Pd(ii)-catalyzed, controllable C-H mono-/diarylation of aryl tetrazoles: Concise synthesis of Losartan

Article abstract of DOI:10.1039/c4ob02453b

A palladium(ii)-catalyzed C-H arylation directed by tetrazole, a metabolically stable surrogate for the carboxylic acid group in drug design, has been developed. Excellent mono-/di-selectivity was achieved through adjustment of the protecting site on the tetrazole ring. The synthetic utility of this new transformation was demonstrated in the concise total synthesis of Losartan. This journal is

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DOI: 10.1039/C4OB02453B
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Pd(II)-Catalyzed Controllable C-H Mono-/Diarylation
of Aryl Tetrazoles: Concise Synthesis of Losartan
Cite this: DOI: 10.1039/x0xx00000x
Yan-Jun Ding, Yan Li,* Sheng-Yu Dai, Quan Lan and Xi-Sheng Wang*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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Table
1 Pd-catalyzed controllable C–H mono-/diarylation:
A palladium(II)-catalyzed C–H arylation directed by tetrazole,
a metabolically stable surrogate for the carboxylic acid group
in drug design, has been developed. Excellent mono-/di-
selectivity was achieved through the protecting site adjustment
on tetrazole ring. The synthetic utility of this new
transformation was demonstrated in the concise total synthesis
of Losartan.
optimization of reaction conditions a,b
With the rapid development in the past two decades, transition-
metal-catalyzed direct C–H functionalization has emerged as a
potential valuable tool in the total synthesis of natural products and
drugs due to its atom-economy and step-economy.1 To address the
inert nature of C–H bonds and the requirement of site selectivity
control, directing groups were introduced to direct the catalysts to
active the desired C–H bonds by coordination with the metal centers.2
While a variety of directing groups were successfully used in direct
C–H functionalizations with different transition metals,2 the
additional installing and removing steps of such ligands remarkably
limited the application of this strategy. One good solution is to utilize
the functional groups available in the target molecules or key
intermediates as directing groups.
The tetrazole, commomly known as a bioisostere of carboxylic acid
moiety, served as a metabolically stable surrogate for the carboxyl
functionality in drug design.3 Many biologicly active aromatics,
including the highly commercially succesful Losartan and Valsartan,
was dramatically improved in both binding affinity and oral
bioavailability. To the best of our knowledge, such tetrazoles have
been less studied in direct C–H functionalizations catalyzed by
transtion metal,4,5 especially for palladium catalyst.5 Within our
continous efforts to develop synthetic useful C–H functionalization
methods towards total synthesis of complex molecules,6 we herein
report a controllable mono/diarylation of aryl tetrazoles through
palladium-catalyzed C–H activation,7 whose synthetic potential is
a Conditions: 1a or 2a (0.2 mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), silver salt (4.0
c
equiv), TFA, 150 oC, 24 h. b Isolated yield of monoarylation product. Pd(OAc)2
(5 mol%) was used. d Without Pd(OAc)2. e In the absence of TFA. f Pd(OAc)2 (15
mol%) was used. g PhBr was used instead of PhI.
We commenced our study with 1-benzyl-5-phenyl-1H-tetrazole (1a)
as the pilot substrate in the presence of Pd(OAc)2 (10 mol%) and
AgOAc (4 equiv.) in trifluoroacetic acid (TFA) at 150 °C for 24 hours
in sealed tube. To our delight, only monophenylation product 4a was
obtained at 48% yield, presumably due to the steric hindrance of 1-
illustrated by application in the concise total synthesis of Losartan benzyl group, with 8 equiv iodobenzene used. (entry 1, Table 1). The
from commercially available starting materials.4g
careful examination of concentration indicated 1.0 M was optimal
(entries 2-3). Survey of silver species was next undertaken, which
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showed AgOAc gave the best result (entries 4-5). To further improve aryltetrazoles 2 were arylated smoothly to produce the corresponding
the yield, investigation of the amount of iodobenzene was carried out, biaryl tetrazole with good to excellent yields. Additionally, 2-benzyl
