NMR (MeOH-d ,
4
130.6, 129.7, 126.5, 122.6, 110.8, 39.1, 32.0, 22.3. Anal.
þ
214.1212.
4
2
1
00 MHz) d 8.61 (d, 1H, J¼2.3 Hz), 8.34 (dd, 1H, J¼8.5,
.4 Hz), 7.69 (d, 1H, J¼8.5 Hz), 5.90 (ddt, 1H, J¼17.0,
0.3, 6.6 Hz), 5.00 (dd, 1H, J¼10.1, 1.4 Hz), 4.93 (dd, 1H,
HRMS (EI ) calcd for C H ClNO (M): 214.1218. Found:
2
9
8
1
3
J¼17.1, 1.6 Hz), 3.84 (d, 2H, J¼6.5 Hz), C NMR
3.1.8. 5-(2-Cyclohex-2-enylmethylphenyl)tetrazole (10h).
The reaction was performed according to the synthesis of
10e starting from 5-(2-methylphenyl)tetrazole (3.0 mmol
scale) and using 3-bromocyclohexene as electrophile. The
crude product (oil) was crystallized from heptane/EtOAc to
(
MeOH-d , 100 MHz) d 157.7, 148.5, 148.0, 136.6, 133.4,
4
2
1
1
1
2
27.3, 126.3, 125.7, 117.5, 38.5. IR (KBr, cm ) n 1523 (s),
347 (s). HRMS (CI ): calcd for C H N O : [(MþH)]:
þ
32.0836. Found: 232.0821.
1
0 10 5 2
give 450 mg (63%) of 10h as white crystals: mp 97–988C;
1
3
(
.1.5. 5-(2-(1-Hydroxy-prop-2-enyl)phenyl)tetrazole
10e). sec-BuLi (1.3 M in cyclohexane, 6.9 mL, 9.0 mmol)
H NMR (CDCl , 400 MHz) d 7.66 (d, 1H, J¼7.6 Hz), 7.48
3
(t, 1H, J¼7.5 Hz),7.40–7.25(m, 2H),5.75(m, 1H), 5.48(brd,
1H, J¼9.9 Hz), 2.87 (dd, 1H, J¼13.5, 7.6 Hz), 2.80 (dd, 1H,
J¼13.5, 8.3 Hz), 2.35 (m, 1H), 1.98 (m, 2H), 1.75–1.58 (m,
was added dropwise to a stirred solution of 5-phenyl-
tetrazole (438 mg, 3 mmol) and TMEDA (0.45 mL,
3
1
3
mmol) in THF (20 mL) at 2358C under argon atmos-
2H), 1.48(m, 1H), 1.29(m, 1H); C NMR (CDCl , 100 MHz)
3
phere. The yellow reaction mixture was stirred for 50 min
maintaining the temperature followed by addition of
acrolein (0.80 mL, 12.0 mmol) in one portion. The tem-
perature of the decolorized reaction mixture was gradually
warmed to room temperature. The pH of the reaction
mixture was adjusted to pH¼2 with dilute aqueous HCl
d 156.2, 140.7, 131.6, 131.2, 130.8, 130.1, 128.7, 126.8, 123.4,
þ
39.9, 36.8, 28.9, 25.4, 20.9. Anal. HRMS (EI ) calcd for
C H ClNO (M): 240.1375. Found: 240.1371.
9
8
2
3.1.9. 5-Iodomethyl-6,7-dihydro-tetrazolo[1,5-a]pyrrole
(11a) and 6-iodo-5,6,7,8-tetrahydro-tetrazolo[1,5-a]pyri-
dine (12). Iodine (382 mg, 1.50 mmol) was added in one
portion to stirred solution of 10a (61 mg, 0.5 mmol) and
NaHCO (420 mg, 5.0 mmol) in dry CH CN (2 mL) under
(
0.05 M) and the solution was then concentrated at reduced
pressure. The residue was extracted twice with EtOAc and
the combined organic phases were washed with three
portions of dilute aqueous HCl (0.05 M) and then dried
3
3
argon atmosphere at 08C. The red-brown reaction mixture
was then stirred for 3 h at 08C. Saturated aqueous Na SO
3
(
Na SO ). The solvent was removed at reduced pressure
2 4
2
followed by column chromatography (heptane/EtOAc/
MeOH/AcOH 5:4:1:0.05) of the crude product, which
gave 420 mg (69%) of 10e as a pale yellow oil. H NMR
(3 mL) was added to the reaction mixture and H O and
2
EtOAc were added to the colorless reaction mixture. The
phases were separated and the aqueous phase was extracted
with EtOAc. The combined organic phases were washed
1
(
(
(
acetone-d , 400 MHz) d 7.81 (dd, 1H, J¼7.7, 1.3 Hz), 7.71
6
dd, 1H, J¼7.7, 1.3 Hz), 7.58 (dt, 1H, J¼7.5, 1.4 Hz), 7.47
with saturated aqueous NaHCO followed by brine. Drying
3
dt, 1H, J¼7.6, 1.4 Hz), 6.01 (ddd, 1H, J¼17.2, 10.5,
(Na SO ) and removal of the solvent at reduced pressure
4
2
4
.8 Hz), 5.74 (dt, 1H, J¼4.7, 1.8 Hz), 5.19 (dt, 1H, J¼17.2,
gave 90 mg (72%) of a mixture (1:1) of 11a and 12 as white
1
1
3
1
d , 100 MHz) d 156.2, 143.7, 140.6, 131.9, 130.6, 129.2,
128.6, 123.7, 114.4, 72.1. Anal. HRMS (EI ) calcd for
C H ClNO (M): 202.0855. Found: 202.0856.
