A synthon for the convenient and efficient introduction of tetrazolylmethyl groups into nucleophile-bearing compounds

Article abstract of DOI:10.1002/ejoc.200901335

An activated synthon for the efficient introduction of a protected tetrazolylmethyl group into nucleophile-bearing compounds is presented. The β-cyanoethyl protecting group allows for very effective deprotection under mild basic conditions. The synthon can be prepared by a two-step procedure (42 %) starting from cheap starting material and can alkylate piperidine in 91 % yield. Even quadruple alkylation to form a protected version of the hexadentate ligand EDTT gives decent yields. Simultaneous removal of the four protecting groups furnishes the lithium salt of a formally zwitterionic ligand in 75 % yield. Finally, the synthon's performance has been assessed by comparison with its benzyl-protected counterpart and was found to be equally efficient in the alkylation of simple amines but superior in deprotection. For substrates bearing basic amine sites, the β-cyanoethyl group is largely preferable.

Full text of DOI:10.1002/ejoc.200901335

FULL PAPER
DOI: 10.1002/ejoc.200901335
A Synthon for the Convenient and Efficient Introduction of Tetrazolylmethyl
Groups into Nucleophile-Bearing Compounds
Faycal Touti,[a] Frederic Avenier,[a] Quentin Lefebvre,[a] Philippe Maurin,[a] and
Jens Hasserodt*[a]
Keywords: Nitrogen heterocycles / Protecting groups / N ligands / Acidity
An activated synthon for the efficient introduction of a pro-
decent yields. Simultaneous removal of the four protecting
tected tetrazolylmethyl group into nucleophile-bearing com- groups furnishes the lithium salt of a formally zwitterionic
pounds is presented. The β-cyanoethyl protecting group al- ligand in 75% yield. Finally, the synthon’s performance has
lows for very effective deprotection under mild basic condi-
tions. The synthon can be prepared by a two-step procedure
(42%) starting from cheap starting material and can alkylate
piperidine in 91% yield. Even quadruple alkylation to form
a protected version of the hexadentate ligand EDTT gives
been assessed by comparison with its benzyl-protected coun-
terpart and was found to be equally efficient in the alkylation
of simple amines but superior in deprotection. For substrates
bearing basic amine sites, the β-cyanoethyl group is largely
preferable.
We have been interested in such N(x) ligands that can
compensate the positive charges of metal centers to give
Introduction
Over the past few decades, the tetrazole functional group electroneutral complexes for medical applications.[7] The
has attracted increasing interest in fields as diverse as drug value in using coordinating sites with a pKa lower than
discovery, organocatalysis, and coordination chemistry. In physiological pH (7.4) has been recognized by experts for
drug design in particular it is regarded as an isoster for the their ability to preserve high complex stability under these
carboxylate group,[1] with the N–H acidity being remark- specific conditions.[8] They stressed the need to prevent
ably close to the O–H acidity of the latter (pKa ≈ 5.5). The competition between protonation and metal coordination
tetrazole moiety is also generally accepted to exhibit of the coordinating site to avoid disruption of the metal-to-
stronger resistance to in vivo metabolization than the carb- ligand bond. As seen with most other N donor moieties
oxylate group, thus conferring to the corresponding drug such as pyridyl or imidazolyl, tetrazolyl groups should be
longer lifetimes in blood.[2,3] In the field of organocatalysis, preferably introduced into multidentate ligands in such a
it is used as an attractive substitute for the carboxylic acid fashion as to give 1,4-chelating motifs, leading to favorable
group to increase solubility in organic solvents.[4,5] Last but five-membered chelate rings. This requires an extra chain
not least, the tetrazole group has been investigated for its member, usually a methylene group, to be placed between
coordination properties in metal complexes.[6] Here, it is re- the tetrazole ring and the next coordinating heteroatom. In-
garded as a reasonably hard N ligand that can compensate troduction of a tetrazolylmethyl group on to a heteroatom
positive charges stemming from the metal center so as to should thus be the focal point in ligand design.
