Detritylation of protected tetrazoles by naphthalene-catalyzed lithiation

Article abstract of DOI:10.1055/s-0033-1338623

Treatment of N-tritylated tetrazoles bearing aliphatic, aromatic, or heteroaromatic substituents (including functionalized ones) with lithium powder and a catalytic amount of naphthalene led to reductive removal of the trityl group to give excellent yields of the corresponding free tetrazoles without decomposition of the tetrazole ring. The detritylation process was successfully extended to several tetrazoles that are components of sartans, an interesting class of drugs. The chemoselectivity between trityl-tetrazole and trityl-amine bond-cleavage reactions was also studied. This method represents an efficient technique for deprotection of tritylated tetrazoles under non-acidic conditions. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338623

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▌2065
paper
Detritylation of Protected Tetrazoles by Naphthalene-Catalyzed Lithiation
Detritylation of Protected Tetrazoles
Cherif Behloul,*a Kenza Bouchelouche,a David Guijarro,b Carmen Nájera,b Miguel Yusb
a
Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Université Constantine 1, Constantine 25000, Algeria
Fax +213(31)818862; E-mail: 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
Received: 03.03.2014; Accepted after revision: 26.03.2014
Dedicated to the honor of Prof. Francisco Foubelo García
activities for several years.10,11 By treatment with an ex-
Abstract: Treatment of N-tritylated tetrazoles bearing aliphatic, ar-
cess of lithium powder, some arenes [mainly naphthalene
omatic, or heteroaromatic substituents (including functionalized
and 4,4′-di-tert-butylbiphenyl (DTBB)] generate highly
reactive radical anions and dianions that are efficient elec-
ones) with lithium powder and a catalytic amount of naphthalene
led to reductive removal of the trityl group to give excellent yields
of the corresponding free tetrazoles without decomposition of the tron carriers that induce reductive cleavage of various
carbon–heteroatom bonds in organic halides,10,11 nonhalo-
tetrazole ring. The detritylation process was successfully extended
to several tetrazoles that are components of sartans, an interesting
class of drugs. The chemoselectivity between trityl–tetrazole and
responding organolithium compounds, including some
trityl–amine bond-cleavage reactions was also studied. This method
represents an efficient technique for deprotection of tritylated tetra-
genated materials,12 or heterocycles,13 leading to the cor-
functionalized examples.14 This lithiation methodology
permits reductive cleavage of C–N bonds in various or-
ganic compounds,15 including detritylation of trityl
amines by a naphthalene-catalyzed lithiation process.16
The application of this lithiation procedure to the reduc-
tive removal of the trityl group from the nitrogen atom of
several protected tetrazoles under very mild reaction con-
ditions is discussed below.
zoles under non-acidic conditions.
Key words: tetrazoles, deprotection, reductions
Sartans are a group of drugs that are effective in treating
hypertension and heart failure. They block the renin–an-
giotensin system and they are among the most effective
treatments for hypertension.1 Of the seven sartans that are
used in clinical practice, five contain tetrazole moieties
within their structures. The protection and deprotection of
the nitrogen atom of the tetrazole ring is a crucial opera-
tion during the synthesis of these sartans.2 One group that
can be used to protect the tetrazole nitrogen is the triphe-
nylmethyl (trityl) group, a very efficient protecting group
for amines3 and amino acids,4 because its bulkiness causes
the nitrogen atom to be much less reactive as a nucleo-
phile. Simple treatment with an aqueous acidic solution
can be used to remove the trityl protecting group,3c but
some side-reactions have been observed under these con-
ditions, such as elimination of tritylamine during detrity-
lation of some tritylated amines.5 Other procedures that
have been shown to be efficient in detritylation processes
include dissolving-metal reduction,3c reactions with mo-
lecular hydrogen catalyzed by palladium,3c reduction with
sodium borohydride in the presence of mercury salts,6 and
reductive cleavage promoted by silanes7 or low-valent ti-
tanium reagents.8 Palladium catalysts in combination with
poly(methylhydrosiloxane) have been shown to permit di-
rect conversion of N-trityl amines into tert-butyl carba-
mates.9
We chose 5-phenyl-1-trityl-1H-tetrazole (1a) as a model
substrate, and we attempted to detritylate this compound
at –78 °C. When a solution of tetrazole 1a in tetrahydro-
furan was added to a green suspension of an excess of lith-
ium powder and a catalytic amount of naphthalene (molar
ratio 1:0.2) in tetrahydrofuran at –78 °C, the mixture
turned red, possibly indicating the formation of a trityl
radical17 and/or a trityl anion.18 When the reaction was
complete, hydrolysis with 1 M hydrochloric acid at the
same temperature gave the corresponding tetrazole 2a, to-
gether with triphenylmethane (Table 1, entry 1). The latter
was probably formed by protonation of the generated
trityllithium in the final hydrolysis step. The yield of the
isolated 5-phenyl-1H-tetrazole was 97%.
