Iron-catalyzed C(sp2)-H and C(sp3)-H arylation by triazole assistance

Article abstract of DOI:10.1002/anie.201311024

Modular 1,2,3-triazoles enabled iron-catalyzed C-H arylations with broad scope. The novel triazole-based bidentate auxiliary is easily accessible in a highly modular fashion and allowed for user-friendly iron-catalyzed C(sp ²)-H functionalizations of arenes and alkenes with excellent chemo- and diastereoselectivities. The versatile iron catalyst also proved applicable for challenging C(sp³)-H functionalizations, and proceeds by an organometallic mode of action. The triazole-assisted C-H activation strategy occurred under remarkably mild reaction conditions, and the auxiliary was easily removed in a traceless fashion. Intriguingly, the triazole group proved superior to previously used auxiliaries. With a little help: A versatile iron catalyst allows the arylation of C(sp²)-H and C(sp³)-H bonds in the presence of a modular and removable triazolyldimethylmethyl (TAM) auxiliary, whose structure can be varied through 1,3-dipolar azide-alkyne cycloadditions.

Full text of DOI:10.1002/anie.201311024

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Angewandte
Communications
DOI: 10.1002/anie.201311024
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C H Activation
2
3
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Iron-Catalyzed C(sp ) H and C(sp ) H Arylation by Triazole
Assistance**
Qing Gu, Hamad H. Al Mamari, Karolina Graczyk, Emelyne Diers, and Lutz Ackermann*
À
Abstract: Modular 1,2,3-triazoles enabled iron-catalyzed C H
arylations with broad scope. The novel triazole-based biden-
bidentate directing groups, this approach continues to be
restricted largely to the 8-aminoisoquinoline auxiliary, and
structural modifications thereof are challenging to realize in
a modular fashion.[9] In consideration of these severe limi-
tations, we became intrigued in establishing a novel family of
tate auxiliary is easily accessible in a highly modular fashion
and allowed for user-friendly iron-catalyzed C(sp ) H func-
tionalizations of arenes and alkenes with excellent chemo- and
2
À
À
diastereoselectivities. The versatile iron catalyst also proved
highly modular bidentate directing groups for C H activa-
3
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applicable for challenging C(sp ) H functionalizations, and
tion. At the outset, we identified the following key criteria as
our prime guidelines for the molecular design. First, the
bidentate scaffold should be easily accessible under mild
reaction conditions. Second, the auxiliary would need to be
available in a highly modular fashion so as to guarantee the
proceeds by an organometallic mode of action. The triazole-
À
assisted C H activation strategy occurred under remarkably
mild reaction conditions, and the auxiliary was easily removed
in a traceless fashion. Intriguingly, the triazole group proved
superior to previously used auxiliaries.
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prerequisite flexibility for C H functionalizations with differ-
ent transition-metal catalysts. Third, the electronic nature of
the bidentate auxiliary should ensure high catalytic efficacy in
the elementary step of the C H activation. Fourth, the
bidentate directing group would need to be removable in
a traceless manner.
Herein, we report on a novel concept that successfully
addresses all of these key challenges by exploiting easily
accessible 1,2,3-triazoles, which are available in a modular
fashion through copper(I)-catalyzed 1,3-dipolar Huisgen
cycloadditions[12] between diversely substituted alkynes and
azides (Scheme 1). It is noteworthy that our strategy was
widely applicable, as illustrated by the effective iron-cata-
lyzed direct functionalizations of arenes, alkenes, and even
À
T
he use of nonprecious metal catalysts for C C bond-
À
forming reactions is highly attractive, because of the cost-
effective nature of these naturally abundant compounds.[1–3]
Considerable advances have been accomplished, in particu-
lar, with inexpensive iron complexes. Methods for the
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functionalization of otherwise unreactive C H bonds have
received considerable recent attention,[4,5] because they avoid
the synthesis and use of prefunctionalized starting materials.[6]
The organic substrates of interest usually display a multitude
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of C H bonds with comparable dissociation energies. There-
fore, controlling site selectivity is of central importance for
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the development of synthetically useful C H activation
2
3
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procedures. One of the most powerful strategies exploits
unactivated alkanes through C(sp ) H and C(sp ) H activa-
tion with excellent chemo-, site-, and diastereoselectivities.