reduce the net charge of the resulting complex, a property
The unprotected tetrazole moiety is commonly prepared
that it shares with many other N–H “acidic” ligands found from a nitrile using excess sodium azide (Scheme 1).[9,10]
in metal complexes. However, those ligands almost exclu- Coordination chemists have used this strategy to create
sively show very high pKa values and their acidity can be tetrazoles in their multidentate ligands in the last step of
regarded as negligible compared with that of the tetrazole the synthesis (Scheme 1).[11] Of course this strategy would
moiety. It is this property that places it in a rather unique not allow further synthetic manipulation without first pro-
position among N coordinating sites in multidentate li- tecting the N–H acidic sites, a measure that leads to unsatis-
gands.
factory results (Scheme 2).[12] These drawbacks do not even
address the challenge of introducing two to four protecting
groups into the same molecule to furnish ligands displaying
multiple tetrazole groups. We have therefore developed an
alternative, highly convergent approach to introducing the
tetrazolylmethyl group by using a regiochemically defined
synthon bearing a benzyl protecting group and activated
[a] Laboratoire de Chimie, University of Lyon – ENS,
46 allée d’Italie, 69364 Lyon, France
Fax: +33-4-72728860
E-mail: jens.hasserodt@ens-lyon.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901335.
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Introduction of Tetrazolylmethyl into Nucleophilic Compounds
for nucleophilic attack (Scheme 3).[13] This strategy is analo-
gous to many other strategies such as the grafting of tert-
butyl-protected acetate groups onto nucleophile-bearing
compounds. Synthon 1[14] was thus applied to the straight-
forward synthesis of the tetrakis-tetrazolyl analogue of
EDTA, namely EDTT.[13] No ligand displaying multiple
units of free tetrazoles has been synthesized by using a pre-
protected tetrazole synthon before. However, its synthesis
was hampered in the last step by the requirement of large
amounts of palladium/carbon to remove four units of the
benzyl protecting group. Thus, we describe an alternative
synthon bearing a protecting group with properties orthog-
onal to those of the benzyl group. The scope of both our
synthons is demonstrated through a few syntheses as exam-
ples.
Scheme 3. Our strategy of employing a preprotected synthon, ap-
plied to the exemplary synthesis of EDTA-analogous ligand 3.[13]
Scheme 4. Synthesis of the BCE-protected tetrazole moiety, as used
in the field of medicinal chemistry.
Results and Discussion
The classic conditions using hydrazoic acid (HN3) intro-
duced by von Braun[27] (see also ref.[28]) have served well to
synthesize large quantities of synthon 1. The protocol for
the synthesis of BCE derivative 5 is similar to that of the
benzyl derivative 1 that we developed[13] based on the origi-
nal report by Harvill et al.[14] Economic β-aminopropioni-
trile is treated with chloroacetyl chloride to give solid N-
cyanoethylchloroacetamide (4) in good yield (80%,
Scheme 5). Great care is crucial for the success of the next
two steps: The transformation to the chloroimine interme-
diate (INT) by use of PCl5 requires the removal of all HCl
generated in the process.[36]
Scheme 1. Examples of tetrazole syntheses from nitriles.[9–11]
Scheme 2. Regioisomers formed when protecting free tetrazoles.[12]
In the field of medicinal chemistry, the creation of β-
cyanoethyl (BCE)-protected tetrazole rings is now a fairly
established procedure.[15–19] The BCE group can be cleaved
under comparatively mild conditions by the use of LiOH
or DBU in a retro-hetero-Michael reaction releasing acrylo-
nitrile. On the other hand, the BCE-protected tetrazole
moiety is exclusively synthesized from the corresponding
BCE-substituted carboxamide (Scheme 4). Costly commer-
cial reagents are required and the transformations give
moderate yields and large amounts of waste material
(Scheme 4).[20–26]
Scheme 5. Preparation of new BCE-protected tetrazole synthon 5.
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J. Hasserodt et al.
