Reductive removal of the pivaloyl protecting group from tetrazoles by a naphthalene-catalyzed lithiation process

Article abstract of DOI:10.1055/s-0034-1378681

The reaction of various 1-pivaloyl-1H-tetrazoles with excess lithium and a catalytic amount of naphthalene (20 mol%) led, after treatment with methanol, to the corresponding free tetrazoles through reductive C-N bond cleavage. This methodology represents a reasonable alternative to other nonreductive protocols.

Full text of DOI:10.1055/s-0034-1378681

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 507–510
paper
507
C. Behloul et al.
Paper
Synthesis
Reductive Removal of the Pivaloyl Protecting Group from
Tetrazoles by a Naphthalene-Catalyzed Lithiation Process
Cherif Behloul*a
i) Li, C10H8 (20 mol%)
THF, 0 °C
N
N
N
Aicha Choutia
David Guijarrob
Carmen Nájerab
Miguel Yusb
N
N
R
R
N
ii) MeOH, 0 to 20 °C
R = alkyl, aryl, benzyl
N
N
H
Piv
a Laboratoire des Produits Naturels d’Origine Végétale et de
Synthèse Organique, Université Constantine 1, 25000
Constantine, Algeria
+
2
1
3
3
(
1
8
)
1
8
8
6
2
afiza72@gmail.com
b Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Dedicated to the memory of Professor Alan R. Katritzky
Received: 09.10.2014
Accepted: 22.10.2014
Published online: 27.11.2014
DOI: 10.1055/s-0034-1378681; Art ID: ss-2014-z0601-op
In the last few years our research group has been using
arene-catalyzed lithiation to perform metalations under
very mild reaction conditions.9–12 This lithiation methodol-
ogy has been applied to the reductive cleavage of trityl
ethers13 and amines,14 the desilylation of silylated alcohols,
amines, and thiols,15 the cleavage of carbonates, carba-
mates, and thiocarbonates,16 and the deacylation of esters,
thioesters, and amides.17 Very recently, we have reported a
reductive cleavage of tritylated tetrazoles using this lithia-
tion methodology, which leads to the deprotected tetra-
zoles without affecting the heterocyclic ring.18
Abstract The reaction of various 1-pivaloyl-1H-tetrazoles with excess
lithium and a catalytic amount of naphthalene (20 mol%) led, after
treatment with methanol, to the corresponding free tetrazoles through
reductive C–N bond cleavage. This methodology represents a reason-
able alternative to other nonreductive protocols.
Keywords tetrazoles, pivaloyl, lithium, deprotection
The pivaloyl group is widely used in organic synthesis to
protect alcohols, amines, and thiols, due to its easy intro-
duction, stability under a variety of reaction conditions,
and relatively easy removal to give the corresponding de-
pivalated compounds.1 Among the different methodologies
reported for the deacylation of protected alcohols and
amines, we can find hydrolysis under basic or acidic condi-
tions,2 reduction with alkali metals in liquid ammonia,3 re-
ductive cleavage using an arene-catalyzed lithiation,4 reac-
tion with hydride sources,5 electrolysis,6 and enzymatic
methods.7
The tetrazole moiety is present in several biologically
active compounds, such as sartans, which are pharmaceuti-
cals that are efficient for the treatment of hypertension,
kidney damage caused by diabetes, and heart failure. The
synthesis of sartans generally requires protection and
deprotection steps to the tetrazole ring.8 The effective pro-
tection caused by the high steric demand of the pivaloyl
group, together with the ease of its introduction into and its
removal from the nitrogen atom, are features that poten-
tially make the pivaloyl group useful in the preparation of
this interesting family of drugs. Thus, the development of
procedures that remove the pivaloyl protecting group with-
out affecting the tetrazole ring would be very interesting.8
In this paper we wish to report the use of a naphtha-
lene-catalyzed lithiation to perform the removal of the piv-
aloyl protecting group from tetrazoles under very mild con-
ditions.
