Direct C-H arylation and alkenylation of 1-substituted tetrazoles: Phosphine as stabilizing factor

Article abstract of DOI:10.1021/jo902180u

(Chemical Equation Presented) Direct arylation and alkenylation of 1-substituted tetrazoles was achieved via Pd catalysis in the presence of CuI and Cs₂CO₃. Unlike the related reactions of imidazoles and purines, phosphine ligand was

Full text of DOI:10.1021/jo902180u

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energetic salts6 and other useful compounds including nat-
Direct C-H Arylation and Alkenylation
of 1-Substituted Tetrazoles: Phosphine
As Stabilizing Factor
ural products.7 Their preparation from 5-substituted tetra-
zoles is accompanied by the formation of regioisomers which
are often difficult to separate, while syntheses starting with
acyclic precursors and using classical reagents suffer from
long reaction times, high temperatures, low yields, difficult
workup, and use of toxic and/or explosive reagents.8,9 As
regards metal-catalyzed reactions, Buchwald reported two
examples of a successful Negishi10 and Suzuki11 coupling of
1-phenyl-5-chlorotetrazole, while the only systematic study12
published thus far involved the Suzuki reaction of 1-benzyl-
5-bromotetrazole with various boronic acid reagents. An
unsuccessful attempt13 to effect a Stille coupling between
1-phenyl-5-iodotetrazole and 5-ethyl-3-tributylstannyl-2,5-
dihydrofuran-2-one14 was also recently reported by us.
Thus, we became interested in exploring a more attractive
possibility of a direct activation of the C5-H bond, since
these reactions constitute an attractive alternative to tradi-
tional cross-couplings. Even though direct activation reac-
tions15 have been described for a variety of heteroarenes,16
including the closely related triazoles,17 there are, to the best
of our knowledge, no reported examples of direct C-H
arylation/alkenylation of tetrazoles. Since 1-substituted tet-
razoles can be prepared in a one-pot process from primary
amines, orthocarboxylic acid ester, and sodium azide,18
subsequent C-H bond activation would enable a rapid entry
into a range of 1,5-disubstituted tetrazoles from primary
ꢀ
Marcel Spulak, Richard Lubojacky, Petr Senel, Jirı Kunes,
ꢀ
ꢁ
ꢁ
and Milan Pour*
ꢀ
ꢀ
Centre for New Antivirals and Antineoplastics, Department of
Inorganic and Organic Chemistry, Charles University in
ꢁ
ꢁ
Prague, Faculty of Pharmacy in Hradec Kralove,
ꢁ ꢁ ꢁ
Heyrovskeho 1203, CZ-500 03 Hradec Kralove, Czech
Republic
pour@faf.cuni.cz
Received October 15, 2009
Direct arylation and alkenylation of 1-substituted tetra-
zoles was achieved via Pd catalysis in the presence of CuI
and Cs2CO3. Unlike the related reactions of imidazoles
and purines, phosphine ligand was necessary to prevent
the intermediate tetrazolyl-PdII species from fragmenta-
tion into the corresponding cyanamide. Various 1,5-dis-
ubstituted tetrazoles were prepared with good to excellent
isolated yields.
(7) (a) Frija, L. M. T.; Khmelinskii, I. V.; Cristiano, M. L. S. Tetrahedron
Lett. 2005, 46, 6757. (b) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc.
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Lett. 2000, 41, 275. (d) Quintin, J.; Lewin, G. J. Nat. Prod. 2004, 67, 1624.
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New heteroaryl compounds continuously emerge as lead
structures for novel pharmaceuticals. Among them, 1,5-dis-
ubstituted tetrazoles occupy an important place because of
being able to act as NAD(P)H oxidase inhibitors,1 glucoki-
nase activators,2 hepatitis C virus (HCV) serine protease
S3 inhibitors,3 calcitonine gene-related peptide receptor
antagonists, and antimigraine agents.4 In addition, they
also serve as synthetic intermediates5 for the synthesis of
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J. E. Nature 2002, 417, 507. (b) Godula, K.; Sames, D. Science 2006, 312, 67.
(16) For general conditions of C-H arylation of heteroarenes, see:
(1) Seki, M.; Tarao, Y.; Yamada, K.; Nakao, A.; Usui, Y.; Komatsu, Y.
PCT Int. Appl. WO 2005-JP2974, 2005; Chem. Abstr. 2005, 143, 266938.
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Appl. WO 2004-JP19843, 2005; Chem. Abstr. 2005, 143, 153371.
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1430. (b) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan, V. Org.
Lett. 2007, 9, 2336. (c) Ackermann, L.; Vicente, R.; Born, R. Adv. Synth.
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(5) Brigas, A. F. In Science of Synthesis; Storr, R. C., Gilchrist, T. L.,
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DOI: 10.1021/jo902180u
r
Published on Web 12/08/2009
J. Org. Chem. 2010, 75, 241–244 241
2009 American Chemical Society