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Thorough degassing limits the presence of 4 in the final 70 °C in water, resin-like 5 dissolves in water above 50 °C.
product 5 to less than 5% after treatment of the chloroim- According to LCMS/UV-monitoring, the reaction never
ine INT with a toluene solution of hydrazoic acid (HN3) went to completion and partially alkylated species were al-
and a yield of crude 5 of 72% can be reliably attained. Silica ways detected, no matter what conditions were used. Both
gel chromatography then removes residual 4 and phospho- 2,6-lutidine and triethylamine were tested as helper bases,
ryl chloride (POCl3) to give pure 5 as a colorless oil in 42% and water, acetonitrile, THF, and toluene as solvents. The
yield over three steps, and this on the gram scale. The pres- results of these experiments revealed the optimal procedure
ence of polar 4 exceeding 5% will greatly compromise the to involve heating the mixture at 50 °C for 4 days in acetoni-
success of this purification step. Synthon 5 is soluble in trile whereupon the mixture is concentrated in vacuo and
most organic solvents, sparely soluble in water, and totally the resultant resin washed with DCM and water to give
soluble in hot water. It can be kept for months without already pure 8 (yield 32%). The presence of lutidine did not
taking particular precautions.
seem to have an adverse effect on the base-sensitive BCE
The essence of this work resides in the comparison of the protective group.
performances of the synthons 1 and 5 in the alkylation of
nucleophile-bearing compounds and the deprotection of the
resulting species. We were not surprised to find that
monoalkylation of a simple substrate with 5 is highly effec-
tive. In fact, with rare exceptions,[21] most drug targets only
sport one tetrazole moiety, a statement that holds true also
for organocatalysts. Although an initial test of 5 with piper-
idine in acetonitrile at reflux gave crude 6 along with side-
products (70% yield after chromatography), its transforma-
tion over 12 h with the same slight excess (1.07 equiv.) of
Scheme 7. Performance of BCE-protected synthon 5 in the synthe-
piperidine, but at room temperature, gave pure solid 6 in
91% yield without further purification (Scheme 6). Neither
the presence of an excess of TEA as helper base nor the
sis of EDTA analogue EDTT (3).
We then reexamined the deprotection conditions of benz-
presence of piperidine appeared to endanger the BCE ylated 2[13] to decide on the overall performance of the two
group. According to Biot et al.,[26] LiOH in acetonitrile strategies. Two flaws in the hydrogenative debenzylation of
proved to be the most effective base for removing the BCE this particular compound can be identified: (1) The need
group, whereas organic bases such as DBU/TBAF in DCM for large amounts and a high quality/freshness of the Pd/C
produced free tetrazoles of lower purity. In our hands, the catalyst and (2) LCMS-monitoring to pinpoint the moment
application of 1.05 equiv. of LiOH in mixtures of acetoni- at which work-up should be launched. Indeed, Sajiki and
trile and methanol indeed gave very satisfactory results. Re- Hirota described how they could control the performance
actions at room temperature were complete after 1 h of the catalyst towards hydrogenation or hydrogenolysis of
(NMR) and a simple work-up involving evaporating the aliphatic or aromatic benzyl ethers by poisoning the catalyst
mixture to dryness and washing the residue with acetoni- with ammonia or more sophisticated nitrogen bases.[29] Eth-
trile gave excellent yields of the free tetrazole 7 (Scheme 6). ylenediamine or diethylenetriamine showed the “best” re-
sults. They concluded that the important criterion for good
Pd/C poisoning is a 1,4-didentate coordinating motif giving
five-membered chelates with palladium. In addition, from
their results they proposed a two-step coordination process
with a fast first step in which a loose interaction between
ethylenediamine and Pd/C is formed, and a second step that
may take more than 30 h in which the chelate is formed.