chelation assistance.[7] Monodentate Lewis-basic functional-
ities embedded in the substrate have thus proven instrumental
[4]
À
for advancing the field of C H activation. The studies by
Daugulis and co-workers indicated the power of bidentate
directing groups derived from 8-aminoquinoline,[8,9] which set
the stage for novel approaches for bond disconnection.[10] The
practical importance of the 8-aminoquinoline directing group
was particularly highlighted by a very recent elegant iron-
catalyzed direct functionalization devised by Nakamura and
co-workers.[11] Despite remarkable advances achieved with
[*] Dr. Q. Gu, Dr. H. H. Al Mamari, M. Sc. K. Graczyk, E. Diers,
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.org.chemie.uni-goettingen.de/ackermann/
À
Scheme 1. Triazole-assisted C H activation strategy.
We initiated our studies by preparing a representative set
of novel benzamides 1 containing 1,2,3-triazoles through
Huisgen cycloadditions under mild reaction conditions (see
the Supporting Information). We then probed various reac-
tion conditions for the iron-catalyzed C H bond arylation
[**] 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 CaSuS PhD
program is gratefully acknowledged. We also thank Benjamin
Schrçder (Gçttingen University) for the synthesis of substrates.
[13]
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of triazolyldimethylmethyl (TAM) amide 1a. Detailed opti-
mization studies revealed C H functionalizations to be viable
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311024.
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with a catalyst system consisting of FeCl3 as the metal source
and dppe as the ligand (see Tables S1 and S2 in the Supporting
Information). With this system, direct arylations proceeded
efficiently on the benzamides 1a under considerably mild[14]
reaction conditions (Scheme 2). It is noteworthy that an iron
catalyst derived from the dppe ligand previously only
provided an unsatisfactory low yield (9%) when using the
8-aminoquinoline auxiliary.[11]
Intermolecular competition experiments between the
triazole- and the quinolinyl-derived benzamides 1a and 3a
clearly revealed the TAM group to display a significantly
more powerful directing group ability (Scheme 4).
Scheme 4. Competition experiment.
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Scheme 2. Optimized reaction conditions for iron-catalyzed C H aryla-
tion. dppe=1,2-bis(diphenyphosphanyl)ethane, TMEDA=N,N,N’,N’-
tetramethylethylenediamine, Bn=benzyl.
Having identified the TAM group as the ideal substituent,
À
we probed the scope of the optimized iron catalyst in C H
arylations of various substrates 1 (Scheme 5). Benzamides
1 with an ortho- or para-substitution pattern were efficiently
converted into the corresponding products 2b–v.[15] Substrates
The optimized iron catalyst also proved amenable to
substrate 1c with a spiro substitution pattern in the amide
backbone (Scheme 3). Likewise, the N-alkyl- and N-aryl-
substituted triazole 1d,e were converted efficiently into the
desired products. However, in line with the proposed
bidentate mode of action, tertiary amide 1 f failed to undergo
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1w–z bearing two chemically inequivalent ortho-C H bonds
were site-selectively functionalized at the sterically less
congested site within intramolecular competition experi-
ments.
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The user-friendly iron catalyst was not limited to C H
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the C H activation, thus highlighting the importance of the
arylations of arenes, but also enabled alkenylic functionaliza-
tions (Scheme 6). It is noteworthy, that the formation of
alkene 6 occurred with excellent diastereoselectivity, thereby
delivering the thermodynamically less-stable Z-olefin as the
sole product.
acidic, free NH functional group. In accordance with this
hypothesis, the corresponding ester 1g was not a viable
substrate for the iron-catalyzed direct arylation. Simple
secondary amides 1h,i, being devoid of the second Lewis
basic nitrogen atom, were not converted by the iron catalyst.
