Ruthenium-Catalyzed Peri- and Ortho-Alkynylation with Bromoalkynes via Insertion and Elimination

Article abstract of DOI:10.1021/acs.orglett.7b02655

The alkynylation of naphthols takes place with total regiocontrol at the peri position of the hydroxyl group in the presence of [RuCl₂(p-cymene)]₂ as the catalyst. This reaction features high functional group tolerance. The related o

Full text of DOI:10.1021/acs.orglett.7b02655

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Peri- and Ortho-Alkynylation with
Bromoalkynes via Insertion and Elimination
†
†
†
†
́
Eric Tan, Andrey I. Konovalov, Gabriela A. Fernandez, Ruth Dorel,
,
†,‡
and Antonio M. Echavarren*
†Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007
Tarragona, Spain
‡
̀
Departament de Química Analítica i Química Organica, Universitat Rovira i Virgili, C/Marcel·li Domingo s/n, 43007 Tarragona,
Spain
*
S Supporting Information
ABSTRACT: The alkynylation of naphthols takes place with total regiocontrol at the peri position of the hydroxyl group in the
presence of [RuCl (p-cymene)] as the catalyst. This reaction features high functional group tolerance. The related ortho-
2
2
alkynylation of benzoic acids proceeds under similar conditions and also shows wide functional group tolerance. Both reactions
proceed through metalation, insertion of the alkyne, and bromide elimination.
ollowing the pioneering work of Miura on the Pd-catalyzed
Table 1. Ruthenium-Catalyzed Peri C−H Alkynylation:
1
a
F
peri (C-8) arylation of naphthols with iodoarenes, many
Deviation from Optimized Conditions
2
,3
other related transformations have been developed. The
reaction of symmetrical disubstituted alkynes with 1-naphthols in
the presence of Rh(III) catalysts leads to benzo[de]chromenes
by C−C bond formation at the peri position followed by
4
,5
cyclization. Benzo[de]chromenes can also be obtained from 1-
6
naphthols using [RuCl (p-cymene)] as the catalyst. The metal-
2
2
catalyzed chelation-assisted ortho-alkynylation of aromatic
b,c
7
entry
variation from the “standard conditions”
yield (%)
compounds has been performed with haloalkynes and with
8
,9
1
2
3
4
5
6
7
8
9
none
95 (92)
ethynylbenziodoxolone reagents (EBX). Among the weakly
10
under Ar
in MeCN
95
25
10
0
coordinating directing groups, carboxylic acids have been the
1
1,12
most important.
with internal alkynes leads to isocoumarins.
alkynylation of benzoic acids with (bromoethynyl)-
Ru(II)-catalyzed reaction of benzoic acids
13,14
without K CO3
2
Recently, the
without K CO and NaOAc
2
3
15
16
[Cp*RhCl ] instead of [Ru]
17
32
0
2
2
triisopropylsilane has been reported with Ir and Ru catalysts.
Here, we report the first peri-alkynylation of readily available
naphthols with bromoalkynes using [RuCl (p-cymene)] as the
[Cp*IrCl ] instead of [Ru]
2
2
Cp*Co(CO)I instead of [Ru]
2
2
2
Pd(OAc) instead of [Ru]
0
2
catalyst, which proceeds without cyclization at temperatures
lower than those required for most peri-functionalizations
catalyzed by late transition metals (typically 110 °C).
Furthermore, although the reaction is carried out in the presence
of a mild base, the competitive formation of (Z)-2-bromovinyl
1
0
with TIPS-EBX instead of 2a
0
a
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), K CO (1
2
3
equiv), NaOAc (0.2 equiv), [RuCl (p-cymene)] (5 mol %), air, 14 h.
Yield determined by H NMR using dodecane as internal standard.
Isolated yield in parentheses. TIPS-EBX: 1-{[tris(1-methylethyl)-
2
2
b
1
c
1
7
phenyl ethers was not observed.
silyl]ethynyl]}-1,2-benziodoxol-3(1H)-one.