This may then be at the root of the hydrogenation problems
described above, especially in view of the facts that (1) we
Scheme 6. Performance of BCE-protected synthon 5 during the
monoinstallation of a tetrazolylmethyl unit onto a nucleophile-
bearing compound.
have reported the deprotection of 1 under “truly catalytic
As described in Scheme 3, we recently reported the appli- conditions”[13] and (2) the reaction time for 2 should not
cation of benzyl-protected synthon 1 in the exemplary prep- exceed 2 days (point 2 from above) to avoid losses due to
aration of the EDTA analogue EDTT (3).[13] We now excessive absorption.[13] Other research teams similarly ob-
wished to determine whether the use of BCE-protected syn- served that the debenzylation of tetrazoles requires excess-
thon 5 would approach the remarkably efficient four-fold ive amounts of palladium catalyst.[21,30–32] Surfraz et al.,
alkylation of ethylenediamine that we observed for 1 who tried to deprotect aminocyclitols bearing two benzyl-
(Scheme 7). The driving force responsible for the almost ated secondary alcohol groups, noticed that the presence of
quantitative yields of 2 was its precipitation in water even a secondary or tertiary nitrogen atom prevented hydro-
at 70 °C. Unfortunately, we were not able to develop such genolysis altogether (0% yield) whereas its absence allowed
favorable conditions when using 5. Whereas 1 is a crystal- smooth deprotection under truly catalytic conditions
line colorless solid that melts and gives a white emulsion at (quantitative yield)![33]
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Eur. J. Org. Chem. 2010, 1928–1933

Introduction of Tetrazolylmethyl into Nucleophilic Compounds
The report by Sajiki and Hirota,[29] that the poisoning tion. The yield of 60% combined with that of the previous
effect of nitrogen bases can be repressed by the presence of double alkylation step leads to an overall yield of 42%
strong acids, prompted us to investigate the effect of tri- starting from ethylene glycol, a decent performance.
fluoroacetic acid (TFA) on the deprotection of 2 (Table 1).
All in all, the best yield of 3 was achieved with 300 wt.-%
Conclusions
of 5% Pd/C in TFA (which corresponds to 1 equiv. based
on Pd) for 48 h (84%). This can be compared with the yield
of 70% achieved in DCM/EtOH and in the absence of TFA
for the same duration.[38]
We have prepared a BCE-protected tetrazolylmethyl syn-
thon (5) and assessed its merits in the installation of one or
four units of the free tetrazolylmethyl group into nucleo-
phile-bearing compounds by comparison with its benzyl-
ated analogue (1). The removal of the benzyl group from
those compounds resulting from the use of synthon 1 is
severely hampered by the presence of chelating units; the
presence of acid may mitigate catalyst poisoning to some
extent. Even compounds displaying ether moieties instead
of aliphatic amines appear to impair catalyst performance.
We therefore cannot but conclude that tetrazoles that are
part of chelating motifs may interact detrimentally with Pd/
C. On the other hand, benzylated tetrazoles that are not
part of such a motif appear to react with truly catalytic
amounts of catalyst.
Table 1. Hydrogenation conditions and results for the deprotection
of 1, 2, and 9.
Reaction
time [h]
Isolated
yield [%]
Solvent
Pd/C(% w/w)
1
1
2
2
EtOH
EtOH
24
1
48
–
20
99[a]
99[b]
70[c]
100
600
600
DCM/EtOH 1:1
DCM/EtOH 1:1 +
10 equiv. TFA
TFA (neat)
DCM/EtOH 1:1
DCM/EtOH 1:1
DCM/EtOH 1:1
[d]
–
2
2
9
9
48
48
12
3
300
300
250
500
84[e]
21
[f]
–
60
By contrast, the new β-cyanoethyl-protected synthon 5
performs superbly under very mild conditions during
monoalkylation and subsequent deprotection to the free
tetrazole compound. Even in the challenging case of qua-
druple alkylation the yield of the hexadentate ligand is ac-
ceptable and its mild deprotection to a difficult-to-handle
zwitterionic system gives very satisfactory yields.
[a] Not isolated, hydrogenation also resulted in partial loss of the
chlorine atom and formation of a methyl group (40%). [b] Not
isolated, hydrogenation also resulted in partial loss of the chlorine
atom and formation of a methyl group (66%). [c] See ref.[13]. [d]
Reaction stopped midway. [e] Approximate yield. [f] Not deter-
mined because reaction still not complete.