Detritylation of two other protected tetrazoles bearing ar-
omatic substituents (1b and 1l) under the optimized reac-
tion conditions gave the expected free tetrazoles 2b and 2l
in 99 and 75% yield, respectively (Table 1, entries 2 and
12). A tritylated tetrazole bearing a heteroaromatic 2-pyr-
idyl substituent was also deprotected with very good re-
sults (entry 6). The detritylation procedure was also
effectively applied to tetrazoles 1d, 1e, and 1i, which were
substituted on the carbon atom of the ring with aliphatic
chains, including a sterically hindered tert-butyl group
(entries 4, 5, and 9). The benzylic substituents of protected
tetrazoles 1c and 1k were unaffected by these reaction
conditions, leading to the expected deprotected tetrazoles
2c and 2k in 82 and 84% yield, respectively (entries 3 and
11).
The arene-catalyzed lithiation method for generating or-
ganolithium compounds has been a topic of our research
SYNTHESIS 2014, 46, 2065–2070
Advanced online publication: 30.04.2014
DOI: 10.1055/s-0033-1338623; Art ID: SS-2014-H0676-OP
© Georg Thieme Verlag Stuttgart · New York
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protonation with butyllithium effectively protects this
group against reductive cleavage of the Tr–N bond.
Table 1 Reductive Detritylation of Protected Tetrazoles 1 by a Naph-
thalene-Catalyzed Lithiation Processa
N
N
Interestingly, compound 1j, which contains a keto-
functionalized substituent, could be detritylated under our
mild reaction conditions without affecting the carbonyl
group, which might have been expected to be reduced by
the naphthalene radical-anion or dianion. As a result, 1-
(1H-tetrazol-5-yl)acetone (2j) was isolated in 80% yield
(Table 1, entry 10).19
R
i) Li, C10H8 (10 mol%), THF, –78 °C
N
N
N
N
N
R
ii) HCl (1 M), –78 to 20 °C
R = alkyl, aryl, benzyl
N
Ph
Ph
H
Ph
1
2
Entry
R
Time (h) Product
Yieldb (%)
In all cases, triphenylmethane, formed by protonation of
trityllithium in the final hydrolysis process, was easily
separated from the deprotected tetrazoles by column chro-
matography.
1
2
3
4
5
6
Ph
3.0
2a
2b
2c
2d
2e
2f
97
99
82
97
81
86
2-(4-MeC6H4)C6H4 4.0
Bn
3.0
4.0
3.0
4.0
The starting tritylated tetrazoles 1 were prepared by treat-
ment of the corresponding tetrazoles with trityl chloride in
the presence of triethylamine and a catalytic amount of 4-
(dimethylamino)pyridine.
t-Bu
(CH2)10Me
2-pyridyl
In summary, we have developed an efficient method for
detritylation of protected tetrazoles by a naphthalene-
catalyzed lithiation process. The method proved to be use-
ful for the removal of trityl groups from N-trityltetrazoles
containing aromatic, heteroaromatic, benzylic groups or
optionally functionalized aliphatic groups. N-Trityltetra-
zoles containing a secondary C-tritylamino group can be
selectively detritylated. This method represents a good al-
ternative to the commonly used detritylation procedures,
which require acidic conditions.
N
N
H2N
7c
TrNH
TrNH
4.0
2.5
93
94
N
HN
2g
Tr
N
N
HN
8d
N
HN
2h
2i
9
10
11
12
Me
2.5
4.0
2.0
6.5
93
80
84
75
CH2COt-Bu
CHPh2
2j
2k
2l
FT-IR spectra were recorded on a Nicolet Impact 400D spectropho-
tometer using KBr pellets. NMR spectra were recorded on a Bruker
AC-300 spectrometer (300 MHz for 1H and 75 MHz for 13C) using
CDCl3, DMSO-d6, or CD3OD as solvent and TMS (δ = 0.00 ppm,
9-anthryl
1
1H) or CDCl3 (δ = 77.0 ppm, 13C), DMSO-d6 (δ = 2.50 ppm, H;
a All reactions were performed at –78 °C.
1
δ = 39.75 ppm, 13C), or CD3OD (δ = 4.87 ppm, H; δ = 49.0 ppm,
b Yield of isolated product after purification by column chromatogra-
phy (basic Al2O3, hexane–EtOAc), based on starting material 1.
c Compound 1g was deprotonated with BuLi and treated with TMSCl
before performing the naphthalene-catalyzed lithiation step.
d Compound 1g was deprotonated with BuLi before performing the
naphthalene-catalyzed lithiation step.
