Amino Acid Ligands for Ruthenium(II)-Catalyzed C–H Arylation of Aryltetrazoles with Chlorides: Expedient Access to Antihypertension Drugs

Article abstract of DOI:10.1002/ejoc.201600742

Versatile ruthenium(II) complexes derived from amino acids enabled the first general C–H arylations of aryltetrazoles with inexpensive aryl chlorides. The user-friendly Piv-Val-OH-based ruthenium(II) catalyst was characterized by a broad substrate scope, excellent functional group tolerance, and high catalytic activity. Thereby, the ruthenium(II) catalysis set the stage for the step-economical preparation of the blockbuster antihypertension drug Valsartan, while displaying unique robustness in the C–H arylation regime.

Full text of DOI:10.1002/ejoc.201600742

DOI: 10.1002/ejoc.201600742
Communication
C–H Activation
Amino Acid Ligands for Ruthenium(II)-Catalyzed C–H Arylation
of Aryltetrazoles with Chlorides: Expedient Access to
Antihypertension Drugs
Jonathan Hubrich[a] and Lutz Ackermann*[a]
Abstract: Versatile ruthenium(II) complexes derived from and high catalytic activity. Thereby, the ruthenium(II) catalysis
amino acids enabled the first general C–H arylations of aryltet-
razoles with inexpensive aryl chlorides. The user-friendly Piv-
Val-OH-based ruthenium(II) catalyst was characterized by a
broad substrate scope, excellent functional group tolerance,
set the stage for the step-economical preparation of the block-
buster antihypertension drug Valsartan, while displaying unique
robustness in the C–H arylation regime.
Introduction
Methods for the direct functionalization of otherwise unreactive
C–H bonds have emerged as increasingly viable tools for step-
economical organic syntheses,[1] with transformative applica-
tions to, among others, material sciences[2] and natural product
chemistry.[3] Transition-metal catalysts have also proven instru-
mental for drug development, with major advances achieved by
stable ruthenium(II)[4] catalysis in the synthesis of nonpeptidic
angiotensin II receptor blockers (ARBs), which are prevalent in
blockbuster antihypertensive drugs (Figure 1).[5] In this context,
we previously identified the beneficial effect exerted by bifunc-
tional ligands in the C–H activation of C5-aryl-substituted
tetrazoles.[5a] Specifically, carboxylates[6] and phosphinous ac-
ids[7] enabled efficient C–H arylations[8] of aryltetrazoles,
whereas phosphate and sulfonate additives were subsequently
also utilized.[9] Moreover, we very recently disclosed the signifi-
cant rate acceleration by amino acid ligands[10] in ruthenium-
catalyzed remote alkylations.[11] Given the practical importance
of biaryl-substituted tetrazoles in the medicinal chemistry and
pharmaceutical industries, we became attracted to probing
ruthenium(II) amino acid catalysts for direct C–H arylations of
5-aryltetrazoles, on which we report herein. Notable features of
Figure 1. Selected biaryltetrazole antihypertension drugs.
our findings include (1) efficient C–H arylations by amino acid Results and Discussion
ruthenium(II) complexes, (2) step-economical syntheses of biar-
At the outset of our studies, we probed reaction conditions for
yltetrazoles with ample scope, (3) tetrazole-assisted C–H aryla-
tions with inexpensive aryl chlorides, and (4) a comparative ki-
netic study, highlighting the unique long-term efficiency of
ruthenium amino acid catalysts in C–H activation chemistry.
the envisioned C–H arylation of 5-phenyl-1H-tetrazole 1a with
aryl chloride 2a (Table 1 and Tables S1–S5 in the Supporting
Information).[12] Orienting ligand optimization studies indicated
carboxylic acids to be particularly suitable (Table 1, entries 1–
6). However, amino acid derivatives outperformed carboxylic
acids, and optimal results were achieved with N-pivaloylvaline
(Table 1, entries 7–17). In contrast, selected dipeptides failed
short in improving the catalytic efficacy (Table 1, entries 18–
20). Further optimization revealed the key importance of the
substrate concentration (Table 1, entries 17 and 21). It is note-
worthy that well-defined single-component catalyst 4 displayed
[a] Institut für Organische und Biomolekulare Chemie, Georg-August-
Universität
Tammannstraße 2, 37077 Göttingen, Germany
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
http://www.org.chemie.uni-goettingen.de/ackermann/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600742.