Finally, we wished to assess the influence of tetrazoles
on catalyst performance and synthesized the model com-
pound 10. The double alkylation of ethylene glycol with
benzylated synthon 1 in THF at reflux and in the presence
of sodium hydride was straightforward (Scheme 8). Dibenz-
ylated 9 turned out to be remarkably polar, but could be
Experimental Section
Caution: Experimentation with sodium azide and hydrazoic acid can
be hazardous. Safety precautions should include working in a prop-
purified on silica gel with up to 5% MeOH, albeit contain- erly working fume hood and wearing gloves and safety glasses. Az-
ides of heavy metals can be explosive and thus contact with heavy
metals must be avoided. Contact of azides with chlorinated solvents
should also be avoided, as should any unnecessary scale-up of the
described reactions.[34,35]
ing residual polar impurities (70% yield). The speed of hy-
drogenative deprotection of 9 was again very much depend-
ent on the quality (batch) of the (commercial) palladium
catalyst. The conditions that we were able to reproduce sev-
eral times comprised 500 wt.-% of 5% Pd/C (0.5 equiv. per
benzyl moiety), that is, as much as was used to deprotect 2,
but 10 was furnished in a sixteenth of the time (3 h) found
for 3 (Table 1). Free bis-tetrazole 10 is a colorless resin that
slowly precipitates as a powder from an acetonitrile solu-
N-Cyanoethylchloroacetamide (4): Chloroacetyl chloride (7 mL,
89 mmol) was added dropwise to a vigorously stirred solution of
aminopropionitrile (13 mL, 180 mmol, 2 equiv.) in toluene (50 mL)
at 0 °C using a mechanical stirrer. A colorless precipitate formed
immediately and the suspension thickened progressively, thus po-
tentially requiring the addition of further toluene. Once the ad-
dition of the reactant was complete, stirring was continued for
20 min before quenching the reaction with water (100 mL). The
addition of ethyl acetate (50 mL) caused the solid to dissolve com-
pletely. The phases were separated and the aqueous phase was ex-
tracted with ethyl acetate (2ϫ50 mL), dried with Na2SO4, filtered,
and concentrated. N-Cyanoethylchloroacetamide (4) was thus ob-
tained as a colorless solid (10.07 g, 79%). 1H NMR (CDCl3, 300 K,
200 MHz): δ = 4.08 (s, 2 H), 3.59 (q, J = 6.4 Hz, 2 H), 2.37 (t, J =
6.4 Hz, 2 H) ppm.
1-Cyanoethyl-5-chloromethyltetrazole (5). Step 1: Phosphorus
pentachloride (16.8 g, 81 mmol) was added portionwise to a vigor-
ously stirred suspension of N-cyanoethylchloroacetamide (4; 10.2 g,
70 mmol) in dichloromethane (250 mL) at 0 °C. The reaction mix-
ture was raised to ambient temperature and thoroughly degassed
for at least 2 h to remove all HCl. Extra dichloromethane was
Scheme 8. Satisfactory performance of the installation and depro-
tection of benzylated synthon 1 on compounds bearing nucleo-
philes other than amine groups.
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J. Hasserodt et al.
FULL PAPER
added sporadically to avoid drying of the reaction mixture. The
solution of crude N-cyanoethyl-1,2-dichloroacetylimine thus ob-
tained was then used directly in the next step.
4 H), 1.47 (m, 6 H) ppm. 13C NMR (CDCl3, 300 K, 50 MHz): δ =
152.8, 116.4, 54.7, 51.5, 43.2, 25.9, 23.7, 18.5 ppm.