Under the optimal reaction conditions using [RuCl (p-
2
cymene)] as the catalyst, 1-naphthol (1a) reacted with TIPS-
protected bromoacetylene (2a) in 1,2-dichloroethane (DCE) to
2
(
Table 1, entries 4 and 5). In the presence of other metal
complexes, the reaction did not take place satisfactorily (Table 1,
give peri-alkynylated derivative 3a in excellent yield at 40 °C in
1
the presence of K CO and NaOAc (Table 1, entry 1). The
2
3
reaction could be carried out in the presence of air (Table 1,
Received: August 29, 2017
entries 1 and 2) and required a stoichiometric amount of K CO3
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entries 6−9). No reaction was observed with TIPS-EBX instead
of 2a (Table 1, entry 10).
reaction of acetal protected 1,4,5-trihydroxynapthalene 1v with
2a afforded binaphthol 3v as a result of the oxidative dimerization
of the electron-rich naphthol. The structure of 3i was confirmed
Reaction of 1a with TMS- (2b) and TES-protected
bromoacetylene (2c) gave 3a and 3a in lower yields (Scheme
18
by X-ray diffraction.
2
3
1). Similarly, reaction of 1a with 1-bromo-3,3-dimethylbut-1-yne
Alkynylation of 4-hydroxycoumarin (1x) afforded 3x in 66%
yield. The reaction can also be applied for the alkynylation of
Scheme 1. Ruthenium-Catalyzed Peri C−H Alkynylation of
nitrogen heterocycles, which are often problematic substrates in
a
11m,19
Naphthols
C−H functionalizations.
Thus, 4-hydroxyquinolines 1y,z
gave rise to 3y,z, whereas decoquinate (1aa) led to 3aa in an
example of late-stage functionalization of a pharmaceutical
compound.
In contrast to the known formation of benzo[de]chromenes by
6
-endo-dig cyclization in metal-catalyzed reactions of 1-naphthols
4
,6
with internal alkynes, the cyclization of 3a with gold(I)
1
proceeds in a 5-exo-dig manner to form naphtofuranylidene 5,
18
whose structure was determined by X-ray diffraction (Scheme
).
2
Scheme 2. Synthesis of Naphthofuranylidene 5 and
Fluoranthenes 8,9
a
[
LAuL′]X = [(2,4-tBu C H O) PAuNCMe]SbF .
2
6
3
3
6
The hydroxy group can be used as a handle for the formation
of C−C bonds via the corresponding triflates. Thus, we prepared
benzo[k]fluoranthene (8) in three steps from aryl triflate 6 by
Suzuki cross-coupling to give 7a, desilylation, and [4 + 2]
20
intramolecular cycloaddition of 7b (Scheme 2). As a second
1
c,21
a
example in the context of fluoranthene synthesis,
[
overall yield.
benzo-
Reaction conditions: 1a−u (0.2 mmol), K CO (1 equiv), NaOAc
2
3
5,6]indeno[1,2,3-cd]pyrene (9) was obtained from 3s in 10%
(
(
0.2 equiv), [RuCl (p-cymene)] (5 mol %), 2a−d (1.2 equiv), DCE
2
2
b c
1.5 mL), 40 °C, air, 14 h. 7 mmol scale. KOAc (2 equiv) instead of
d
e
f
g
Under conditions similar to those developed for the peri-
alkynylation, but using tert-amyl alcohol as the solvent at 90 °C,
benzoic acids were alkynylated at the ortho position in a general
manner (Scheme 3). These conditions allow the alkynylation
with a broad scope. Indeed, the reaction tolerates a wide range of
functional groups including halides (11a,b, 11i,j, 11m,n),
hydroxyl groups (11c, 11o, 11y), nitro (11q), thioether (11r),
carbonyl (11f,g, 11v), ester (11x), and nitrile (11u). Products of
double alkynylation (11h−k, 11m−x, 11ac) were obtained for
substrates with two free ortho positions, although 10l with a tert-
butyl group at meta gave monoalkynylated 11l as the major
compound. Carboxylic acid derivatives of many heterocyclic
systems, including thiophenes, benzothiophenes, benzofurans,
indoles, pyrazoles, pyridines, and quinolines were also
alkynylated to give the corresponding products 11ad-ar in
K CO and NaOAc (0.2 equiv). 60 °C. 95 °C. 110 °C. 2a (2.2
equiv) and K CO (2.0 equiv) and NaOAc (0.4 equiv).