The reaction of various 5-substituted 1-pivaloyltetra-
zoles 1a–f with excess lithium powder (1:20 molar ratio)
and a catalytic amount of naphthalene (1:0.4 molar ratio) in
tetrahydrofuran at 0 °C for three hours led, after quenching
with methanol, to the corresponding free tetrazoles 2a–f
(Equation 1, Table 1).
i) Li, C10H8 (20 mol%)
THF, 0 °C
N
N
N
N
N
N
R
R
ii) MeOH, 0 to 20 °C
R = alkyl, aryl, benzyl
N
N
H
Piv
1
2
Equation 1
The deprotected tetrazoles 2a–f were isolated generally
in good yields (Equation 1 and Table 1). In general, moder-
ate to good yields were obtained in the deprotection of 5-
aryl-1-pivaloyltetrazoles 2a,b (entries 1 and 2), 5-alkyl-1-
pivaloyltetrazoles 2c,e (entries 3 and 5), or 5-benzhydryl-1-
pivaloyltetrazole 2f (entry 6). Interestingly, 5-(3,3-dimeth-
yl-2-oxobutyl-1-pivaloyl)-1H-tetrazole (1d), containing a
carbonyl group in the 5-substituent that could undergo re-
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Synthesis
Table 1 Reductive Removal of the Pivaloyl Group from Protected
Tetrazoles 1
In conclusion, we report an efficient method to remove
the pivaloyl protecting group from various 1-pivaloyl-1H-
tetrazoles bearing various aliphatic, aromatic, or benzylic
substituents in the 5-position under very mild reaction
conditions. This procedure is an alternative to other meth-
odologies, especially those involving hydrolysis, which usu-
ally require harsh reaction conditions.
Entry Substrate
Time Product
(h)
Yielda
(%)
N
N
N
N
N
NH
N
N
O
O
1
3
63
FT-IR spectra were obtained on a Nicolet Impact 400D spectropho-
tometer using KBr plates (for solid compounds). NMR spectra were re-
corded on a Bruker spectrometer (400 MHz for 1H and 100 MHz for
13C) using CDCl3, DMSO-d6, CD3OD as solvents and TMS (δ = 0.00, 1H)
and CDCl3 (δ = 77.0, 13C), DMSO-d6 (δ = 2.50, 1H and δ = 39.75, 13C),
CD3OD (δ = 4.87, 1H and δ = 49.0, 13C) as internal standards. Elemental
analysis were measured by the Technical Services at the University of
Alicante. Column chromatography was performed using silica gel 60
(35–70 mesh) or basic alumina (50–160 μm particle size). Li powder
was prepared according to the procedure described.19 Commercially
available BuLi was titrated with a 1 M solution of s-BuOH in xylene
using 1,10-phenanthroline as indicator.20 Commercially available an-
hyd THF (99.9%, water content ≤ 0.006%, Acros) was used as solvent in
all the lithiation reactions.
1a
2a
H
N
N
N
N
N
N
2
3
56
N
N
2b
2c
1b
1c
N
N
N
O
All reagents used for the synthesis of substrates 1 and naphthalene
were commercially available (Acros, Aldrich) and were used without
further purification. All glassware was dried in an oven at 100 °C and
cooled to r.t. under argon before use.
3
3
55
N
N
N
H
N
N
Tetrazoles 2a–f were prepared following the procedure recently de-
scribed by us.18 Physical and spectroscopic data of the obtained com-
pounds 2a–f were identical with those previously reported.18
N
N
O
N
O
N
N
N
N
4
5
3
3
62
61
N
CAUTION! Several tetrazole derivatives or their salts have been
shown to have explosive properties, especially tetrazoles with elec-
tron-withdrawing substituents in position 5 of the ring.21 Although
we had no problems during the synthesis of any of the tetrazoles in-
cluded in this paper, proper protective measures should be taken.