Interestingly, a similar observation was made when using the
pyridyl-substituted amide 1j.
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Scheme 3. Influence of the substitution pattern.
Scheme 5. Scope of the iron-catalyzed C H arylation.
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Scheme 6. Iron-catalyzed C H arylation of alkene 5.
Scheme 8. Kinetic isotope effect studies.
2
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Transformations of C(sp ) H bonds are favored by
precoordination of the arene p system, and the resulting
aryl–metal bonds are typically stronger than the correspond-
ing alkyl–metal bonds. Hence, for both kinetic and thermo-
dynamic reasons, metal-catalyzed functionalizations of unac-
3
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tivated C(sp ) H bonds are considered to be particularly
challenging.[16] Therefore, we were pleased to find that iron
catalysis in the presence of our modular triazole-based TAM
auxiliary also resulted in the direct arylation of otherwise
3
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inert C(sp ) H bonds (Scheme 7).
Scheme 9. Complementary site selectivity of iron- versus rutheni-
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um(II)-catalyzed C H activation. Reaction conditions: [Fe]: FeCl3
(10 mol%), dppe (10 mol%), PhMgBr, DCIB, ZnBr2·TMEDA, THF,
558C, 36 h. [Ru]: [{RuCl2(p-cymene)}2] (2.5 mol%), MesCO2H
(30 mol%), ArBr, K2CO3, toluene, 1208C, 22 h. Ar=4-MeC(O)C6H4.
thereby furnishing the desired products 10 in high yields
(Scheme 10).
In summary, we have reported the development of a novel
family of powerful auxiliaries for the catalyzed activation of
3
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Scheme 7. Iron-catalyzed C(sp ) H arylations.
The selective functionalization of the primary over the
Scheme 10. Removal of the TAM group.
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secondary benzylic C H bond in substrates 7a–f renders an
À
organometallic C H activation mechanism likely to be
2
3
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À
operative. Further support for this hypothesis was gathered
through experiments with the isotopically labeled substrate
[D]5-1n, which led to a considerable kinetic isotope effect
(KIE) of kH/kD ꢀ 1.8 (Scheme 8).
otherwise inert C(sp ) H and C(sp ) H bonds. The triazole-
derived amides were easily accessible in a highly modular
fashion through copper(I)-catalyzed 1,3-dipolar cycloaddi-
tions. The triazole auxiliary proved to be superior to the
hitherto employed bidentate directing groups. Indeed, direct
arylations with inexpensive iron catalysts efficiently pro-
Controlling site selectivity is not only crucial for the
À
development of synthetically meaningful C H functionaliza-
tions,[4,5] but is also mandatory for the late-stage diversifica-
tion of functional molecules in medicinal chemistry, drug
discovery, and material sciences.[17] Hence, it is noteworthy
that we observed a complementary selectivity with N-aryl-
substituted substrates 1e (Scheme 9). Indeed, the judicious
choice of a ruthenium(II) biscarboxylate complex[18] or the
optimized iron catalyst allowed for direct arylations at either
of the two aromatic moieties.
ceeded on arenes and alkenes through chemo-, site-, and
2
À
diastereoselective C(sp ) H bond arylations under mild
reaction conditions. Interestingly, the iron catalysts displayed
a complementary site selectivity compared to a ruthenium(II)
biscarboxylate complex. The versatile iron catalyst also
3
À
enabled high-yielding arylations of unactivated C(sp ) H
bonds. Mechanistic studies provided strong support for an
À
organometallic C H activation by the versatile iron catalyst.
Finally, we were delighted to observe that the TAM
directing group could be easily removed in a traceless fashion,
Received: December 19, 2013
Published online: March 5, 2014
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Keywords: C H activation · chelation · iron · ruthenium ·
triazoles
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À
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À
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À
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3
À
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À
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