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Spulak et al.
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JOCNote
SCHEME 1. Proposed Sequence to 1,5-Disubstituted Tetra-
zoles
only traces again (entry 9). A possible explanation of the
influence of the phosphine ligand is based on the relative
stability of the putative intermediate PdII species (Scheme 3).
SCHEME 3. Reductive Elimination Vs. Decomposition of the
PdII Species
amines (Scheme 1). In fact, the preparation outlined in
Scheme 1 would be more straightforward than the Suzuki
or Negishi coupling of 1-substituted 5-halotetrazoles, since
the necessity to prepare the halotetrazoles would add extra
step(s) to the sequence, which would be less economic and
would mean lower overall yields.
Similar to C2 in imidazoles and C8 in purines, tetrazole C5
is surrounded by two nitrogens. Hence, we assumed we could
use the conditions19 described for imidazoles20 or purines21
as the starting point. Our initial attempts were therefore
based on an attractive phosphine-free protocol developed by
Hocek et al.21 for the intermolecular arylation of C8 in
purines (Scheme 2). Using 1-phenyltetrazole as a model
As indicated by the isolation of phenylcyanamide as the
only product under phosphine-free21 conditions, collapse of
the PdII intermediate into phenylcyanamide via ring frag-
mentation with concomitant release of nitrogen is the major
reaction pathway in the absence of phosphine. On the other
hand, the addition of a phosphine ligand gives rise to a more
stable species22 that has enough time to undergo reductive
elimination.
SCHEME 2. Model Reaction of Tetrazole 1 with Iodotoluene
With the optimized conditions in hand, the introduction of
a variety of aryl and alkenyl groups into tetrazoles bearing
both aromatic and aliphatic R1 substituents was carried
out with very good to excellent isolated yields (Scheme 4,
SCHEME 4. Preparation of the Title Tetrazoles
compound, 4-iodotoluene as an electrophile, and the same
conditions as Hocek et al. (entry 1, Table 1), however, gave
just a trace amount of the desired 1-phenyl-5-p-tolyltetrazole
1a, while phenylcyanamide arising from the fragmentation
of the tetrazole ring was the only isolated product in 20%
yield. Interestingly, the addition of a 10% molar amount of
Ph3P raised the isolated yield of 1a to 59% (entry 2), with nearly
the same yield (60%) having been obtained when Ph3P was
replaced with P(2-furyl)3 (entry 3). Since these reactions re-
quired roughly 4 h for completion, the subsequent experiments
were also allowed to run for 4 h. Further experiments showed
that decreasing the amount of both CuI and the base down to 1
and 1.1 mol equiv, respectively, increased the yield to 69%
(entry 4) and DMF could be replaced with the more user-
friendly MeCN (entry 5). When Ph3P was used under the same
conditions (entry 6), the reaction rate slowed down.
Table 2). The possibility of introduction of a highly functio-
nalized alkene moiety (1f, 2f, and 3f) is particularly notable.
On the other hand, somewhat lower yields obtained for 3b
and 3e may indicate a lower stability of the corresponding
PdII intermediates (see Scheme 3), which could be resolved
by the use of a different phosphine. Studies in this direction
are in progress, and will be reported in due course.
In conclusion, we have explored the conditions for the
direct C-H arylation/alkenylation of 1-substituted tetra-
zoles, and developed a high-yielding and reliable protocol
to achieve this transformation. Unlike the related reactions
of purines and imidazoles, the process requires the presence
Further variation of the ligand had negative influence
(entries 7 and 8). The reaction in the absence of CuI furnished
(19) These conditions were first used by Miura et al., see: Pivsa-Art, S.;
Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn.
1998, 71, 467.
(22) Stable tetrazolyl-PdII or PtII complexes with Me3P as ligand have
been reported, see: (a) Kim, Y.-J.; Kim, D.-H.; Lee, J.-Y.; Lee, S.-W.
J. Organomet. Chem. 1997, 538, 189. (b) Kim, Y.-J.; Kwak, Y.-S.; Lee, S.-W.
J. Organomet. Chem. 2000, 603, 152. (c) Kim, Y.-J.; Lee, S.-H.; Jeon, S.-I.;
Lim, M.-S.; Lee, S.-W. Inorg. Chem. Acta 2005, 538, 650. (d) Kim, Y.-J.;
Kwak, Y.-S.; Joo, Y.-S.; Lee, S.-W. J. Chem. Soc., Dalton Trans. 2002, 144.
(e) Kim, Y.-J.; Joo, Y.-S.; Han, J.-T.; Han, W.-S.; Lee, S.-W. J. Chem. Soc.,
Dalton Trans. 2002, 3611.
(20) (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S.
J. Org. Chem. 2005, 70, 3997. (b) Bellina, F.; Cauteruccio, S.; Mannina, L.;
Rossi, R.; Viel, S. Eur. J. Org. Chem. 2006, 693. (c) Bellina, F.; Cauteruccio,
S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379.
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(21) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8,
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5389.
242 J. Org. Chem. Vol. 75, No. 1, 2010