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affording slightly higher yield with the addition of 10 equiv. of PhI aryltetrazoles 2 showed also higher reactivity even for the meta-
(entries 6-8). To our satisfactory, the decrease of the catalyst loading substituted tetrazoles, compared with the 1-DbOenI:z1y0l.1s0u3b9s/tCra4tOeBs012.4N53oBt
to 5 mol% gave even the best yield to 85% (entry 9). Lastly, control only electon-donating groups, such as MeO, Me, but also weak
experiments demonstrated no desired product was generated without electron-withdrawing groups, such as F, Cl, Br, were well tolerated in
Pd(OAc)2 as catalyst (entry 10), and the yield would be only trace or our new catalytic system. Notably, heterocycle substrate was also
significantly reduced without Ag or TFA (entries 11-12). Notably, compatible with this method at acceptable yield (4q). We next set out
only diphenylation product 5a was obtained at excellent yield (96%) to examine the substuent efffect of iodobenzene, which showed the
by changing the protecting site of benzyl group from 1- to 2-position ortho- and meta-substituted iodobenzenes, including both electron-
on tetrazole ring (entry 13). Additionally, only 23% yield of 5a was rich and electron-deficient substituents, coupled with phenyltetrazoles
afforded when PhBr was used instead of PhI.
pretty well with good yields. Of particular note is, the presence of
halogen atoms at both aryl rings of the products 4 offered potential
synthetic elaboration via transition metal-catalyzed cross coupling
reactions.
Fig. 1 Controllable mono-/diarylation of aryltetrazoles. a Conditions: 1 or 2 (0.2
mmol, 1.0 equiv), 3a (10.0 equiv), Pd(OAc)2 (5 mol%), AgOAc (4.0 equiv), TFA
b
c
d
(0.2 mL), 150 oC, 24 h. Isolated yield. Pd(OAc)2 (15 mol%) was used.
Determined by 1H NMR analysis of crude products.
With the optimized reaction conditions in hand, we set out to
investigate the substrate scope for the controllable mono-/diarylation
of tetrazoles 1 and 2. A variety of para-substituted aryltetrazoles were
arylated smoothly with iodobenzene to give the corresponding
coupling products 4 or 5 in modest to excellent yield (up to 96%,
Table 2). As for the 1-benzyl protecting para-substitued aryl
tetrazoles 1, only monoarylation products were obtained with
moderate to good yields. On the other hand, 2-benzyl protecting aryl
tetrazoles 2 with both electon-donating and electron-withdraing
substituents afforded the diarylation tetrazoles, albeit with minor
monoarylation products for the latter substrates.
Fig. 2 Monoarylation of 2-benzyl aryltetroazoles. a Conditions: 2 (0.2 mmol, 1.0
equiv), 3 (10.0 equiv), Pd(OAc)2 (5 mol%), AgOAc (4.0 equiv), TFA (0.2 mL), 150
oC, 24 h. b Isolated yield c 140 oC. d 130 oC. e 120 oC.
To demonstrate the synthetic potential of this new method, we next
carried out a concise total synthesis of Losartan, an angiotensin II
receptor antagonist drug used to treat hypertension, with our newly
developed C–H monoarylation as key step. Whereas previous
Subsequently, we further investigated the generatity for the arylation
of ortho- and meta-subsituted aryltetrazoles. While the ortho-
substitued 1-benzyl aryltetrazoles 1 gave almost none of the desire
products, presumably due to the steric hindrance effect, 2-benzyl
2 | J. Name., 2012, 00, 1-3
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deprotection of N-benzyl group and reduction of the formyl group of
7 under 1 atm H2 atmosphere in the presence of 10% Pd/C.9
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Scheme 1 Total synthesis of Losartan
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In summary, we have developed the first example of tetrazole-
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on tetrazole ring. The synthetic potencial of this new transformation
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We gratefully acknowledge NSFC (21372209), the Chinese Academy
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Department of Chemistry, University of Science and Technology of China,
96 Jinzhai Road, Hefei, Anhui 230026, China. xswang77@ustc.edu.cn
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supplementary information available should be included here]. See
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