.8 Hz), 5.01 (dt, 1H, J¼10.5, 1.8 Hz); C NMR (acetone-
crystals. H NMR (acetone-d , 400 MHz, 11a) d 4.86 (m,
6
1H), 3.86 (dd, 1H, J¼11.0, 5.0 Hz), 3.82 (dd, 1H, J¼11.0,
6
þ
1
3.9 Hz), 3.30–2.96 (m, 3H), 2.72 (m, 1H). H NMR
(acetone-d , 400 MHz, 12) d 5.05 (m, 1H), 4.96 (dd, 1H,
9
8
2
6
J¼14.0, 4.3 Hz), 4.78 (dd, 1H, J¼14.0, 5.0 Hz), 3.30–2.96
1
3
3.1.6. 5-(2-(But-3-enyl)phenyl)tetrazole (10f). The reac-
tion was performed according to the synthesis of 10e
(m, 2H), 2.42 (m, 2H); C NMR (acetone-d , 100 MHz,
6
11aþ12) d 163.7, 151.2, 57.5, 55.5, 36.5, 31.6, 21.3, 19.4,

F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
6765
1
2
8.8, 8.9. Anal. calcd for C H IN : C, 24.02; H, 2.82; N,
5
2.41. Found: C, 24.15; H, 2.86; N, 22.55.
124 mg (76%) of 11e (white solid) as a diastereoisomeric
1
7
4
mixture (1.7:1). H NMR (acetone-d , 400 MHz) d 8.12–
6
8
.05 (m, 1H), 8.12–8.05 (m, 1H), 7.76 (br d, 1H, J¼7.5 Hz),
3
.1.10. 5-Iodomethyl-5,6,7,8-tetrahydro-tetrazolo[1,5-
7.70–7.58 (m, 2H), 7.70–7.58 (m, 2H), 5.53 (d, 1H,
J¼5.8 Hz), 5.45 (dd, 1H, J¼5.3, 3.8 Hz), 5.30 (dd, 1H,
J¼11.0, 5.7 Hz), 5.02 (m, 1H), 4.94 (dd, 1H, J¼10.7,
4.9 Hz), 4.12 (dd, 1H, J¼10.2, 5.5 Hz), 3.90 (dd, 1H,
J¼10.2, 8.7 Hz), 3.81 (dd, 1H, J¼11.2, 6.8 Hz), 3.72 (dd,
a]pyridine (11b). The reaction was performed according
to the synthesis of 11a starting with 10b (0.5 mmol scale)
which gave 112 mg (85%) of 11b as a colorless oil
containing 7% 13. Two crystallizations (heptane/EtOAc
1
3
3
8
3
3
:1) gave 73 mg (55%) of pure 11b as white crystals: mp
1
1H, J¼11.2, 5.0 Hz); C NMR (acetone-d , 100 MHz) d
6
8–898C. H NMR (acetone-d , 400 MHz) d 4.50 (m, 1H),
6
150.7, 150.5, 137.9, 137.3, 133.1, 133.0, 130.4, 130.4,
129.7, 129.5, 126.1, 121.3, 120.8, 71.3, 68.9, 62.6, 62.3, 3.1,
22.1. Anal. calcd for C H IN O: C, 36.61; H, 2.76; N,
.96 (dd, 1H, J¼10.8, 5.9 Hz), 3.91 (dd, 1H, J¼10.8,
.2 Hz), 3.13–3.05 (m, 1H), 2.95–2.85 (m, 1H), 2.45–2.35
1
0
9
4
1
3
(m, 1H), 2.25–2.15 (m, 1H), 2.05–1.90 (m, 2H); C NMR
(acetone-d , 100 MHz) d 153.4, 56.6, 29.6, 21.1, 18.9, 9.0.
17.08. Found: C, 36.74; H, 2.84; N, 16.99.
6
Anal. calcd for C H IN : C, 27.29; H, 3.44; N, 21.22.
6
Found: C, 27.30; H, 3.41; N, 21.29.
3.1.14. 5-Iodomethyl-6,7-dihydro-tetrazolo[5,1-a][2]-
benzazepine (11f). The reaction was performed according
to the synthesis of 11a starting with 10f (0.5 mmol scale).
The crude product was dissolved in heptane/EtOAc (1:1)
and filtered through a pad of silica. Concentration of the
organic phase at reduced pressure gave 160 mg (98%) of 11f
as a colorless oil containing 15% of 14. Column
chromatography (heptane/EtOAc 3:1) of the crude product
9
4
3
.1.11. 5-Iodomethyl-6,7,8,9,10,11-hexahydro-5H-tetra-
zolo[1,5-a]azonine (11c). Compound 10c (90 mg,
.5 mmol) in dry CH Cl (1 mL) was added, using a syringe
0
2
2
pump, during 48 h to bis(collidine)iodo hexafluoro-
phosphate (400 mg, 0.78 mmol, synthesized according to
literature) in dry CH Cl (10 mL). The precipitate was
1
gave 122 mg (75%) of pure 11f as a pale yellow oil. H
NMR (CDCl , 400 MHz) d 8.31 (dd, 1H, J¼7.4, 1.8 Hz),
2
2
filtered off and the remaining solution was concentrated at
reduced pressure. Column chromatography (heptane/EtOAc
3
7.45 (m, 2H), 7.29 (br d, 1H, J¼7.4 Hz), 4.88 (m, 1H), 3.73
1
3
2
crystals: mp 125–1268C H NMR (acetone-d , 400 MHz) d
:1) of the residue gave 60 mg (41%) of 11c as white
1
(m, 2H), 2.99(m, 2H), 2.65 (m, 1H). 2.35 (m, 1H); C NMR
(CDCl , 100 MHz) d 153.9, 140.2, 131.9, 130.6, 129.8,
6
3
5
.04 (m, 1H), 3.85 (br d, 2H, J¼7.2 Hz), 3.38 (ddd, 1H,
127.8, 123.0, 60.5, 32.8, 30.5, 7.9. Anal. calcd for
C H IN : C, 40.51; H, 3.40; N, 17.18. Found: C, 40.36;
H, 3.35; N, 17.22.