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Communication
a catalytic activity comparable to the one observed upon using
the in situ generated catalyst (Table 1, entries 21 and 22).
Table 1. Optimization of the ruthenium(II)-catalyzed C–H arylation.[a]
Entry
[Ru]
Additive
Yield [%]
1
2
3
4
5
6
7
8
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
–
–
22
38
36
36
39
47
42
44
16
17
50
51
46
48
37
41
58
45
32
–
(PhO)2P(O)OH
KOAc
1-AdCO2H
tBuCO2H
MesCO2H
Piv-Leu-OH
Piv-Phe-OH
Piv-Met-OH
Piv-Asn-OH
Piv-Asp-OH
Piv-Ile-OH
Ac-Ile-OH
Ad-Ile-OH
MeO2C-Ile-OH
Boc-Ile-OH
Piv-Val-OH
Boc-Val-Gly-OH
Boc-Ile-Phe-OH
Piv-Val-OH
Piv-Val-OH
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
[{RuCl2(p-cymene)}2]
[RuCl(O-Val-Piv)(p-cymene)] (4)
77[b,c]
79[b,c]
[a] Reaction conditions: 1a (0.30 mmol), 2a (0.90 mmol), [{RuCl2(p-cymene)}2]
(5.0 mol-%), additive (30 mol-%), K2CO3 (0.9 mmol), 1,4-dioxane (2.0 mL),
140 °C, 24 h; yields of isolated products are given; Ad = adamantyl, Mes =
mesityl (2,4,6-trimethylphenyl), Piv = pivaloyl, Boc = tert-butoxycarbonyl.
[b] 1,4-Dioxane (0.3 mL). [c] 7–10 % of diarylated product 3aa′ was also iso-
lated.
Scheme 1. Scope of ruthenium(II)-catalyzed C–H arylation.
lysts enabled C–H arylations with phenol-derived triflates by C–
H/C–O cleavage.[13] Likewise, along with aryl chlorides (Table 2,
entries 3 and 4), aryl bromides and iodides were identified as
With the optimized reaction conditions in hand, we next per- viable arylating reagents (Table 2, entries 5–8), as they chemo-
formed a detailed comparative study on the efficacy of the
best-in-class carboxylic acid and amino acid ligands MesCO2H
and Piv-Val-OH, respectively (Scheme 1). Thus, with both cata-
Table 2. Scope of aryl (pseudo)halides as electrophiles.[a]
lytic systems an excellent chemoselectivity was observed in the
C–H arylation of aryltetrazole 1, thereby tolerating valuable
electrophilic functional groups, such as enolizable ketone, ester,
and thioether substituents. Likewise, both electron-poor as well
as more challenging electron-rich aryl chlorides
2 were
smoothly converted within the C–H activation regime, and even
thiophenyl chloride 2e proved amenable. A representative set
of 5-aryl-1H-tetrazoles 1 with different substitution patterns
were successfully applied to the C–H arylation. Here, intramo-
lecular competition experiments with meta-substituted sub-
strates 1b, 1d, and 1f occurred with excellent site selectivity at
the less-hindered C6–H bond. Generally, the ruthenium catalyst
derived from the amino acid ligand Piv-Val-OH provided im-
proved results in all C–H arylations and clearly outperformed
the MesCO2H-based system.
Entry
X
Additive
Yield [%]
1
2
3
4
5
6
7
8
OTf
OTf
Cl
Cl
Br
Br
I
Piv-Val-OH
MesCO2H
Piv-Val-OH
MesCO2H
Piv-Val-OH
MesCO2H
Piv-Val-OH
MesCO2H
64
51
89
81
97
95
96
95
I
[a] Reaction conditions: 1a (0.30 mmol), 2a (0.90 mmol), [{RuCl2(p-cymene)}2]
(5.0 mol-%), additive (30 mol-%), K2CO3 (3.0 equiv.), 1,4-dioxane (0.3 mL),
140 °C, 24 h; yields of isolated products are given.