13C) as internal standards; chemical shifts are given in δ (ppm) and
coupling constants (J) in Hz. Elemental analyses were performed by
the Technical Services of the University of Alicante. Column chro-
matography was performed on silica gel 60 (35–70 mesh) or basic
aluminum oxide (50–160 μm particle size). Deactivated silica gel
was treated with 5% Et3N in hexane, and the column was eluted
with the same solvent mixture until the eluent was basic, as shown
by pH paper. Naphthalene, TMSCl, and all the reagents used in the
syntheses of the N-trityltetrazoles 1 were commercially available
(Acros or Aldrich) and were used without further purification. Li
powder was prepared according to a previously described proce-
dure.20 Commercially available BuLi was titrated with a 1 M solu-
tion of s-BuOH in xylene, with 1,10-phenanthroline as indicator.21
Commercially available anhyd THF (99.9%, H2O content
≤ 0.006%; Acros) was used as the solvent for all the lithiation reac-
tions.
Our method could also be applied to the chemoselective
deprotection of a trityl tetrazole in the presence of a trityl
amine group. The starting material 1g has an NH proton
that is acidic enough to decompose the naphthalene radi-
cal-anion and dianion that act as lithiation agents in this
process. To prevent this decomposition, substrate 1g was
deprotonated with butyllithium and treated with chlo-
ro(trimethyl)silane before performing the naphthalene-
catalyzed lithiation step. This operation led to double de-
tritylation of the starting material to give 1H-tetrazol-5-
amine (2g) in 93% yield (Table 1, entry 7). However,
when deprotonated 1g was directly submitted to the lithi-
ation step without previous treatment with chloro(trimeth-
Tetrazoles 2a–l; General Procedure22
The mixture of the appropriate nitrile (50 mmol), NaN3 (65 mmol),
and Et3N·HCl (150 mmol) in toluene (100 mL) was stirred at 110 °C
for 17–30 h (2b, 2f, 2k, and 2l for 24 h; 2c and 2d for 17 h; 2e and
2j for 30 h). The mixture was cooled to r.t. and extracted with H2O
(100 mL). The aqueous layer was acidified with 36% aq HCl and
filtered. The resultant solid was washed with H2O and dried under
yl)silane, the trityl group on the tetrazole ring was reduced pressure.
selectively removed (entry 8). Therefore, the negative
5-Phenyl-1H-tetrazole (2a)23
White solid; yield: 1.39 g (95%); mp 215–216 °C.
charge that appears on the tritylamino substituent after de-
Synthesis 2014, 46, 2065–2070
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Detritylation of Protected Tetrazoles
2067
1H NMR (300 MHz, DMSO-d6): δ = 7.55–7.62 (m, 3 H), 8.01–8.10
(m, 2 H).
5-Methyl-1H-tetrazole (2i)25
White solid; yield: 0.78 g (93%); mp 138–140 °C.
IR (KBr): 3005, 2879, 2605, 1578, 1565, 1112, 1052, 899, 683 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 2.46 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 124.1 (2 × CH), 127.0 (C),
129.4 (CH), 131.3 (2 × CH), 155.3 (C).
13C NMR (75 MHz, DMSO-d6): δ = 8.4 (CH3), 152.2 (C).
5-(4′-Methylbiphenyl-2-yl)-1H-tetrazole (2b)24
Brown solid; yield: 1.84 g (78%); mp 149–151 °C.
3,3-Dimethyl-1-(1H-tetrazol-5-yl)butan-2-one (2j)29
Orange solid; yield: 1.43 g (85%); mp 152–154 °C.
IR (KBr): 2973, 2322, 1716, 1365, 1048, 1007, 728 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.18 (s, 9 H), 4.41 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 25.8 (3 × CH3), 32.2 (CH2),
44.0 (C–C=O), 128.2 (C), 209.3 (C=O).
IR (KBr): 3336, 2974, 2900, 1080, 1046, 879, 755 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 2.28 (s, 3 H), 6.98 (d, J = 8.1
Hz, 2 H), 7.12 (d, J = 7.9 Hz, 2 H), 7.55 (ddd, J = 10.3, 5.8, 1.9 Hz,
2 H), 7.63–7.69 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 20.7 (CH3), 123.4 (CH), 127.6
(CH), 128.7 (2 × CH), 128.9 (CH), 130.5 (2 × CH), 130.6 (CH),
131.1 (C), 136.3 (C), 136.8 (C), 141.5 (C), 155.1 (C).
5-(Diphenylmethyl)-1H-tetrazole (2k)30
White solid; yield: 1.70 g (72%); mp 165–166 °C.