J¼15.1, 8.3, 2.7 Hz), 2.79 (ddd, 1H, J¼15.0, 10.4, 2.8 Hz),
1
1
11
4
2
1
0
1
.27–2.14 (m, 2H), 2.00–1.89 (m, 1H), 1.90–1.74 (m, 1H),
.74–1.60 (m, 1H), 1.55–1.43 (m, 3H), 1.25–1.13 (m, 1H),
1
3
.55–0.40 (m, 1H); C NMR (acetone-d , 100 MHz) d
6
3.1.15. 5-Iodomethyl-5-methyl-6,7-dihydro-tetrazolo-
[5,1-a][2]benzazepine
57.8, 61.4, 36.3, 27.6, 26.1, 24.4, 22.5, 6.5. Anal. calcd for
(11g).
The
reaction
was
C H IN : C, 35.31; H, 4.94; N, 18.30. Found: C, 35.35; H,
9
performed according to the synthesis of 11a starting
with 10g (0.5 mmol scale). Recrystallization (heptane/
acetone) of the crude product gave 150 mg (88%) of
15
4
4
.86; N, 18.38.
1
3
.1.12. 9-Nitro-5-iodomethyl-5,6-dihydro-tetrazolo[5,1-
11g as white crystals: mp 118–1198C
H NMR
a]isoquinoline (11d). The reaction was performed accord-
ing to the synthesis of 11a starting with 10d (0.25 mmol
scale). The crude product was dissolved in acetone and
(CDCl , 400 MHz) d 8.43 (dd, 1H, J¼7.4, 1.9 Hz), 7.43
3
(m, 2H), 7.27 (dd, 1H, J¼6.7, 1.6 Hz), 3.92 (d, 1H,
J¼10.6 Hz), 3.69 (d, 1H, J¼10.6 Hz), 3.09–2.95 (m, 2H),
1
3
subsequent addition of heptane precipitated 87 mg (98%) of
1
2.57 (m, 1H), 2.27 (m, 1H), 2.04 (s, 3H); C NMR
(CDCl , 100 MHz) d 153.8, 141.0, 131.7, 131.0, 129.3,
1
1d as white pale yellow crystals: mp 157–1588C. H NMR
3
(
1
3
acetone-d , 400 MHz) d 8.78 (d, 1H, J¼2.3 Hz), 8.43 (dd,
127.6, 123.2, 64.9, 38.1, 29.4, 28.2, 17.6. Anal. calcd for
C H IN : C, 42.37; H, 3.85; N, 16.47. Found: C, 42.67; H,
3.78; N, 16.55.
6
H, J¼8.5, 2.4 Hz), 7.90 (d, 1H, J¼8.5 Hz), 5.21 (m, 1H),
.96 (m, 2H), 3.90 (dd, 1H, J¼17.2, 6.4 Hz), 3.67 (dd, 1H,
1
2
13
4
1
3
J¼17.2, 7.4 Hz); C NMR (acetone-d , 100 MHz) d 150.5,
6
148.7, 141.9, 131.7, 127.1, 123.3, 120.5, 55.7, 35.2, 6.1.
Anal. calcd for C H IN O: C, 33.63; H, 2.26; N, 19.61.
3.1.16. 5-Iodo-4a,5,6,7,8,8a-hexahydro-benzo[c]tetra-
zolo[5,1-a][2]benzazepine (11h). The reaction was per-
formed according to the synthesis of 11a starting with 10h
1
0
8
5
Found: C, 33.52; H, 2.15; N, 19.52.
(0.5 mmol scale) which gave 170 mg (93%) of 11h (white
solid) as a diastereoisomeric mixture (2:1). H NMR
1
3
.1.13. 5-Iodomethyl-6-hydroxy-5,6-dihydro-tetra-
zolo[5,1-a]isoquinoline (11e). Compound 10e (101 mg,
.50 mmol) was dissolved in H O (5 mL) containing
(CDCl , 400 MHz) d 7.97 (br d, 1H, J¼7.5 Hz), 7.74 (br
3
0
d, 1H, J¼7.6 Hz), 7.55–7.39 (m, 4H), 7.32 (br d, 1H,
J¼7.6 Hz), 7.27 (br d, 1H, J¼7.4 Hz), 5.39 (br q, 1H,
J¼3.3 Hz), 4.94 (br s, 1H), 4.83 (br q, 1H, J¼2.8 Hz), 4.54
(br t, 1H, J¼3.3 Hz), 3.24 (m, 1H), 3.09 (br d, 1H,
J¼15.1 Hz), 2.98 (dd, 1H, J¼14.8, 5.7 Hz), 2.80–2.62 (m,
3H), 2.45–2.29 (m, 2H), 2.38 (dd, 1H, J¼14.8, 9.7 Hz),
2.22–2.10 (m, 1H), 2.10–2.00 (m, 1H), 1.94–1.80 (m, 1H),
1.75–1.58 (m, 2H), 1.75–1.58 (m, 3H), 1.18–1.04 (m, 1H);
2
NaHCO3 (84 mg, 1.0 mmol). CHCl3 (5 mL) and iodine
382 mg, 1.50 mmol) were added to the reaction mixture
(
and the biphasic solution was vigorously stirred for 5 h at
room temperature. Saturated aqueous NaHCO3 (2 mL)
followed by saturated aqueous Na SO (5 mL) were then
added to the reaction mixture. The biphasic mixture was
extracted three times with EtOAc and the combined organic
phases were washed with saturated aqueous NaHCO3,
saturated aqueous Na SO and brine. Drying (Na SO ) and
2
3
1
3
C NMR (CDCl , 100 MHz) d 154.5, 153.9, 137.6, 137.5,
3
132.2, 132.0, 130.7, 130.5, 129.6, 129.4, 127.8, 127.7,
126.2, 124.2, 64.3, 63.0, 40.6, 38.6, 38.0, 37.0, 31.8, 28.4,
2
3
2
4
concentration at reduced pressure of the organic phase gave

6766
F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
27.5, 26.5, 25.7, 24.2, 21.5, 15.2. Anal. calcd for C H IN :
C, 45.92; H, 4.13; N, 15.30. Found: C, 46.03; H, 4.15; N,
and the benzylation step was omitted. The reaction yielded
1
1
4
15
4
96 mg (32%) of 15b as white crystals: mp 100–1028C; H
NMR (CDCl , 400 MHz) d 7.42 (br d, 1H, J¼7.6 Hz),
1
5.28.