H
O
2d
1d
1e
O
N
N
N
HN
Protected Tetrazoles 1a–f; General Procedure
N
N
N
N
To a stirred solution of the tetrazole (10.0 mmol) in anhyd THF (10
mL) under argon at 0 °C was added dropwise 2.5 M BuLi in hexane (4
mL, 10.0 mmol); the mixture was stirred at this temperature for 10
min. Pivaloyl chloride (1.23 mL, 10.0 mmol) was added to the mixture
over ca. 5 min and it was stirred at r.t. overnight. The reaction was
quenched with H2O (5 mL) and extracted with EtOAc (3 × 15 mL). The
combined organic phases were washed with brine (5 mL), dried
(Na2SO4), filtered, and the solvent evaporated to give a residue that
was purified by recrystallization (hexane–EtOAc) to afford pure prod-
uct.
2e
O
H
6
3
61
N
N
N
N
N
N
N
N
1f
2f
a Yield of isolated product after extraction and recrystallization, based on
the starting material 1.
2,2-Dimethyl-1-(5-phenyl-1H-tetrazol-1-yl)propan-1-one (1a)
White solid; yield: 1.497 g (65%); mp 218–220 °C.
IR (KBr): 1701, 1608, 1562, 1484, 1409, 1256, 685 cm–1
1H NMR (400 MHz, CD3OD): δ = 1.06 (s, 9 H), 7.45–7.90 (m, 5 H).
13C NMR (100 MHz, CD3OD): δ = 27.6 (3 CH3), 39.3 (C), 125.6 (C), 128.2
duction under these reaction conditions, underwent solely
depivalation to give 2d in 62% yield (entry 4). All the lithia-
tion processes were complete in a reaction time of three
hours.
The starting tetrazoles were prepared by reaction of so-
dium azide with the corresponding nitriles in the presence
of an amine. The isolated tetrazoles were then pivalated on
N1 by reaction with pivaloyl chloride, giving the expected
protected tetrazoles 1 in good yields.
.
(2 CH), 130.5 (2 CH), 132.5 (CH), 157.7 (C).
Anal. Calcd for C12H14N4O: C, 62.69; H, 6.13; N, 24.33. Found: C, 62.66;
H, 6.15; N, 24.37.
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2,2-Dimethyl-1-[5-(4′-methylbiphenyl-2-yl)-1H-tetrazol-1-yl]pro-
pan-1-one (1b)
mL) was carefully added to the mixture, the cooling bath was re-
moved, and the mixture was stirred until it reached r.t. The mixture
was extracted with EtOAc (3 × 15 mL) and the combined organic
phases were washed with brine (5 mL), and then dried (Na2SO4). After
evaporation of the solvents, the resulting residue was purified by re-
crystallization (hexane–EtOAc), giving the corresponding free tetra-
zoles 2 in the following yields: 2a (46 mg, 63%), 2b (66 mg, 56%), 2c
(35 mg, 55%), 2d (52 mg, 62%), 2e (26 mg, 61%), and 2f (72 mg, 61%)
(see also Table 1). The obtained tetrazoles 2 were characterized by
comparison of their physical and spectroscopic data with those previ-
ously synthesized.
Yellow solid; yield: 1.986 g (62%).
IR (KBr): 1712, 1482, 1244, 1078, 823, 754 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 0.92 (s, 9 H), 2.27 (s, 3 H), 6.93–7.08
(m, 4 H), 7.45–7.63 (m, 4 H).
13C NMR (100 MHz, CD3OD): δ = 21.1 (CH3), 27.6 (3 CH3), 124.2 (C),
128.7, 129.9, 130.2, 131.6, 131.8, 132.5 (8 CH), 137.6 (C), 138.8 (2 C),
143.6 (2 C), 156.8 (C).
Anal. Calcd for C19H20N4O: C, 71.23; H, 6.29; N, 17.49. Found: C, 71.23;
H, 6.32; N, 17.53.
Acknowledgement
1-(5-tert-Butyl-1H-tetrazol-1-yl)-2,2-dimethylpropan-1-one (1c)
White solid; yield: 1.472 g (70%); mp 104–106 °C.