IR (KBr): 3264, 2917, 1560, 1446, 743, 695, 632 cm–1.
5-Benzyl-1H-tetrazole (2c)25
White solid; yield: 1.01 g (63%); mp 123–124 °C.
1H NMR (300 MHz, DMSO-d6): δ = 4.28 (s, 2 H), 7.24–7.35 (m, 5
H).
1H NMR (300 MHz, CD3OD): δ = 5.85 (s, 1 H), 7.14–7.30 (m, 10
H).
13C NMR (75 MHz, DMSO-d6): δ = 29.0 (CH2), 127.1 (CH), 128.7
(2 × CH), 128.8 (2 × CH), 136.0 (C), 155.3 (C).
13C NMR (75 MHz, CD3OD): δ = 40.8 (CH), 128.6 (2 × CH), 129.6
(4 × CH), 129.9 (4 × CH), 140.8 (C), 160.0 (2 × C).
5-tert-Butyl-1H-tetrazole (2d)24
White solid; yield: 1.14 g (90%); mp 208–210 °C.
5-(9-Anthryl)-1H-tetrazole (2l)25
Green solid; yield: 1.85 g (75%); mp 215–216 °C.
IR (KBr): 2987, 2900, 1578, 1053, 735 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.45 (d, J = 8.6 Hz, 2 H), 7.56–
IR (KBr): 2986, 2977, 2869, 1717, 1558, 1366, 1066, 1045, 1008
cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.35 (s, 9 H).
7.63 (m, 4 H), 8.23–8.31 (m, 2 H), 8.94 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 28.9 (3 × CH3), 30.3 (C), 163.4
(C).
13C NMR (75 MHz, DMSO-d6): δ = 120.6 (2 × CH), 124.8
(2 × CH), 126.4 (2 × C), 128.2 (CH), 129.2 (C), 130.8 (2 × CH),
131.0 (2 × CH), 138.3 (2 × C), 150.1 (C).
5-Undecyl-1H-tetrazole (2e)26
Brown solid; yield: 1.28 g (57%); mp 72–73 °C.
IR (KBr): 3225, 2914, 2848, 1545, 1471, 1074, 716 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 0.84 (t, J = 6.8 Hz, 3 H), 1.24
(m, 16 H), 1.65–1.68 (m, 2 H), 2.84 (t, J = 7.6 Hz, 2 H).
1-Trityl-1H-tetrazoles 1a–1l; General Procedure
A solution of the appropriate tetrazole 1 (10.0 mmol) in CH2Cl2 (5
mL) was added to a solution of TrCl (3.1 g, 11.0 mmol), Et3N (2.5
mL, 17.6 mmol), and DMAP (92 mg, 0.4 mmol) in CH2Cl2 (10 mL)
at r.t., and the mixture was stirred overnight. The reaction was then
quenched with H2O (5 mL) and the mixture was extracted with
EtOAc (3 × 15 mL). The organic phases were combined, washed
with brine (5 mL), dried (Na2SO4), and concentrated at 15 Torr. The
residue was purified by column chromatography (deactivated silica
gel, hexane–EtOAc) to give the expected tetrazoles 1a–f and 1i–l.
13C NMR (75 MHz, DMSO-d6): δ = 13.9 (CH3), 22.2, 22.7, 27.0,
28.3, 28.6, 28.7, 28.9, 29.0 (2 C), 31.3 (10 × CH2), 155.9 (C).
2-(1H-Tetrazol-5-yl)pyridine (2f)24
Brown solid; yield: 1.25 g (85%); mp 208–210 °C.
1H NMR (300 MHz, DMSO-d6): δ = 7.63 (ddd, J = 7.6, 4.8, 1.2 Hz,
1 H), 8.08 (td, J = 7.8, 1.7 Hz, 1 H), 8.22 (dt, J = 7.9, 1.0 Hz, 1 H),
8.79 (ddd, J = 4.8, 1.7, 0.9 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 122.6 (CH), 126.2 (CH), 138.3
(CH), 143.7 (C), 150.1 (C), 154.8 (CH).
For the preparation of the ditritylated compound 1g, the amounts of
the reagents and solvents used were double those indicated above.
5-Phenyl-1-trityl-1H-tetrazole (1a)23
White solid; yield: 3.69 g (95%); mp 156–158 °C.
IR (KBr): 1491, 1447, 1189, 1026, 876, 762, 747, 729, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.13–7.47 (m, 18 H), 8.12–8.16
1H-Tetrazol-5-amine (2g)27
White solid; yield: 0.79 g (93%); mp 212–214 °C.
IR (KBr): 3399, 3192, 1636, 1263, 1044 cm–1.