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TABLE 1. Development of Reaction Conditions
entry
Cs2CO3 (equiv)
CuI (equiv)
Pd(OAc)2 (equiv)
phosphine (0.1 equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
3
3
3
1.1
1.1
1.1
1.1
1.1
1.1
2.5
2.5
2.5
1
1
1
1
1
0
0.05
0.05
0.05
0.05
0.05
0.05
none
Ph3P
DMF
DMF
DMF
DMF
MeCN
MeCN
DMF
DMF
DMF
traces
59
60
TFPa
TFP
69
TFP
Ph3P
69
46b
8.5
PEPPSI-iPrc
(Cy)2(2-biphenyl)P
TFP
0.05
0.05
41
traces
aTris(2-furyl)phoshine. b41% of starting material was recovered. c[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)
dichloride.
of a phosphine ligand to stabilize the intermediate PdII
species. Even though TFP appeared as the ligand of choice,
the cheaper Ph3P can, in principle, also be used, but the
reaction proceeds at a slower rate. The reaction is widely
applicable and opens up a short and reliable route toward a
range of 1,5-disubstituted tetrazoles.
TABLE 2. Overview of the Prepared Derivatives
Experimental Section
General Procedure for Preparation of Compounds 1a-3f. A
suspension of tetrazole 1-3 (1.00 mmol), aryl/alkenyl iodide
(1.00 mmol), cesium carbonate (1.10 mmol), copper(I) iodide
(1.00 mmol), palladium(II) acetate (0.05 mmol), and tris(2-
furyl)phosphine (0.10 mmol) in dry acetonitrile (3 mL) was
heated under argon atmosphere for 4-6 h (see Table 2). The
resulting mixture was diluted with ethyl acetate (20 mL) and
filtered quickly through Celite, then the solvents were removed
under reduced pressure. The residues were purified by column
chromatography (hexane: ethyl acetate 9:1) to afford the title
tetrazoles 1a-3f.
Synthesis of 5-(4-Chlorophenyl)-1-phenyl-1H-tetrazole23 (1e).
A suspension of tetrazole 1 (146.2 mg, 1.00 mmol), 1-chloro-4-
iodobenzene (238.5 mg, 1.00 mmol), cesium carbonate (358.4
mg, 1.10 mmol), copper(I) iodide (190.4 mg, 1.00 mmol),
palladium(II) acetate (11.2 mg, 0.05 mmol), and tris(2-furyl)-
phosphine (23.2 mg, 0.10 mmol) in dry acetonitrile (3 mL) was
heated at 40 °C under argon atmosphere for 4 h. The resulting
mixture was diluted with ethyl acetate (20 mL) and filtered
quickly through Celite, then the solvents were removed
under reduced pressure. The residue was purified by column
chromatography (hexane:ethyl acetate 9:1) to afford tetrazole
1e (222.9 mg, 87%). Colorless crystals, mp 157-158 °C; 1H
NMR (300 MHz, CDCl3) δ 7.50-7.39 (5H, m), 7.34-7.25 (4H, m);