3
7
.35–7.20 (m, 3H), 7.08 (s, 2H), 5.75 (ddt, 1H, J¼17.1,
3
.1.17. 2-(2-(1-Benzyloxy-prop-2-enyl)phenyl)imidazole
10.3, 6.7 Hz), 4.98–4.89 (m, 2H), 2.95 (br t, 2H, J¼7.8 Hz),
1
3
(
15a). n-BuLi (1.6 M in hexanes, 3 mL, 4.8 mmol) was
added to phenylimidazole (577 mg, 4.0 mmol) in THF
15 mL) at 2208C. The yellow reaction mixture was stirred
2.25 (m, 2H); C NMR (CDCl , 100 MHz) d 140.9, 138.3,
3
130.4, 130.2, 129.6, 129.3, 126.4, 123.7, 115.3, 35.3, 33.1.
þ
Found: 198.1154.
(
Anal. HRMS (EI ) calcd for C H ClNO (M): 198.1157.
8
9
2
for 1 h followed by addition of (2-chloromethoxyethyl)-
trimethylsilane (0.85 mL, 4.8 mmol). The reaction mixture
was then stirred at 2208C for 15 min and for 3.5 h at room
temperature. The clear yellow solution was then cooled to
3.1.19. 2-(2-(3-Methyl-but-3-enyl)phenyl)imidazole
(15c). The reaction was performed according to the
synthesis of 15a starting from 2-(2-methylphenyl)imidazole
(1.5 mmol scale) and using methallyl bromide as electro-
phile except that the crude product, after the addition of the
methallyl bromide, was purified by column chromatography
(heptane/EtOAc 4:1) and the benzylation step was omitted.
2
788C and n-BuLi (1.6 M in hexanes, 3 mL, 4.8 mmol) was
added followed by stirring for 1 h. Chlorotrimethylsilane
0.61 mL, 4.8 mmol) was added and the reaction mixture
(
was stirred an additional hour. The reaction mixture was
warmed to 2408C and again treated with n-BuLi (1.6 M in
hexanes, 3 mL, 4.8 mmol) and then stirred for 2 h. Acrolein
The reaction yielded 90 mg (28%) of 15c as white crystals:
1
(
0.32 mL, 4.8 mmol) was added and the reaction mixture
mp 88–898C; H NMR (CDCl , 400 MHz) d 7.39 (br d, 1H,
3
was stirred for 1 h in the cold before it was gradually
warmed to room temperature and subsequently stirred
overnight. The reaction mixture was poured into saturated
aqueous ammonium chloride and the aqueous layer was
extracted three times with EtOAc. The combined organic
phases were washed with brine and dried (Na SO ).
J¼7.4 Hz), 7.33–7.26 (m, 2H), 7.18 (m, 1H), 7.01 (s, 2H),
4.64 (br s, 1H), 4.56 (br s, 1H), 2.95 (m, 2H), 2.13 (m, 2H),
1.62 (s, 3H); C NMR (CDCl , 100 MHz) d 146.7, 145.7,
1
3
3
141.3, 130.3, 130.2, 129.6, 129.1, 126.1, 122.5, 110.5, 39.4,
þ
212.1313. Found: 212.1315.
32.1, 22.5. Anal. HRMS (EI ) calcd for C H ClNO (M):
9
8
2
2
4
Removal of the solvent at reduced pressure gave an oil,
which was used directly in the next step. The crude oil,
dissolved in dry THF (5 mL), was added dropwise to NaH
3.1.20. 5-Iodomethyl-6-benzyloxy-5,6-dihydro-imi-
dazo[2,3-a]isoquinoline (16a). Bis(collidine)iodine(I)
hexafluorophosphate (386 mg, 0.75 mmol, commercial
quality) was added to 15a (73 mg, 0.25 mmol) dissolved
in dry CH Cl (10 mL). Formation of the product was
(
176 mg, 60%, 4.4 mmol) in dry DMF (5 mL) at 08C under
argon atmosphere. Benzyl bromide (0.52 mL, 4.4 mmol)
was added after 1 h and the stirring was continued for an
additional 2 h at room temperature. MeOH (2 mL) was
2
2
monitored by HPLC. Additional bis(collidine)iodine(I)
hexafluorophosphate (256 mg, 0.50 mmol) was added after
23 h at room temperature. After further 15 days of stirring,
saturated aqueous Na SO was added and the aqueous phase
added carefully to the reaction mixture followed by H O
2
(
20 mL). The aqueous phase was extracted twice with
EtOAc and the combined organic phases were washed three
times with H O and brine. Drying (Na SO ) and concen-
2
3
was extracted twice with ether. The combined organic
phases were washed with H O and brine and then dried
2
2
4
tration at reduced pressure of the organic phase gave an oil
which was used unpurified in the next step. Tetrabutyl-
ammoniumfluoride trihydrate (6.3 g, 20 mmol) was added
to the crude oil dissolved in THF (20 mL) and the reaction
mixture was heated at reflux for 3 h. The reaction mixture
was then cooled and diluted with pH 7.0 phosphate buffer.