1H NMR (300 MHz, CD3OD): δ = 6.56 (s, 2 H).
13C NMR (75 MHz, CD3OD): δ = 158.2 (C).
(m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 83.3 (C), 127.2 (2 × CH), 127.7
(3 × CH), 127.9 (6 × CH), 128.9 (C), 130.5 (6 × CH), 141.5 (CH),
145.3 (2 × CH), 150.8 (3 × C), 164.2 (C).
5-(4′-Methylbiphenyl-2-yl)-1-trityl-1H-tetrazole (1b)31
N-Trityl-1H-tetrazol-5-amine (2h)28
White solid; yield: 3.21 g (67%); mp 180–184 °C.
Yellow solid; yield: 2.95 g (90%); mp 148–150 °C.
IR (KBr): 3056, 1445, 1028, 827, 748, 698, 640 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.19 (s, 3 H), 6.82–6.95 (m, 9 H),
IR (KBr): 3266, 1560, 1445, 757, 695, 633 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.14–7.32 (m, 15 H).
13C NMR (75 MHz, CDCl3): δ = 82.2 (C), 126.9, 127.4, 127.8,
127.9, 128.0, 128.2, 128.4 (6 C), 128.8, 130.0, 130.3 (15 × CH),
141.5 (3 × CH), 162.1 (C).
7.17–7.40 (m, 13 H), 7.81–7.84 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 83.0 (C), 126.6, 127.4,
127.7, 128.1, 128.2, 128.3 (4 C), 129.2, 129.3 (6 C), 129.4, 130.4,
130.5, 130.8, 136.5 (23 × CH), 138.3 (C), 141.4 (C), 142.4 (C),
147.0 (C), 154.1 (3 × C), 164.3 (C).
Anal. Calcd for C20H17N5: C, 73.88; H, 5.61; N, 21.51. Found: C,
73.92; H, 5.21; N, 22.60.
5-Benzyl-1-trityl-1H-tetrazole (1c)32
White solid; yield: 3.54 g (88%); mp 160–164 °C.
© Georg Thieme Verlag Stuttgart · New York
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IR (KBr): 1530, 1252, 1073, 889, 733, 694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.28 (s, 2 H), 7.08–7.12 (m, 6 H),
Anal. Calcd for C21H18N4: C, 77.28; H, 5.56; N, 17.17. Found: C,
77.41; H, 5.57; N, 17.41.
7.23–7.37 (m, 14 H).
3,3-Dimethyl-1-(1-trityl-1H-tetrazol-5-yl)butan-2-one (1j)28
13C NMR (75 MHz, CDCl3): δ = 32.0 (CH2), 83.0 (C), 126.8 (CH),
127.8 (3 × CH), 128.1 (6 × CH), 128.8 (2 × CH), 129.1 (2 × CH),
130.0 (6 × CH), 137.0 (C), 141.5 (3 × C), 164.6 (C).
Pink solid; yield: 2.55 g (62%); mp 190–194 °C.
IR (KBr): 1714, 1445, 1057, 882, 752, 697 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.22 (s, 9 H), 4.17 (s, 2 H), 7.10–
5-tert-Butyl-1-trityl-1H-tetrazole (1d)28
White solid; yield: 2.54 g (69%); mp 132–136 °C.
7.35 (m, 15 H).
13C NMR (75 MHz, CDCl3): δ = 25.8 (3 × CH3), 32.2 (CH2), 44.0
(C–C=O), 82.8 (C), 127.4 (3 × CH), 127.8 (6 × CH), 130.3
(6 × CH), 141.5 (3 × C), 162.1 (C), 209.3 (C=O).
IR (KBr): 3005, 2605, 1578, 1565, 1386, 1255, 1112, 1052, 899,
683, 632 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 9 H), 7.01–7.26 (m, 15 H).
Anal. Calcd for C26H26N4O: C, 76.07; H, 6.38; N, 13.65. Found: C,
76.09; H, 6.37; N, 13.68.
13C NMR (75 MHz, CDCl3): δ = 30.0 (3 × CH3), 41.7 (C), 82.8 (C),
127.4 (3 × CH), 127.8 (6 × CH), 130.3 (6 × CH), 141.5 (3 × C),
162.1 (C).
5-(Diphenylmethyl)-1-trityl-1H-tetrazole (1k)28
Yellow solid; yield: 2.92 g (61%); mp 164–166 °C.
IR (KBr): 1492, 1445, 1048, 748, 697, 639 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.88 (s, 1 H), 7.13–7.38 (m, 25 H).