Thereafter, the scope of viable aryl electrophiles was ex-
plored (Table 2, entries 1 and 2). Thus, the ruthenium(II) cata-
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Communication
Scheme 2. Preparation of protected Valsartan 3af by C–H arylation.
selectively delivered desired monoarylated product 3ba in ex-
Given the unique activity of the amino acid ruthenium(II)
cellent yields of up to 97 %. Again, the amino acid ruthenium(II) catalyst, we became intrigued by rationalizing its outstanding
catalyst compared favorably with the carboxylic acid systems, performance. To this end, comparative kinetic studies revealed
and it furnished the desired products generally in higher yields. the ruthenium(II) carboxylate catalyst to display a slightly
higher initial rate.[12] However, the amino acid derived catalyst
The practical importance of the C–H activation strategy was
showed increased long-term stability, which thereby led to a
higher conversion to the desired product (Figure 2). In contrast,
the ruthenium(II) biscarboxylate featured catalyst deactivation,
which already occurred after a reaction time of approximately
5 h.
reflected by the direct synthesis of the 5-biaryl-1H-tetrazole
scaffold of angiotensin II receptor blockers (ARBs). Hence, we
were pleased to observe that the ruthenium(II)-catalyzed C–H
arylation provided direct access to protected Valsartan 3af
(Scheme 2), which should prove instrumental for future applica-
tions by practitioners in industrial settings. Intriguingly, pro-
Moreover, attempted transformations of substrate 1a in the
tected blockbuster drug Valsartan 3af was accessed in a step- presence of typical radical scavengers failed to give any C–H
economical fashion, even upon employing more difficult to ac- arylated product 3aa under otherwise identical reaction condi-
tivate 4-chloro aryl amino acid 2f.
tions (Scheme 3), which indicated single-electron transfer (SET)-
type processes to be of key relevance.
Scheme 3. Influence of radical scavengers on C–H arylation [TEMPO = 2,2,6,6-
tetramethylpiperidin-1-oxyl, BHT = butylated hydroxytoluene (2,6-di-tert-
butyl-4-methylphenol)].
On the basis of these studies, we suggest the ruthenium-
catalyzed C–H arylation to commence by a chelation-assisted
C–H metalation to deliver cyclometalated ruthenium(II) com-
plex 5 (Scheme 4). Thereafter, formal oxidative addition of aryl
chloride 2 by a SET-type process to the thus-formed ruth-
enium(II) species gives complex 6, which finally undergoes re-
ductive elimination to furnish desired product 3 with regenera-
tion of active catalyst 4.
Figure 2. Kinetic profile of ruthenium(II)-catalyzed C–H arylation with Mes-
CO2H and Piv-Val-OH, as determined by 1H NMR spectroscopy with CH2Br2
as the internal standard.
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Scheme 4. Proposed catalytic cycle for the C–H arylation.
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In summary, we reported on the unprecedented use of cost-
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activation chemistry.
Acknowledgments
Support by the European Research Council under the European
Community's Seventh Framework Program (FP7 2007-2013)/
ERC grant agreement number 307535 is gratefully acknowl-
edged. The authors thank Ms. Svenja Warratz (University of
Göttingen, Germany) for the preparation of complex 4.
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Communication
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Received: June 17, 2016
Published Online: ■
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Communication
C–H Activation
J. Hubrich, L. Ackermann* ............... 1–6
Amino Acid Ligands for Ruth-
enium(II)-Catalyzed C–H Arylation
of Aryltetrazoles with Chlorides: Ex-
pedient Access to Antihypertension
Drugs
Ruthenium(II) complexes derived from scope, excellent functional group tol-
amino acids enable the first general C– erance, and high catalytic activity.
H arylations of aryltetrazoles with inex- Thereby, the ruthenium(II) catalysis al-
pensive aryl chlorides. The user- lows the step-economical preparation
friendly Piv-Val-OH-based ruthenium- of the antihypertension drug Valsar-
(II) catalyst has broad substrate tan.
DOI: 10.1002/ejoc.201600742
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