13C NMR (75 MHz, CDCl3) δ 152.5, 137.4, 134.0, 130.4, 130.0,
129.8, 129.1, 125.1, 121.8; IR (ATR) νmax 997, 1093, 1104, 1134,
1263, 1297, 1431, 1449, 1463, 1495, 1591, 1602, 2852, 2922, 2955,
3068 cm-1; LRMS m/z (rel intensity) 257.1 [M þ H]þ (100),
249.0 (6), 229.4 (8), 216.1 (5), 195.3 (5), 161.2 (2), 119.1 (5). Anal.
Calcd for C13H9ClN4: C, 60.83; H, 3.53; N, 21.83. Found: C,
60.98; H, 3.62; N, 22.00.
Synthesis of 1-Cyclohexyl-5-phenyl-1H-tetrazole24 (3c). A
suspension of tetrazole 3 (152.2 mg, 1.00 mmol), iodobenzene
(204.0 mg, 1.00 mmol), cesium carbonate (358.4 mg, 1.10 mmol),
copper(I) iodide (190.4 mg, 1.00 mmol), palladium(II) acetate
(11.2 mg, 0.05 mmol), and tris(2-furyl)phosphine (23.2 mg,
0.10 mmol) in dry acetonitrile (3 mL) was heated at 60 °C under
argon atmosphere for 6 h. The resulting mixture was diluted
with ethyl acetate (20 mL) and filtered quickly through Celite,
then the solvents were removed under reduced pressure. The
residue was purified by column chromatography (hexane:ethyl
acetate 9:1) to afford tetrazole 3c (150.8 mg, 66%). White
crystals, mp 131-133 °C; 1H NMR (300 MHz, CDCl3) δ
7.62-7.54 (5H, m), 4.39-4.25 (1H, m), 2.20-1.90 (6H, m),
1.77-1.72 (1H, m), 1.41-1.29 (3H, m); 13C NMR (75 MHz,
CDCl3) δ 153.6, 131.1, 129.3, 128.9, 124.5, 58.2, 33.2, 25.3, 24.8;
(23) Houghton, P. G.; Pipe, D. F.; Rees, C. W. J. Chem. Soc., Perkin
Trans. 1 1985, 7, 1471.
(24) Harvill, E. K.; Herbst, R. M.; Schreiner, E. C.; Roberts, C. W. J. Org.
Chem. 1950, 15, 662.
J. Org. Chem. Vol. 75, No. 1, 2010 243

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IR (ATR) νmax 1007, 1078, 1100, 1162, 1244, 1278, 1335, 1378,
of Education, Youth and Sports of the Czech Republic
(projects nos. 1M0508 and MSM0021620822).
1394, 1454, 1468, 1532, 2861, 2946 cm-1
; LRMS m/z
(rel intensity) 229.1 [M þ H]þ (100), 218.9 (2), 195.1 (3), 165.3
(2), 147.1 (19). Anal. Calcd for C13H16N4: C, 68.39; H, 7.06; N,
24.54. Found: C, 68.58; H, 7.27; N, 24.42.
Supporting Information Available: General experimental
procedures, characterization data (1H, 13C NMR, IR, LR-MS,
and elemental analysis), and copies of 1H and 13C NMR spectra
for compounds 1a-3f. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the Czech
Science Foundation (project No. 203/07/1302) and the Ministry
244 J. Org. Chem. Vol. 75, No. 1, 2010