The aqueous layer was extracted with three portions of
EtOAc and the combined organic phases were washed with
pH 7.0 phosphate buffer followed by brine. Drying
2
(Na SO ). Removal of the solvent at reduced pressure
4
2
followed by column chromatography (heptane/EtOAc 1:3)
gave 65 mg (63%) of 16a (pale yellow oil) as a
1
diastereoisomeric mixture (1.4:1). H NMR (acetone-d ,
6
400 MHz) d 8.28 (m, 1H), 7.95 (dd, 1H. J¼7.6, 1.3 Hz),
7.65–7.25 (m, 18H), 7.17 (d, 1H, J¼1.4 Hz), 7.02 (d, 1H,
J¼1.2 Hz), 5.20–5.05 (m, 3H), 4.80–4.50 (m, 5H), 3.79
(dd, 1H, J¼10.2, 5.6 Hz), 3.63 (dd, 1H, J¼10.2, 7.5 Hz),
3.40 (dd, 1H, J¼10.7, 6.3 Hz), 3.33 (dd, 1H, J¼10.7,
(
Na SO ) and concentration at reduced pressure of the
2 4
1
3
organic phase followed by column chromatography
heptane/EtOAc, 1:1) of the residue gave 510 mg (44%)
7.9 Hz); C NMR (acetone-d , 100 MHz) d 141.6, 143.1,
6
(
of 15a as a pale yellow oil. H NMR (CDCl , 400 MHz) d
139.1, 138.8, 132.6, 131.5, 130.9, 130.7, 129.8, 129.5,
129.2, 129.1, 128.9, 128.8, 128.6, 128.6, 128.5, 128.3,
127.5, 126.3, 125.6, 124.3, 121.8, 119.7, 76.6, 72.0, 59.5,
2.0. Anal. calcd for C H IN O: C, 54.82; H, 4.12; N, 6.73.
1
3
8
5
1
1
1
1
.09 (br d, 1H, J¼7.6 Hz), 7.45–7.30 (m, 8H), 7.07 (s, 2H),
.96 (ddd, 1H, J¼17.3, 10.5, 5.4 Hz), 5.21 (dt, 1H, J¼7.4,
.7 Hz), 5.15 (dt, 1H, J¼17.3, 1.6 Hz), 5.12 (dt, 1H, J¼10.5,
1
9
17
2
Found: C, 54.70; H, 4.21; N, 6.79.
1
3
.5 Hz), 4.57 (q, 2H, J¼11.7 Hz); C NMR (CDCl ,
3
00 MHz) d 146.3, 137.4, 136.5, 135.9, 131.2, 130.9, 129.2,
28.9, 128.8, 128.4, 118.0, 83.0, 70.6. Anal. HRMS (EI )
3.1.21. 2,3-Diiodo-5-iodomethyl-6-benzyloxy-5,6-di-
hydro-imidazo[2,3-a]isoquinoline (16b). N-iodosuccini-
mide (0.28 g, 1.25 mmol) was added to 15a (73 mg,
þ
calcd for C H ClNO (M): 290.1419. Found: 290.1414.
9
8
2
0.25 mmol) in DMF at room temperature. Stirring was
continued for 16 h and then saturated aqueous NaHCO and
3
.1.18. 2-(2-(But-3-enyl)phenyl)imidazole (15b). The
3
reaction was performed according to the synthesis of 15a
starting from 2-(2-methylphenyl)imidazole (1.5 mmol
scale) and using allyl bromide as electrophile except that
the crude product, after the addition of allyl bromide, was
purified by column chromatography (heptane/EtOAc 4:1)
saturated aqueous Na SO were added to the reaction
2
3
mixture. The aqueous phase was extracted twice with
EtOAc and the combined organic phases were washed three
times with H O and once with brine followed by drying
2
(Na SO ). Concentration at reduced pressure of the organic
2
4

F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
6767
phase followed by column chromatography (heptane/EtOAc
:1) of the crude product gave 109 mg (65%) of 16b (white
days and purification of the crude product using column
chromatography (heptane/EtOAc 1:3) gave 72 mg (85%) of
16e as a pale yellow oil. H NMR (acetone-d , 400 MHz) d
6
3
solid) as a diastereoisomeric mixture (1:1). H NMR
1
1
(
(
5
acetone-d , 400 MHz) d 7.98 (m, 1H), 7.83 (m, 1H), 7.58
6
8.01 (m, 1H), 7.37 (d, 1H, J¼1.4 Hz), 7.32–7.20 (m, 2H),
7.04 (d, 1H, J¼1.4 Hz), 3.55 (d, 1H, J¼10.7 Hz), 3.42, (d,
1H, J¼10.7 Hz), 2.90–2.78 (m, 2H), 2.49–2.37 (m, 2H),
m, 1H), 7.60–7.25 (m, 15H), 5.39 (br d, 1H, J¼6.0 Hz),
.11 (d, 1H, J¼11.5 Hz), 5.09 (s, 1H), 4.97 (d, 1H,
1
3
J¼11.5 Hz), 4.87 (m, 1H), 4.78 (ddd, 1H, J¼10.6, 4.1,
1.81 (s, 3H); C NMR (acetone-d , 100 MHz) d 147.1,
6
1
3
4
.7 Hz), 4.62 (d, 1H, J¼12.0 Hz), 4.53 (d, 1H, J¼12.0 Hz),
.54 (dd, 1H, J¼11.4, 4.8 Hz), 3.34 (dd, 1H, J¼10.9,
.1 Hz), 3.30 (dd, 1H, J¼11.4, 6.5 Hz), 2.97 (t, 1H,
139.7, 132.6, 132.6, 129.8, 129.1, 128.9, 127.3, 120.9, 60.4,
41.6, 30.5, 29.1, 20.7. Anal. calcd for C H IN : C, 49.72;
H, 4.47; N, 8.28. Found: C, 49.82; H, 4.38; N, 8.34.