13C NMR (75 MHz, CDCl3): δ = 50.9 (CH), 82.1 (C), 125.9, 126.4,
126.8, 127.4 (2 C), 127.6 (4 C), 127.8 (3 C), 127.9, 128.1, 128.4 (6
C), 129.0, 129.6, 130.1, 141.5, 144.0 (25 × CH), 144.8 (C), 147.0
(2 × C), 165.1 (3 × C).
Anal. Calcd for C24H24N4: C, 78.23; H, 6.57; N, 15.21. Found: C,
78.26; H, 6.55; N, 15.23.
1-Trityl-5-undecyl-1H-tetrazole (1e)28
Brown solid; yield: 3.87 g (83%); mp 76–80 °C.
IR (KBr): 2922, 2850, 1493, 1444, 747, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.8 Hz, 3 H), 1.27 (m,
16 H), 1.72–1.79 (m, 2 H), 2.90 (t, J = 7.6 Hz, 2 H), 7.07–7.36 (m,
15 H).
Anal. Calcd for C33H26N4: C, 82.82; H, 5.48; N, 11.71. Found: C,
82.80; H, 5.46; N, 11.69.
13C NMR (75 MHz, CDCl3): δ = 14.3 (CH3), 22.8, 29.2, 29.4, 29.7,
29.8, 32.2, 39.7 (C), 82.7 (C), 127.9 (5 × CH), 128.2, 128.4, 128.7,
129.9, 130.3 (6 × CH), 141.6 (3 × C), 166.2 (C).
5-(9-Anthryl)-1-trityl-1H-tetrazole (1l)28
Green solid; yield: 3.47 g (71%); mp 170–172 °C.
IR (KBr): 1491, 1447, 1189, 876, 762, 747, 694 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.23–7.45 (m, 21 H), 7.70–7.73
(m, 1 H), 8.03 (dd, J = 4.8, 4.2 Hz, 1 H), 8.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 83.7 (C), 125.6 (2 × CH), 126.8
(2 × C), 127.4 (2 × C), 128.0 (3 × CH), 128.1 (CH), 128.2
(6 × CH), 128.6 (2 × CH), 128.7 (2 × CH), 130.4 (6 × CH), 131.3
(C), 141.6 (2 × C), 147.0 (3 × C), 162.6 (C).
Anal. Calcd for C31H38N4: C, 79.79; H, 8.21; N, 12.01. Found: C,
79.76; H, 8.22; N, 12.03.
2-(1-Trityl-1H-tetrazol-5-yl)pyridine (1f)28
Pink solid; yield: 3.31 g (85%); mp 126–128 °C.
IR (KBr): 1489, 1446, 1072, 747, 698 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 6.79–6.94 (m, 15 H), 7.17–
7.21 (m, 1 H), 7.64 (td, J = 7.8, 1.6 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1
H), 8.36 (d, J = 4.4 Hz, 1 H).
Anal. Calcd for C34H24N4: C, 83.58; H, 4.95; N, 11.47. Found: C,
83.55; H, 4.91; N, 11.50.
13C NMR (75 MHz, DMSO-d6): δ = 51.6 (C), 86.4 (CH), 122.6
(CH), 126.1 (CH), 127.0 (3 × CH), 127.9 (6 × CH), 128.2 (6 × CH),
137.0 (3 × C), 138.2 (C), 143.6 (C), 150.1 (CH).
Reductive Cleavage of 1-Trityl-1H-tetrazoles 1a–1f and 1i–1l by
Naphthalene-Catalyzed Lithiation; General Procedure
A solution of N-trityltetrazole 1 (1.0 mmol) in THF (2 mL) was add-
ed dropwise to a green suspension of Li powder (70 mg, 10.0 mmol)
and naphthalene (26 mg, 0.2 mmol) in THF (5 mL) under argon at
–78 °C. The mixture, which turned dark red after the addition of a
few drops of the solution of tetrazole 1, was stirred at –78 °C for the
time indicated in Table 1. 1 M aq HCl (5 mL) was carefully added,
the cooling bath was removed, and the mixture was stirred until it
reached r.t. The mixture was then extracted with EtOAc (3 × 15 mL)
and the organic phases were combined, washed with brine (5 mL),
dried (Na2SO4), and concentrated at 15 Torr. The residue was puri-
fied by column chromatography (basic Al2O3, hexane–EtOAc), af-
fording the corresponding free tetrazoles 2 in the following yields:
2a (142 mg, 97%), 2b (234 mg, 99%), 2c (131 mg, 82%), 2d (122
mg, 97%), 2e (182 mg, 81%), 2f (127 mg, 86%), 2i (78 mg, 93%),
2j (135 mg, 80%), 2k (198 mg, 84%) and 2l (185 mg, 75%).
Anal. Calcd for C25H19N5: C, 77.10; H, 4.92; N, 17.98. Found: C,
77.08; H, 4.88; N, 18.00.
