Weak O-Assistance Outcompeting Strong N,N-Bidentate Directing Groups in Copper-Catalyzed C?H Chalcogenation

Article abstract of DOI:10.1002/chem.201601821

A copper-mediated C?H chalcogenation of triazoles has been achieved by weak coordination. The user-friendly protocol showed high functional-group tolerance and ample substrate scope, yielding fully substituted 1,2,3-triazoles with complete positional site-selectivity. The C?H selenylation could likewise be achieved by means of copper catalysis. Our findings highlight for the first time that weak O-coordination can outcompete the strong N,N-bidentate coordination mode in C?H functionalization technology.

Full text of DOI:10.1002/chem.201601821

DOI: 10.1002/chem.201601821
Communication
&
CÀH Functionalization
Weak O-Assistance Outcompeting Strong N,N-Bidentate Directing
Groups in Copper-Catalyzed CÀH Chalcogenation
Gianpiero Cera and Lutz Ackermann*[a]
CuAAC and CÀH functionalization technology constitutes an
Abstract: A copper-mediated CÀH chalcogenation of tria-
zoles has been achieved by weak coordination. The user-
friendly protocol showed high functional-group tolerance
and ample substrate scope, yielding fully substituted
1,2,3-triazoles with complete positional site-selectivity. The
CÀH selenylation could likewise be achieved by means of
copper catalysis. Our findings highlight for the first time
that weak O-coordination can outcompete the strong N,N-
bidentate coordination mode in CÀH functionalization
technology.
attractive alternative to traditional CuAAC protocols.[5,6] Aryl
chalcogenides are ubiquitous in material science and in bioac-
tive organic compounds.[7] However, syntheses of sulfur- and
selenium-containing compounds are often challenging, be-
cause the required chalgonide reagents inhibit effective cataly-
sis by poisoning the active metal species. Recent progress was
represented by the direct introduction of chalcogenides by
means of CÀH functionalization strategies[8] in order to over-
come the limitations of traditional metal-catalyzed cross-cou-
pling methods.[9] Therefore, we became attracted to develop-
ing a site-selective protocol for merging CuAAC click-chemistry
with atom-economical CÀH chalcogenation by late-stage diver-
sification.[10] In this context, our group has developed, in the
past few years, a new family of bidentate 1,2,3-triazole TAM
auxiliaries for the selective ortho-CÀH functionalization using
inexpensive metal catalysts.[11] Hence, we disclosed iron-cata-
lyzed CÀH activations exploiting the strong bidentate binding
motif.[11a] Within our program on copper-mediated CÀH func-
tionalizations,[12] we have now observed the CÀH chalcogena-
tion on 1,2,3-triazoles by weak[13] O-monodentate assistance,
counterintuitively overriding a strong N,N bidentate[14] chela-
tion assistance (Figure 2). Notable features of our findings in-
clude: i) the use of an inexpensive copper catalyst, ii) effective
CÀH sulfenylation and selenylation, iii) step-economical access
to fully substituted triazoles, and iv) the unprecedented weak
O-coordination outcompeting the N,N-bidentate directing
group.
Fully functionalized 1,2,3-triazoles constitute a privileged struc-
tural motif in various applied areas, inter alia present in medici-
nal chemistry and material sciences as well as in pharmaco-
phores of numerous bioactive compounds.[1] For instance, car-
boxylamidotriazole I (CAI) shows anticancer activity,[2a] the
sulfur-containing triazole II is a potential herbicide with anti-
fungal activity,[2b] and triazole III is a powerful ligand in asym-
metric catalysis (Figure 1).[2c]
Figure 1. Important C5-functionalized triazoles I, II, and III.
The copper(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddi-
tion (CuAAC) is widely recognized as the most efficient tool to
access 1,2,3-triazoles with high levels of chemo- and regiocon-
trol.[3] However, except a few rare examples,[4] this methodolo-
gy continues to be severely restricted to terminal alkynes and
thus fails short in providing a platform for the selective synthe-
sis of fully functionalized 1,2,3-triazoles. Therefore, the nexus of
Figure 2. Weak (O) coordination overrides strong (N,N) bidentate motif.
[a] Dr. G. Cera, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
At the outset of our studies, we probed the CÀH selenyla-
tion of N-(triazolyl)-anilide 1a in the presence of Cu(OAc)2 and
Ph2Se2 (Table 1, entry 1). Interestingly, the CÀH selenylation of
substrate 1a exclusively proceeded at the C5 position of the
triazole moiety through the weakly coordinating O-bonding
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601821.
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Table 1. Optimization of CÀH chalcogenation by weak coordination.[a]
Entry
[TM]
Base
Yield [%]
1
2
Cu(OAc)2
–
K2CO3
K2CO3
39
–
3
4
5
6
7[b]
8[b]
9[b]
10[b]
11
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuTc
K2CO3
50
52
47
59
81
70
58
–
Li2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
CuCl
CuI
Pd(OAc)2 (5 mol%)
–