1
4
15
2
1
3
J¼10.8 Hz); C NMR (acetone-d , 100 MHz) d 148.3,
6
1
1
1
7
47.7, 138.7, 138.6, 133.8, 131.6, 131.0, 130.6, 130.3,
30.2, 129.4, 129.2, 129.1, 129.0, 128.9, 128.6, 128.5,
26.3, 126.2, 125.3, 124.3, 123.6, 97.9, 97.3, 85.1, 84.0,
6.7, 76.2, 73.6, 70.7, 62.4, 57.6, 1.2, 0.3. Anal. calcd for
3.1.25. 5-Methylen-5,6,7,8-tetrahydro-tetrazolo[1,5-
a]pyridine (17). A mixture of 11b (66 mg, 0.25 mmol),
KCN (49 mg, 0.75 mmol) and 18-crown-6 (3.3 mg,
0.013 mmol) in DMF (2 mL) was stirred for 24 h at 708C.
The reaction mixture was then cooled to room temperature
C H I N O: C, 34.16; H, 2.26; N, 4.19. Found: C, 34.22;
9 15 3 2
1
H, 2.20; N, 4.14.
and H O was added. The aqueous phase was extracted twice
2
with EtOAc and the combined organic phases were washed
twice with H O and brine. Drying (Na SO ) and concen-
3
.1.22. 5-Methylene-6,7-dihydro-imidazo[2,3-a][2]-
2
2
4
benzazepine (16c). The reaction was performed according
to the synthesis of 16a starting from 15b (0.25 mmol scale).
The reaction was stirred for 9 days and 83 mg of a crude
product as yellow oil was isolated. The yield of
tration at reduced pressure of the organic phase and column
chromatography (heptane/EtOAc 1:3) of the residue gave
1
24 mg (71%) of 17 as white crystals: mp 55–568C. H NMR
(acetone-d , 400 MHz) d 5.76 (br s, 1H), 5.04 (br s, 1H),
6
1
3
5
-iodomethyl-6,7-dihydro-imidazo[2,3-a][2]benzazepine
1
3.11 (t, 2H, J¼6.4 Hz), 2.80 (m, 2H), 2.05 (m, 2H); C
NMR (acetone-d , 100 MHz) d 152.5, 138.4, 101.3, 28.8,
was determined to be 87% by H NMR spectroscopy using
anisole as internal standard. Column chromatography
6
21.4, 20.8. Anal. calcd for C H N : C, 52.93; H, 5.92; N,
8 4
6
(
heptane/EtOAc 1:1) of the crude oil gave an inseparable
41.15. Found: C, 52.82; H, 5.84; N, 41.22.
mixture of 16c and 5-iodomethyl-6,7-dihydro-imidazo[2,3-
a][2]benzazepine as a pale yellow oil. The residual oil was
therefore dissolved in acetone and treated with diisopropyl-
amine (0.5 mL) at reflux for 16 h. Concentration of the
reaction mixture at reduced pressure followed by column
3.1.26. O-Ethyl S-(5,6,7,8-tetrahydro-tetrazolo[1,5-
a]pyridine-5-yl-methyl) dithiocarbonate (18). Potassium
ethyl xanthate (190 mg, 1.5 mmol) was added to 11b
(132 mg, 0.50 mmol) in acetone (5 mL) at room tempera-
ture. Stirring was continued for 3 h during which the initial
yellow solid disappeared and a white precipitate (KI) was
chromatography (heptane/EtOAc 1:3) gave 30 mg (61%) of
1
1
6c as a yellow oil. H NMR (CDCl , 400 MHz) d 7.96 (dd,
3
1
H, J¼7.3, 1.8 Hz), 7.30 (m, 2H), 7.18 (br d, 1H,
slowly formed. H O was then added to the reaction mixture
2
J¼7.2 Hz), 7.17 (d, 1H, J¼1.3 Hz), 7.15 (d, 1H,
J¼1.3 Hz), 4.99 (br s, 1H), 4.81 (br s, 1H), 3.07 (m, 2H),
and the aqueous phase was extracted twice with EtOAc. The
combined organic phases were washed with H O and brine
2
1
3
2
1
1
6
.87 (m, 2H); C NMR (CDCl , 100 MHz) d 146.8, 142.9,
3
followed by drying (Na SO ). Concentration at reduced
2
4
38.8, 130.4, 129.5, 129.2, 129.1, 128.7, 127.2, 120.7,
07.0, 36.3, 31.3. Anal. calcd for C H N : C, 79.56; H,
.16; N, 14.27. Found: C, 79.66; H, 6.24; N, 14.21.