N-[(Tetrazol-5-yl)methyl]piperidine (7). Lithium Salt: The same pro-
cedure as applied to 8 was applied to 6 (254 mg, 1 equiv., 1.2 mmol)
by using LiOH·H2O (51 mg, 1.05 equiv., 1.2 mmol). The desired 7
Step 2: Under a properly operating fumehood, a solution of con-
centrated sulfuric acid (25 mL) was added dropwise under cooling
to a gently stirred solution of sodium azide (15 g, 0.35 mol) in water
(15 mL) overlaid by toluene (60 mL). The phases were separated
and the aqueous layer was extracted with toluene (2ϫ20 mL). The
combined extracts were dried with Na2SO4. This hydrazoic acid
(HN3) solution was slowly added to the cooled chloroimine solu-
tion from step 1 and stirred overnight at room temperature; over
time a red-brown resin precipitated from the mixture. The excess of
HN3 was removed under reduced pressure (under a well operating
fumehood) followed by removal of the dichloromethane and
eventually toluene. The proportion of residual 4 in the green resin
obtained was assessed by NMR spectroscopy. The latter is dis-
solved in chloroform/ethyl acetate (9:1; to separate an orange insol-
uble) and purified by silica gel chromatography (9:1 to 6:4) to give
pure 5 (6.4 g, 53%) as a colorless oil. 1H NMR (CDCl3, 300 K,
200 MHz): δ = 4.94 (s, 2 H), 4.75 (t, J = 6.7 Hz, 2 H), 3.15 (t, J =
6.7 Hz, 2 H) ppm. 13C NMR (CDCl3, 300 K, 50 MHz): δ = 151.9,
116.0, 43.5, 31.2, 18.7 ppm. HRMS: calcd. for C5H6ClN5Na [M +
Na]+ 194.0209; found 194.0215.
1
was obtained as a colorless solid (190 mg, 96%). H NMR (D2O,
300 K, 200 MHz): δ = 3.53 (s, 2 H), 2.17 (m, 4 H), 1.25–1.05 (m,
6 H) ppm. 13C NMR (D2O, 300 K, 50 MHz): δ = 158.2, 52.8, 51.2,
24.8, 23.0 ppm. HRMS: calcd. for C7H13N5Na [M + Na]+
190.1069; found 190.1074.
O,OЈ-Bis[(1-benzyltetrazol-5-yl)methyl]-1,2-ethanediol (9): A stock
solution of ethylene glycol (5 mL, 1 equiv., 2.3 mmol, 0.46 ) was
added dropwise under argon to a cooled and stirred suspension of
sodium hydride (previously washed with petroleum ether) in THF
(5 mL) in a two-necked round-bottomed flask equipped with a con-
denser. Under continued cooling, 1 (1.0 g, 2.1 equiv., 4.8 mmol) in
THF (5 mL) was added dropwise. The solution was raised to room
temperature and heated at reflux overnight. The orange suspension
obtained was quenched under cooling with water (15 mL) and ex-
tracted with DCM (3ϫ70 mL). After evaporation under reduced
pressure a yellow resin was obtained and purified by silica gel
chromatography (ethyl acetate/petroleum ether, 50:50, to pure ethyl
acetate) to give reasonably pure 9 (700 mg, 70%). 1H NMR
(CDCl3, 300 K, 200 MHz): δ = 7.31–7.19 (m, 2 H), 2.17 (m, 10 H),
5.54 (s, 4 H), 4.65 (s, 4 H), 3.47 (s, 4 H) ppm. 13C NMR (CDCl3,
300 K, 50 MHz): δ = 151.4, 133.3, 129.2, 129.1, 127.9, 70.0, 61.5,
51.5 ppm. HRMS: calcd. for C20H22N8O2Na [M + Na]+ 429.1763;
found 429.1764.
N,N,NЈ,NЈ-Tetrakis[(1-cyanoethyltetrazol-5-yl)methyl]-1,2-ethanedi-
amine (8): A solution of ethylenediamine (1 equiv., 0.36 mmol) was
prepared by combining a stock solution of ethylenediamine (6 mL,
60 m) in acetonitrile with 2,6-lutidine (0.17 mL, 4.2 equiv.,
1.5 mmol). The resulting solution was treated with 5 (0.26 g,
4.2 equiv., 1.5 mmol). The mixture was heated at 50 °C and after
1 day at 60 °C. The pH was adjusted to 8 by regular addition of
2,6-lutidine. The reaction was monitored by LC–MS, a white solid
precipitated, and the solution turned from yellow to red. After 4 d,
the acetonitrile was evaporated and the resulting dark-red resin was
washed with dichloromethane and water to yield pure 8 (70 mg,
32%). 1H NMR (CD3CN, 300 K, 200 MHz): δ = 4.65 (t, J =
6.6 Hz, 8 H), 4.14 (s, 8 H), 3.07 (t, J = 6.7 Hz, 8 H), 2.90 (s, 4
H) ppm. 13C NMR (CD3CN, 300 K, 50 MHz): δ = 152.3, 117.4,
51.1, 46.3, 43.2, 18.2 ppm.