N,1-Ditrityl-1H-tetrazol-5-amine (1g)28
White solid; yield: 1.42 g (25%); mp 220–222 °C.
IR (KBr): 1560, 1493, 1446, 1184, 881, 743, 696, 632 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.82 (s, 1 H), 6.84–7.40 (m, 30 H).
13C NMR (75 MHz, CDCl3): δ = 71.7 (C), 82.1 (C), 125.9, 126.4,
126.8, 127.6, 127.8, 127.9, 128.0 (5 C), 128.4 (6 C), 129.0 (5 C),
129.6 (6 C), 130.1, 141.5 (30 × CH), 144.8 (3 × C), 147.8 (3 × C),
165.1 (C).
Anal. Calcd for C39H31N5: C, 82.22; H, 5.48; N, 12.29. Found: C,
82.22; H, 5.46; N, 12.24.
Compounds 2a, 2g, and 2i were commercially available, and com-
pounds 2b–f, 2h, and 2j–l were prepared by us (see above). All the
compounds were characterized by comparison of their physical and
spectroscopic properties with those of authentic samples.
5-Methyl-1-trityl-1H-tetrazole (1i)28
White solid; yield: 2.25 g (69%); mp 172–174 °C.
IR (KBr): 1507, 1492, 883, 748, 696, 635 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.56 (s, 3 H), 7.09–7.12 (m, 6 H),
7.21–7.38 (m, 9 H).
Reductive Cleavage of N,1-Ditrityl-1H-tetrazol-5-amine (1g) by
Naphthalene-Catalyzed Lithiation
A 1.6 M solution of BuLi in hexane (0.45 mL, 0.7 mmol) was added
dropwise to a solution of tetrazole 1g (186 mg, 0.5 mmol) in THF
(2 mL) at 0 °C under argon until a red color developed. The mixture
was stirred for 10 min then TMSCl was added until the red color
vanished (0.15 mL, 1.2 mmol). The mixture was stirred for 10 min
13C NMR (75 MHz, CDCl3): δ = 11.4 (CH3), 82.8 (C), 126.9
(3 × CH), 128.1 (6 × CH), 130.3 (6 × CH), 141.5 (3 × C), 162.1
(C).
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PAPER
Detritylation of Protected Tetrazoles
2069
and then transferred dropwise by syringe to a green suspension of
Li powder (50 mg, 7.2 mmol) and naphthalene (26 mg, 0.2 mmol)
in THF (5 mL) under argon at –78 °C. The mixture turned dark red
and was stirred at –78 °C for the time indicated in Table 1. 1 M aq
HCl (5 mL) was carefully added, the cooling bath was removed, and
the mixture was stirred until it reached r.t. The mixture was then
acidified with 2 M aq HCl (5 mL) and extracted with EtOAc (3 × 15
mL). The organic phases were discarded and the aqueous phase was
basified with 2 M NaOH (5 mL) and extracted with CH2Cl2 (3 × 15
mL). The organic phases were combined, dried (Na2SO4), and con-
centrated to give the pure tetrazole 2g [yield: 79 mg (93%)], which
was characterized by comparison of its physical and spectroscopic
properties with those of an authentic sample.
(5) For example, see: Sharma, S. K.; Songster, M. F.; Colpitts,
T. L.; Hegyes, P.; Barany, G.; Castellino, F. J. J. Org. Chem.
1993, 58, 4993.
(6) Maltese, M. J. Org. Chem. 2001, 66, 7615.
(7) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org.
Chem. 2001, 66, 7542.
(8) Rele, S.; Nayak, S. K. Synth. Commun. 2002, 32, 3533.
(9) Chandrasekhar, S.; Nagendra Babu, B.; Reddy, C. R.
Tetrahedron Lett. 2003, 44, 2057.
(10) For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155.
(b) Ramón, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225.
(c) Yus, M. Synlett 2001, 1197. (d) Yus, M.; Ramón, D. J.
Latv. Kim. Z. 2002, 79. (e) Ramón, D. J.; Yus, M. Rev.
Cubana Quim. 2002, 14, 76. (f) Yus, M. In The Chemistry of
Organolithium Compounds; Vol. 2; Rappoport, Z.; Mareck,
I., Eds.; Wiley: Chichester, 2004, Chap. 11. For mechanistic
studies, see: (g) Yus, M.; Herrera, R. P.; Guijarro, A.
Tetrahedron Lett. 2001, 42, 3455. (h) Yus, M.; Herrera, R.
P.; Guijarro, A. Chem. Eur. J. 2002, 8, 2574. (i) Herrera, R.
P.; Guijarro, A.; Yus, M. Tetrahedron Lett. 2003, 44, 1309.