pressure of the organic phase and column chromatography
(heptane/EtOAc 1:3) of the residue gave 99 mg (77%) of 18
1
3 12 2
1
as white crystals: mp 82–838C H NMR (acetone-d6,
4
00 MHz) d 4.85 (m, 1H), 4.68 (q, 2H, J¼7.1 Hz), 4.10 (dd,
3
.1.23. 2,3-Diiodo-5-iodomethyl-6,7-dihydro-imi-
1H, J¼14.3, 4.6 Hz), 3.67 (dd, 1H, J¼14.3, 7.5 Hz), 3.10–
dazo[2,3-a][2]benzazepine (16d). The reaction was per-
formed according to the synthesis of 16b starting from 15b
2.90 (m, 2H), 2.45–2.34 (m, 1H), 2.22–2.13 (m, 1H), 2.07–
1.92 (m, 2H), 1.43 (t, 3H, J¼7.1 Hz); C NMR (acetone-d6,
1
3
(
1.0 mmol scale). The reaction mixture was stirred for 16 h.
100 MHz) d 214.0, 153.2, 71.6, 56.5, 39.2, 27.7, 21.2, 18.8,
13.9. Anal. HRMS (EI ) calcd for C H ClNO (M):
þ
258.0609. Found: 258.0600.
Column chromatography (heptane/EtOAc 3:1) of the crude
product gave 420 mg (73%, 95% purity according to HPLC
analysis) of 16d as a white solid. Recrystallization from
9
8
2
heptane/EtOAc (4:1) gave analytically pure 16d as white
1
3.1.27. 4-(5,6,7,8-Tetrahydro-tetrazolo[1,5-a]pyridin-5-
yl)-butyronitrile (19). Compound 11b (132 mg,
0.5 mmol), acrylonitrile (0.33 mL, 5.0 mmol), NaCNBH3
(63 mg, 1.0 mmol), chlorotributylstannane (16 mg,
0.05 mmol) and AIBN (8 mg, 0.05 mmol) were mixed in
degassed tert-butanol (10 mL) and heated at reflux. The
consumption of 11b was monitored by TLC. After 3 h
crystals: mp 148–1498C. H NMR (CDCl , 400 MHz) d
3
7
.83 (m, 1H), 7.34 (m, 2H), 7.22 (m, 1H), 4.79 (m, 1H), 2.99
(
2
dd, 1H, J¼10.5, 7.1 Hz), 2.88 (dd, 1H, J¼10.5, 9.1 Hz),
1
3
.79 (m, 2H), 2.67 (m, 1H), 2.31 (m, 1H); C NMR
(
CDCl , 100 MHz) d 151.5, 138.6, 130.5, 130.0, 129.2,
3
129.0, 128.1, 97.0, 86.8, 60.2, 35.9, 30.6, 8.4. Anal. calcd
for C H I N : C, 27.11; H, 1.93; N, 4.86. Found: C, 27.08;
H, 1.86; N, 4.77.
the reaction mixture was cooled and H O was added. The
2
1
3
11 3
2
aqueous phase was extracted twice with EtOAc and the
combined organic phases were washed with brine and then
dried (Na SO ). Concentration at reduced pressure of the
3
.1.24. 5-Iodomethyl-5-methyl-6,7-dihydro-imidazo[2,3-
2
4
a][2]benzazepine (16e). The reaction was performed
according to the synthesis of 16a starting from 15c
organic phase followed by column chromatography
(CH Cl –CH CN 4:1) of the crude product gave 53 mg
(55%) of 19 as a colorless oil. H NMR (acetone-d6,
2
2
3
1
(
0.25 mmol scale). The reaction mixture was stirred for 7

6768
F. Ek et al. / Tetrahedron 59 (2003) 6759–6769
4
2
1
00 MHz) d 4.56 (quint, 1H, J¼6.3 Hz), 3.07–2.89 (m, 2H),
2. Grimmett, M. R. Compr. Heterocycl. Chem. II 1996, 3,
77–220.
.59 (t, 2H, J¼7.0 Hz), 2.35–2.24 (m, 2H), 2.20–2.07 (m,
1
3
H), 2.00–1.77 (m, 5H); C NMR (acetone-d , 100 MHz)
6
3. Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393.
4. Abell, A. D. Lett. Pept. Sci. 2002, 8, 267–272.
5. Zabrocki, J.; Smith, G. D.; Dunbar, J. B., Jr.; Iijima, H.;
Marshall, G. R. J. Am. Chem. Soc. 1988, 110, 5875–5880.
d 152.5, 119.9, 56.6, 33.8, 27.9, 22.1, 20.8, 18.5, 16.6. Anal.
calcd for C H N : C, 56.53; H, 6.85; N, 36.62. Found: C,
9
13 5
5
6.38; H, 6.76; N, 36.54.
6
. Zabrocki, J.; Marshall, G. R. Methods Mol. Med. 1999, 23,
417–436.
3
.1.28. O-Ethyl S-(2,3-diiodo-6,7-dihydro-imidazo[2,3-
a][2]benzazepine-5-yl-methyl) dithiocarbonate (20). The
reaction was performed according to the synthesis of 18
starting from 16d (1.0 mmol scale). The reaction mixture
was stirred for 16 h. Recrystallization (heptane/EtOAc 4:1)
of the crude pale yellow solid gave 230 mg (81%) of 20 as
7. Moderhack, D. J. Pract. Chem. 1998, 340, 687–709.
8. Ostrovskii, V. A.; Pevzner, M. S.; Kofman, T. P.; Shcherbinin,
M. B.; Tselinskii, I. V. Targets Heterocycl. Syst. 1999, 3,
467–526.
9. Daya, S.; Kaye, P. T.; Mphahlele, M. J. Med. Sci. Res. 1996,
24, 137–141.
