Cobalt-catalyzed C-H arylations with weakly-coordinating amides and tetrazoles: Expedient route to angiotensin-ii-receptor blockers

Article abstract of DOI:10.1002/chem.201500552

Cobalt-catalyzed C-H arylations enabled the synthesis of biaryl tetrazoles, which are key structural motifs in antihypertensive angiotensin-II-receptor blockers. Thus, weakly-coordinating benzamides were employed for step-economical C-H arylations with ample scope. Further, a low-valent NHC complex enabled first cobalt-catalyzed C-H functionalization by tetrazole assistance.

Full text of DOI:10.1002/chem.201500552

DOI: 10.1002/chem.201500552
Communication
&
CÀH Activation
Cobalt-Catalyzed CÀH Arylations with Weakly-Coordinating
Amides and Tetrazoles: Expedient Route to Angiotensin-II-
Receptor Blockers
Jie Li and Lutz Ackermann*[a]
tinue to face major limitations in that strongly coordinating di-
Abstract: Cobalt-catalyzed CÀH arylations enabled the
recting groups, namely pyridines, imines or pyrimidines, are
synthesis of biaryl tetrazoles, which are key structural
motifs in antihypertensive angiotensin-II-receptor blockers.
Thus, weakly-coordinating benzamides were employed for
step-economical CÀH arylations with ample scope. Fur-
ther, a low-valent NHC complex enabled first cobalt-cata-
lyzed CÀH functionalization by tetrazole assistance.
a prerequisite for all direct arylations (Scheme 1a), which ren-
ders further modifications of the obtained products often par-
ticularly challenging. Hence, cobalt-catalyzed CÀH functionali-
zations with weakly coordinating[13,14] amides or tetrazoles
have unfortunately thus far proven elusive. Within our program
on the use of inexpensive metals for sustainable CÀH activa-
tion,[15,16] and inspired by elegant studies from Nakamura and
Ilies on catalyzed alkylations,[17] we have established two novel
Hypertension is among the most prevalent diseases
in developed countries, and nonpeptidic angiotensin-
II-receptor blockers (ARBs), such as Valsartan, Losartan
or Candesartan (Figure 1), have been identified as
particularly effective antihypertensives.[1,2] As a direct
consequence, ARBs are produced in more than
1000 t annual scale for clinical treatment. The unify-
ing structural motif of numerous nonpeptidic ARBs is
represented by the 5-biaryl tetrazole scaffold. Thus
Figure 1. ARBs featuring biaryl tetrazoles.
far, these biaryl moieties were mostly accessed
through palladium-catalyzed cross-coupling reactions
using nucleophilic organometallic coupling re-
agents.[3] The required prefunctionalized nucleophiles are not
readily available and their syntheses involve numerous synthet-
ic operations, which generate undesired waste. A significantly
more step-economical alternative is represented by the direct
arylation of otherwise unreactive CÀH bonds.[4] Despite the
practical importance of biaryl tetrazoles, CÀH arylations of aryl
tetrazoles were thus far only accomplished with ruthenium(II)
catalysts.[1,5]
protocols, providing expedient access to biaryl tetrazoles of
type 4 (Scheme 1b). Thus, we devised cobalt-catalyzed CÀH ar-
ylations with weakly-coordinating benzamides 1, as well as
direct arylations of synthetically useful aryl tetrazoles 3. Nota-
ble features of our strategy include i) the use of an inexpensive
cobalt catalyst, ii) an unusually broad substrate scope that in-
volves weakly-coordinating X-type amides and L-type[18] tetra-
zoles, as well as iii) a high catalytic efficacy reflected by short
The relatively high costs of 4d or 5d late transition metal CÀ reaction times of 30 min and/or low catalyst loadings.
H activation catalysts have resulted in a strong demand for
a novel catalyst design, exploiting naturally abundant first row
transition metals.[6] In recent years, inexpensive cobalt com-
plexes have emerged as powerful catalysts for CÀH functionali-
zations with organic electrophiles.[7–9] However, in spite of con-
siderable progress,[7,10–12] cobalt-catalyzed CÀH arylations con-
In consideration of the facile transformation of amides 5 to
tetrazoles 4,[19] we initially set out to probe different reaction
conditions for the CÀH arylation of weakly-coordinating benza-
mide 1 with inexpensive aryl chlorides 2 (Table 1 and Table S1
in the Supporting Information). Thus far, all reported cobalt-
catalyzed direct arylations with organic (pseudo)halides were
accomplished with either of the two N-heterocyclic carbene
(NHC)[20,21] preligands IMesHCl (6a) or IPrHCl (6b).[10–12] Howev-
er, preligands 6a and 6b delivered the desired product 5aa
only in unsatisfactory low yields, even at a relatively high cata-
lyst loading of 10 mol % (entries 1 and 2). A similar observation
was made when employing the saturated analogues sIMesHCl
(6c), and sIPrHCl (6d) (entries 3 and 4), or the tertiary phos-
phine PPh3 (entry 5). Cobalt catalysts derived from isopropyl-
[a] J. Li, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500552.
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Scheme 1. Cobalt-catalyzed CÀH arylation to access key ARB intermediates
4.
Table 1. Optimization of cobalt-catalyzed CÀH arylation.[a]
Scheme 2. Scope of cobalt-catalyzed CÀH arylation.[a] 30 min.[b] Co(acac)2
(2.0 mol%), 6g (2.0 mol%).[c] Co(acac)2 (10 mol%), 6g (10 mol%).[d] Major re-
gioisomer shown, isolated yield of the minor C-6 regioisomer.
Entry
Co(acac)2 [mol%]
Ligand
Yield[b] [%]
tion with benzamides 1a (entries 6 and 7), highlighting the
challenge associated with the use of weakly-coordinating
amides. In contrast, among various NHC precursors, ICyHCl
(6g) proved to be optimal with an ideal ligand to cobalt ratio