(11) For a polymer-supported version of this reaction, see:
(a) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39,
1397. (b) Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999,
55, 7017. (c) Yus, M.; Gómez, C.; Candela, P. Tetrahedron
2002, 58, 6207.
(12) For reviews, see: (a) Guijarro, D.; Pastor, I. M.; Yus, M.
Curr. Org. Chem. 2011, 15, 375. (b) Guijarro, D.; Pastor, I.
M.; Yus, M. Curr. Org. Chem. 2011, 15, 2362.
(13) For reviews, see: (a) Yus, M.; Foubelo, F. Rev. Heteroat.
Chem. 1997, 17, 73. (b) Yus, M.; Foubelo, F. Targets
Heterocycl. Syst. 2002, 6, 136. (c) Yus, M. Pure Appl. Chem.
2003, 75, 1453.
Monodetritylation of N,1-Ditrityl-1H-tetrazol-5-amine (1g) by
Naphthalene-Catalyzed Lithiation
A 1.6 M solution of BuLi in hexane (0.45 mL, 0.7 mmol) was added
dropwise to a solution of tetrazole 1g (186 mg, 0.5 mmol) in THF
(2 mL) under argon at 0 °C until a red color developed. The mixture
was stirred for 10 min and then transferred dropwise by syringe to
a green suspension of Li powder (50 mg, 7.2 mmol) and naphtha-
lene (26 mg, 0.2 mmol) in THF (5 mL) under argon at –78 °C. The
mixture turned dark red and was stirred at –78 °C for 2.5 h. 1 M aq
HCl (5 mL) was then carefully added, the cooling bath was re-
moved, and the reaction was stirred until it reached r.t. The mixture
was acidified with 2 M aq HCl (5 mL) and extracted with EtOAc
(3 × 15 mL). The organic phases were discarded and the aqueous
phase was basified with 2 M NaOH (5 mL) and extracted with
CH2Cl2 (3 × 15 mL). The organic phases were combined, dried
(Na2SO4), and concentrated to give the pure tetrazole 2h [yield: 308
mg (94%)], which was characterized by comparison of its physical
and spectroscopic properties with those of an authentic sample.
(14) For reviews, see: (a) Nájera, C.; Yus, M. Trends Org. Chem.
1991, 2, 155. (b) Nájera, C.; Yus, M. Recent Res. Dev. Org.
Chem. 1997, 1, 67. (c) Nájera, C.; Yus, M. Curr. Org. Chem.
2003, 7, 867. (d) Nájera, C.; Sansano, J. M.; Yus, M.
Tetrahedron 2003, 59, 9255. (e) Chinchilla, R.; Nájera, C.;
Yus, M. Chem. Rev. 2004, 104, 2667.
(15) (a) Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1994, 59,
3210. (b) Almena, J.; Foubelo, F.; Yus, M. Tetrahedron
1994, 50, 5775. (c) Almena, J.; Foubelo, F.; Yus, M.
Tetrahedron 1996, 52, 8545. (d) Alonso, E.; Guijarro, D.;
Martínez, P.; Ramón, D. J.; Yus, M. Tetrahedron 1999, 55,
11027. (e) Guijarro, D.; Martínez, P. J.; Nájera, C.; Yus, M.
ARKIVOC 2004, (iv), 5.
Acknowledgment
This work was financially supported by the Agence Nationale pour
le Développement de la Recherche en Santé (ANDRS; Algeria) and
by the Department of Organic Chemistry of the University of
Alicante (Spain). We are very grateful to the Spanish Ministerio de
Asuntos Exteriores y de Cooperación for a cooperation grant
(AP/039112/11). We are also very grateful to Dr. Rosa Ortiz for her
valuable help.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
(16) Yus, M.; Behloul, C.; Guijarro, D. Synthesis 2004, 1274.
(17) The formation of orange-red solutions of the trityl radical in
THF has been described in the literature. For an example,
see: Ashby, E. C.; Goel, A. B.; DePriest, R. N. J. Org. Chem.
1981, 46, 2429.
(18) Chadwick, D. J.; Hodgson, S. T. J. Chem. Soc., Perkin
Trans. 1 1983, 93.
(19) With the aim of trying to broaden the substrate scope, we
tried to prepare some other tetrazoles functionalized with
either ester or amide groups but, unfortunately, all our
attempts were unsuccessful.
(20) Yus, M.; Martínez, P.; Guijarro, D. Tetrahedron 2001, 57,
10119.
(21) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
165.
(22) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998,
910.
(23) Zhang, C. X.; Zheng, G. J.; Bi, F. Q.; Li, Y. L. Chin. Chem.
Lett. 2008, 19, 759.
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