1
white crystals: mp 131–1328C H NMR (acetone-d6,
4
1
2
1
2
8
00 MHz) d 7.68 (m, 1H), 7.42–7.33 (m, 3H), 5.02 (m,
H), 4.62 (q, 2H, J¼7.1 Hz), 3.32 (dd, 1H, J¼14.4, 5.3 Hz),
.94–2.85 (m, 1H), 2.84–2.74 (m, 2H), 2.40–2.29 (m, 1H),
10. Huang, R.-Q.; Bell-Horner, C. L.; Dibas, M. I.; Covey, D. F.;
Drewe, J. A.; Dillon, G. H. J. Pharmacol. Exp. Ther. 2001,
298, 986–995.
1
3
.37 (t, 3H, J¼7.1 Hz); C NMR (acetone-d , 100 MHz) d
11. Jung, M. E.; Lal, H.; Gatch, M. B. Neurosci. Biobehavioral
Rev. 2002, 26, 429–439.
6
14.0, 151.8, 139.6, 131.3, 130.7, 130.0, 128.9, 128.0, 97.1,
8.3, 71.3, 58.1, 41.8, 35.9, 30.7, 14.0. Anal. calcd for
12. Davis, B.; Brandstetter, T. W.; Smith, C.; Hackett, L.;
Winchester, B. G.; Fleet, G. W. J. Tetrahedron Lett. 1995,
36, 7507–7510.
C H I N OS : C, 33.70; H, 2.83; N, 4.91. Found: C,
1
6
16 2
2
2
3
3.82; H, 2.76; N, 4.89.
1
3. Brandstetter, T. W.; Davis, B.; Hyett, D.; Smith, C.; Hackett,
L.; Winchester, B. G.; Fleet, G. W. J. Tetrahedron Lett. 1995,
36, 7511–7514.
3
.1.29. O-Ethyl S-(2-iodo-6,7-dihydro-imidazo[2,3-
a][2]benzazepine-5-yl-methyl) dithiocarbonate (21).
i-PrMgBr (0.5 M in THF, 0.50 mL, 0.25 mmol) was added
dropwise to 20 (143 mg, 0.25 mmol) in dry THF at 2408C
under argon atmosphere. The disappearance of the starting
material was monitored by TLC and after 20 min another
portion of i-PrMgBr (0.5 M in THF, 0.25 mL, 0.13 mmol)
was added. After additional 25 min no starting material
remained and saturated aqueous ammonium chloride was
added to the reaction mixture and the temperature was
gradually increase to room temperature. The aqueous layer
was extracted twice with EtOAc and the combined organic
phases were washed with brine, dried (Na SO ) and
14. Ek, F.; Wistrand, L.-G.; Frejd, T. J. Org. Chem. 2003, 68,
1911–1918.
15. Sakakida, Y.; Kumanireng, A. S.; Kawamoto, H.; Yokoo, A.
Bull. Chem. Soc. Jpn 1971, 44, 478–480.
16. Mphahlele, M. J. J. Chem. Soc., Perkin Trans. 1: Org. and
Bioorg. Chem. 1999, 3477–3482.
17. Smith, P. A. S.; Clegg, J. M.; Hall, J. H. J. Org. Chem. 1958,
23, 524–529.
18. Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091–4094.
19. Kadaba, P. K. J. Org. Chem. 1976, 41, 1073–1075.
20. Joule, J. A.; Mills, K. Heterocyclic Chemistry; 4th ed.
Blackwell: Oxford, 2000; pp 402–503.
2
4
concentration at reduced pressure to give 130 mg of a red
oil. Column chromatography (heptane/EtOAc 4:1) of the
21. Aldabbagh, F.; Bowman, W. R. Tetrahedron Lett. 1997, 38,
3793–3794.
1
residual oil gave 70 mg (63%) of 21 as a pale yellow oil. H
NMR (acetone-d , 400 MHz) d 7.72 (m, 1H), 7.47 (s, 1H),
6
22. Grimmett, M. R. Imidazole and Benzimidazole Synthesis;
Academic: San Diego, Califonia, 1997.
7
1
8
1
1
1
.37–7.29 (m, 2H), 4.58 (dq, 2H, J¼7.1, 2.2 Hz), 4.51 (m,
H), 3.58 (dd, 1H, J¼14.4, 6.1 Hz), 3.51 (dd, 1H, J¼14.4,
.2 Hz), 2.81 (m, 1H), 2.71 (m, 1H), 2.50 (m, 1H), 2.29 (m,
H), 1.32 (t, 3H, J¼7.1 Hz); C NMR (acetone-d6,
00 MHz) d 214.0, 149.7, 139.2, 131.1, 130.1, 129.9,
29.2, 127.8, 126.3, 82.1, 71.4, 56.4, 40.1, 36.9, 30.9, 13.8.
23. Korotkikh, N. I.; Aslanov, A. F.; Raenko, G. F.; Shvaika, O. P.;
Russ, J. Org. Chem. (Translation of Zhurnal Organicheskoi
Khimii) 1999, 35, 730–740.
1
3
24. Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998,
910–914.
Anal. calcd for C H IN OS : C, 43.25; H, 3.86; N, 6.30.
2
Found: C, 43.20; H, 3.95; N, 6.24.
25. Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58,
4139–4141.
1
6
17
2
2
6. Flippin, L. A. Tetrahedron Lett. 1991, 32, 6857–6860.
7. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4, p 363.
2
Acknowledgements
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71–197.
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We thank Amersham Health R&D AB, the Swedish
Research Council and The Royal Physiographic Society in
Lund for financial support and Einar Nilsson for obtaining
mass spectral data.
2
3
1
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3
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3
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