This work was financially supported by the A.N.D.R.S. (Agence Natio-
nale pour le Développement de la Recherche en Santé) (Algérie) and
the Department of Organic Chemistry of the University of Alicante
(Spain). We are very grateful to the Spanish Ministerio de Asuntos Ex-
teriores y de Cooperación for a cooperation grant (AP/039112/11). We
are very grateful to Dr. Rosa Ortiz for her valuable help.
IR (KBr): 1732, 1264, 1218, 1045, 703 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 1.42 (s, 18 H).
13C NMR (100 MHz, CD3OD): δ = 29.5 (3 CH3), 31.8 (3 CH3), 165.7 (C),
214.1 (CO).
Anal. Calcd for C10H18N4O: C, 57.12; H, 8.63; N, 26.64. Found: C, 57.12;
H, 8.62; N, 26.66.
Supporting Information
3,3-Dimethyl-1-(1-pivaloyl-1H-tetrazol-5-yl)butan-2-one (1d)
Brown solid; yield: 2.018 g (80%).
1H NMR (400 MHz, CD3OD): δ = 2.74 (s, 18 H), 2.80 (s, 2 H).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379457.
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13C NMR (100 MHz, CD3OD): δ = 26.4, 26.8, 27.5 (3 CH3), 27.6, 27.7,
27.9 (3 CH3), 31.7 (CH2), 39.3 (C), 45.5 (C), 152.5 (C), 182.5 (C=O),
210.1 (C=O).
References
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Anal. Calcd for C12H20N4O2: C, 57.12; H, 7.99; N, 22.21. Found: C,
57.10; H, 8.01; N, 22.24.
2,2-Dimethyl-1-(5-methyl-1H-tetrazol-1-yl)propan-1-one (1e)
White solid; yield: 1.430 g (85%); mp 152–157 °C.
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1H NMR (400 MHz, CD3OD): δ = 0.92 (s, 9 H), 2.31 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 8.4 (CH3), 26.8 (CH3), 27.6 (2 CH3),
39.3 (C), 154.1 (C), 182.5 (CO).
(4) Behloul, C.; Guijarro, D.; Yus, M. Synthesis 2006, 309.
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H, 7.14; N, 33.33.
1-[5-(Diphenylmethyl)-1H-tetrazol-1-yl]-2,2-dimethylpropan-1-
one (1f)
White solid; yield: 2.884 g (90%); mp 154–158 °C.
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(m, 10 H).
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13C NMR (100 MHz, CD3OD): δ = 26.8, 27.5, 27.6 (3 CH3), 39.3 (C), 47.8
(CH), 128.6 (2 CH), 129.6 (4 CH), 129.9 (4 CH), 140.8 (2 C), 159.9 (C),
182.5 (C=O).
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H, 6.26; N, 17.45.
Naphthalene-Catalyzed Lithiation of Compounds 1: Preparation of
Products 2; General Procedure
To a green suspension of Li powder (70 mg, 10 mmol) and naphtha-
lene (26 mg, 0.2 mmol) in THF (5 mL) under argon at 0 °C was added
dropwise a solution of the protected tetrazole 1 (0.5 mmol) in THF (2
mL) and the mixture was stirred at this temperature for 3 h. MeOH (5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 507–510

510
C. Behloul et al.
Paper
Synthesis
(11) For a polymer version of this reaction, see: (a) Gómez, C.; Ruiz,
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S.; Yus, M. Tetrahedron 1999, 55, 7017. (c) Yus, M.; Gómez, C.;
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very sensitive functionalized organolithium compounds,12b–g
reductive ring-opening of heterocycles,12h–j generation of polyli-
thium synthons,12k,l and for the activation of other metals,12m
especially nickel.12n,o For reviews from our group, see:
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(b) Nájera, C.; Yus, M. Trends Org. Chem. 1991, 2, 155. (c) Nájera,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 507–510