of 1:1 (entries 8 and 9). Under these reaction conditions the
catalyst loading could also be significantly reduced (entry 9).
The more electron-rich pre-NHC 6h, the bidentate derivative
6i and the unsymmetrically substituted pre-NHC 6j failed to
improve the catalytic efficacy (entries 10–13).
1
2
3
4
5
6
7
8
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
5.0
–
5.0
5.0
5.0
IMesHCl (6a)
IPrHCl (6b)
sIMesHCl (6c)
sIPrHCl (6d)
PPh3
6e
6 f
6g
6g
6g
6h
6i
23[c]
<5[c]
16[c]
[c]
–
13[c]
29[c]
<5[c]
47[c]
78
9
10
11
12
13
–
32
<5
26
With the optimized cobalt catalyst in hand, we tested its ver-
satility in the CÀH arylation with weakly coordinating benza-
mides 1 (Scheme 2). Various aryl chlorides 2 as well as un- or
para-substituted benzamides 1 were identified as viable sub-
strates for direct arylations under remarkably mild reaction
conditions.[23] Intramolecular competitions with meta-substitut-
ed arenes 1g and 1h were largely governed by steric interac-
tions, unless a secondary directing group effect was exerted by
an additional Lewis-basic entity (5ia). More sterically hindered
6j
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), cat. Co(acac)2,
ligand (5 mol%), CyMgCl (3.0 equiv), DMPU (1.0 mL), 608C, 16 h. [b] Yield
of isolated product. [c] 2a (0.75 mmol), ligand (20 mol%).
substituted NHC 6e were previously shown to be effective for
direct alkylations,[22] but proved unsuitable for the CÀH aryla-
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Given the efficacy of the versatile cobalt-catalyzed
CÀH arylation by weak coordination, we performed
studies to delineate its working mode. Independent
experiments with isotopically labeled substrates indi-
cated the CÀH cobaltation not to be kinetically rele-
vant (KIEꢀ1.0), and provided evidence for a reversible
D/H exchange reaction (Scheme S1 and S2 in the
Supporting Information). A set of intermolecular
competition experiments revealed electron-deficient
benzamides 1 and electron-poor aryl chlorides 2 to
be more reactive than their electron-rich counter-
parts (Scheme 4). These observations can be rational-
ized in terms of a catalytic cycle involving an initial
reversible CÀH cobaltation.[8]
The unique synthetic utility of the cobalt-catalyzed
CÀH arylation by weak amide assistance was illustrat-
ed by the facile transformation[19] of the ortho-arylat-
ed benzamides 5 to the desired biaryl tetrazoles 4
(Scheme 5).
Scheme 3. Cobalt-catalyzed CÀH arylation of N-aryl amides 1.[a] 30 min.
Scheme 5. Facile preparation of biaryl tetrazoles 4.
Finally, we explored the possibility of devising an even more
step-economical approach to biaryl tetrazoles 4 through un-
precedented cobalt-catalyzed CÀH activation by tetrazole assis-
tance. Intriguingly, a low-valent cobalt catalyst derived from
preligand 6a proved effective here, thereby chemo-selectively
delivering the desired products 4.[26] It is noteworthy that the
tetrazole-assisted CÀH arylation proceeded by CÀH/CÀO clea-
vages[27] with challenging aryl carbamates 7 as the electro-
philes (Scheme 6). While the reactions proceeded with rather
modest yields, they represent—to the best of our knowledge -
the first example of CÀH functionalization of aryl tetrazoles
using inexpensive first row transition metals.
Scheme 4. Competition experiments between a) aryl chlorides 2 and b) ben-
zamides 1.
ortho-substituted benzamides 1j and 1k were successfully em-
ployed as well, which should prove instrumental for potential
applications of this technology to asymmetric synthesis.[24,25]
The widely applicable cobalt catalyst was not limited to aro-
matic benzamides. Indeed, heteroaromatic indole derivatives
1l and 1m also led to site-selective CÀH arylations. The out-
standing catalytic efficacy and robustness of the user-friendly
cobalt catalyst was among others reflected by CÀH functionali-
zations i) with low catalyst loading of only 2.0 mol%, ii) on
1.4 g scale and/or iii) with remarkably short reaction times of
only 30 min. Generally, the mass balance was accounted for by
recovered unreacted starting material as well as small amounts
of diarylated products.
Intramolecular competition experiments with various N-aryl
benzamides 1n–p bearing two aromatic moieties led to the
chemo-selective CÀH arylation on the benzamide, while the
anilide motif remained untouched (Scheme 3).
Scheme 6. Tetrazole-assisted CÀH arylation with carbamates 7.
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as well as ample scope, and provided expedient access to
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Acknowledgements
Generous support by the European Research Council under
the European Community’s Seventh Framework Program (FP7
2007–2013)/ERC Grant agreement no. 307535, and the Chinese
Scholarship Program (fellowship to J.L.) is gratefully acknowl-
edged.
Keywords: amides · arylation · CÀH activation · cobalt ·
tetrazoles
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Received: February 10, 2015
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COMMUNICATION
&
CÀH Activation
J. Li, L. Ackermann*
&& – &&
Cobalt-Catalyzed CÀH Arylations with
Weakly-Coordinating Amides and
Tetrazoles: Expedient Route to
Angiotensin-II-Receptor Blockers
Broadly applicable cobalt-catalyzed CÀ
H arylations with weakly-coordinating
amides or tetrazoles provided step-eco-
nomical access to biaryl tetrazoles as
key structural motifs of angiotensin-II-
receptor blockers (ARBs), such as the
blockbuster drug Losartan (see scheme).
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