[a] General reaction conditions: 1a (0.2 mmol), Ph2Se2 (0.4 mmol), [Cu]
(0.1 mmol), base (0.2 mmol), DMSO (0.2m), air, 1308C, 16 h. [b] DMSO
(0.2m).
Scheme 2. Scope of CÀH selenylation with triazoles 1.
motif. Among a variety of copper salts, CuOAc gave optimal
results, particularly with Na2CO3 as the base, affording product
3a in 59% yield (entries 1–6). The performance of the CÀH se-
lenylation could further be improved by increasing the concen-
tration (entry 7). Other copper(I) salts provided less satisfactory
results (entries 8 and 9), and CuI failed to convert substrate
1 (entry 10). It is also worth noting that Pd(OAc)2 was found to
be entirely ineffective for the CÀH functionalization under oth-
erwise identical reaction conditions (entry 11), highlighting the
challenging nature of the CÀH selenylation approach.
such as cyano, ester, and nitro substituents. Likewise, aryl bro-
mides (1j) and chlorides (1n) were fully accepted without any
sign of cross-coupling byproducts. The CÀH selenylation strat-
egy further proved amenable to heterocyclic substrates, includ-
ing pyridine, indoline, and thiophene derivatives 1r–1t.
Thereafter, we investigated the CÀH selenylation with struc-
turally diverse diselenides 2 (Scheme 3). Hence, electron-donat-
ing and -withdrawing groups at the para-, meta-, and ortho-po-
sition were well tolerated by the optimized reaction condi-
tions. Notably, the protocol was not restricted to aromatic dise-
lenides 2. Indeed, heteroaryl and alkyl derivatives 2z and 2aa
were also efficiently converted as well to deliver products 3z
and 3aa, respectively.
With the optimized CÀH selenylation being established, its
versatility was probed with differently substituted triazoles
1 (Scheme 1). Although secondary amides 1b and 1c efficient-
ly delivered the desired products 3b and 3c, respectively, terti-
ary amide 1d failed short in providing the desired product 3d,
as did aryl- or monosubstituted triazoles 1e and 1 f, respec-
tively. These findings provided strong support for the chelation
assistance regime.
Scheme 3. CÀH functionalization with diselenides 2.
Scheme 1. CÀH selenylation by weak coordination.
The robustness of the widely applicable protocol also ena-
bled the challenging CÀH sulfurylation on substrates
1 (Scheme 4), again with weak O-coordination overriding the
bidentate N,N-coordination mode.
The optimized protocol proved to be widely applicable to
the CÀH selenylation of various triazole-functionalized anilides
1 (Scheme 2). The robust nature of the CÀH selenylation was
reflected by the tolerance of sterically hindered substrates as
well as synthetically useful electrophilic functional groups,
In consideration of the unique features of the CÀH chalcoge-
nation by preferential weak O-coordination, we became in-
trigued by delineating its mode of action. To this end, reac-
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Scheme 4. CÀH sulfurylation by weak O-coordination.
tions with the well-defined copper(I) selenide PhSeCu (6a) as
the selynylation reagent furnished the desired product 3a
under an atmosphere of air (Scheme 5a). Furthermore, the stoi-
chiometric use of the radical inhibitors 2,2,6,6-tetramethylpi-
peridine N-oxide (TEMPO) and butylated hydroxytoluene (BHT)
led to a slight, yet notable decrease in efficacy (Scheme 5b).
Finally, the CÀH selenylation proved viable with catalytic
amounts of CuOAc provided that PhI(OAc)2 was employed as
the additive (Table 2).
Scheme 6. Catalytic CÀH selenylation by weak O-coordination.
copper(I)-promoted CÀH chalcogenations were viable by an
amide assistance, furnishing fully decorated 1,2,3-triazoles with
excellent chemo- and positional selectivities. The optimized
protocol proved broadly applicable to CÀH selenylation as well
as CÀH sulfenylation with ample scope, and was accomplished
by means of cost-effective copper catalysis though weak O-as-
sistance.
Acknowledgements
Generous support by the Alexander von Humboldt-foundation
(fellowship to G. C.) and the European Research Council under
the Seventh Framework Program of the European Community
(FP720072013; ERC Grant Agreement No. 307535) is gratefully
acknowledged.
Scheme 5. Mechanistic studies.
Table 2. Copper(I)-catalyzed CÀH selenylation.[a]
Keywords: CÀH activation
sulfenylation · triazoles
·
copper
·
selenylation
·
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Cu(OAc)2
CuOAc
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MnO2
PhI(OTFA)2
PhI(OAc)2
PhI(OAc)2
42
34
–
38
72
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broadly applicable (Scheme 6). Hence, a variety of substituted
diselenides 2 enabled the site-selective CÀH functionalization
on substrates 1 by weak mono O-coordination (Scheme 3).
In summary, we have shown that the weak monodentate O-
assistance can outcompete strong N,N-bidentate directing
groups in catalyzed CÀH activation technology. Thus, efficient
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Received: April 18, 2016
Published online on May 12, 2016
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