O,OЈ-Bis[(tetrazol-5-yl)methyl]-1,2-ethanediol (10): A solution of 9
(0.27 g, 0.67 mmol) in a 1:1 mixture of DCM/EtOH (20 mL) was
treated with 5% palladium on carbon (“Degussa” quality) (1.4 g,
1 equiv., 500 wt.-%). The stirred solution was saturated with hydro-
gen, the flask sealed with a septum and the gas phase purged with
hydrogen, and finally placed under 1 atm. of hydrogen. Stirring was
continued at room temperature for 3 h. The mixture was filtered
through Celite, washed with ethanol, and concentrated to give the
crude product as a colorless oil. Acetonitrile was added to the oil
and the mixture was stored in the fridge until the precipitation of
colorless 10 was complete. Decantation and drying yielded 90 mg
N,N,NЈ,NЈ-Tetrakis[(tetrazol-5-yl)methyl]-1,2-ethanediamine
(3).
1
of 9 (60%). H NMR (D2O, 300 K, 200 MHz): δ = 4.82 (s, 4 H),
Lithium Salt (obtained from 8): A solution of LiOH·H2O (1 mL,
4.1 equiv., 26.7 mg, 0.64 mmol) was added to a stirred solution of
8 (93 mg, 0.16 mmol) in acetonitrile (5 mL) under argon. After
20 min a creamy red solid began to precipitate and the reaction
was carried on for another 1.5 h. The solvents were evaporated un-
der reduced pressure and the light-red solid obtained was washed
with dichloromethane and acetonitrile to yield pure 3 (45 mg,
73%). 1H NMR (D2O, 300 K, 200 MHz): δ = 3.96 (s, 8 H), 2.76
(s, 4 H) ppm. 13C NMR (D2O, 300 K, 50 MHz): δ = 159.1, 50.2,
47.3 ppm.
3.69 (s, 4 H) ppm. 13C NMR (D2O, 300 K, 50 MHz): δ = 154.2,
70.2, 61.4 ppm. HRMS: calcd. for C6H10N8O2Na [M + H]+
249.0824; found 249.0831.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra.
Acknowledgments
This work was supported by a grant from the French Institut
National du Cancer (INCa, program Projets Libres 2007). Ad-
ditional financial support from the French Ministère de la Recher-
che and from the Centre National de la Recherche Scientifique
(CNRS) is acknowledged.
N-[(1-Cyanoethyltetrazol-5-yl)methyl]piperidine (6): A basic solu-
tion of piperidine (1 equiv., 1.6 mmol) was prepared by combining
a stock solution of piperidine (0.32 , 5 mL) in acetonitrile with
triethylamine (1 mL, 4.5 equiv.). The resulting solution was treated
with 5 (0.25 g, 0.94 equiv., 1.5 mmol). The reaction mixture was
stirred at room temperature and monitored by TLC. After 12 h,
acetonitrile was evaporated under reduced pressure and water
(20 mL) was added. The mixture was extracted with chloroform
(2ϫ50 mL). The organic phases were combined, dried with
Na2SO4, and concentrated to dryness to give 6 as a colorless solid
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1
(300 mg, 91%). H NMR (CDCl3, 300 K, 200 MHz): δ = 4.75 (t,
J = 6.8 Hz, 2 H), 3.80 (s, 2 H), 3.06 (t, J = 6.8 Hz, 2 H), 2.35 (m,
1932
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Eur. J. Org. Chem. 2010, 1928–1933

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Published Online: February 19, 2010
Eur. J. Org. Chem. 2010, 1928–1933
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1933