2
3
2
3
(2d) gave 3a in 40% yield. Reaction with 1-bromo-1-octyne,
4
bromophenylacetylene, or TBS-protected 3-bromo-1,1-diphe-
nylprop-2-yn-1-ol did not lead to alkynylated products. Under
the conditions optimized for the formation of 3a , or using
1
slightly different conditions, naphthols 1b−r bearing a wide
range of substituents and pyren-1-ol (1s) provided alkynylated
products 3b−s in 41−93% yields. Hydrogen-bonded naphthols
1
e and 1r with o-keto or ester groups reacted uneventfully.
Similarly, free NH (3n) and OH (3o) groups were well
2
tolerated. The double alkynylation of 1,5-dihydroxynaphthalenes
1
t,u afforded products 3t,u in 43−45% yields. On the other hand,
B
DOI: 10.1021/acs.orglett.7b02655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Ruthenium-Catalyzed Ortho C−H Alkynylation of
selectively to 11ar. The structures of 11h, 11af, 11aj, and 11aq
were confirmed by X-ray diffraction.
a
18
Benzoic Acids
The C−H ruthenation has been proposed to be the rate-
13
determining step, which is supported by DFT calculations in
the reaction of [Ru(p-cymene)(OAc) ] with diphenylacety-
2
22
lene. According to our DFT data, this is also the case for the
1
8,23
peri-alkynylation reaction (Scheme 4).
Thus, I leads to
Scheme 4. Simplified Mechanism of the Ru-Catalyzed Peri-
a
Alkynylation Based on DFT Calculations
aValues in parentheses are free energies in kcal·mol−1 (T = 298.15 K)
ruthenacycle II by acetate-assisted C−H activation via TS
I−II
⧧
−1
(
ΔG = 19.9 kcal·mol ), which is followed by dissociative ligand
substitution through a coordinatively unsaturated complex (not
shown) to form III. Alternative ortho-ruthenation was also
considered and ruled out on the basis of higher activation energy
⧧
−1
(
ΔG = 26.0 kcal·mol ). Subsequent alkynylation proceeds via
⧧
−1
insertion to produce IV (ΔG = 13.5 kcal·mol ), which then
undergoes KOAc-assisted bromide elimination from V with a
minimal barrier of 0.5 kcal·mol− to furnish VI and VII. Exchange
with the potassium salt of the starting naphthol liberates the
product of peri-alkynylation and closes the catalytic cycle. The
C−C bond formation via oxidative addition of the C−Br bond to
1
⧧
the Ru(II) center was found to be much less likely (ΔG = 31.7
−1
kcal·mol ). Calculations for the benzoic acid show similar
activation barriers 20.0 and 13.7 kcal/mol for C−H activation
a
Reaction conditions: 10a−at (0.2 mmol), K CO (0.5 equiv),
2
3
23
[
RuCl (p-cymene)] (5 mol %), 2a (1.2 equiv), tert-amyl alcohol
and alkyne insertion, respectively.
2
2
b
c
d
(
1.5 mL), 90 °C, air, 14 h. 10 mmol scale. 70 °C. 2a (2.2 equiv)
In summary, we have found that the peri-alkynylation of
naphthols takes place in a general manner with total regiocontrol
and high functional group tolerance in the presence of
commercially available [RuCl (p-cymene)] as the catalyst. In
e
and K CO (1.0 equiv) MeI (5 equiv), K CO (2 equiv), and MeCN
2
3
2
3
f
added after 14 h. 120 °C and KHCO (0.5 equiv) instead of K CO .
3
2
3
g
h
K CO (1 equiv). K CO (1.5 equiv).
2
3
2
3
2
2
most cases, the peri-alkynylation can be performed at 40−95 °C.
Under similar conditions, benzoic acids are ortho-alkynylated.
Both reactions can be applied to heterocyclic substrates,
including those containing basic nitrogen. Application of these
results for the synthesis of large polyarenes is underway.
moderate to good yields. As an exception, the alkynylation of 2-
hydroxynicotinic acid (10an) had to be performed at higher
temperature (120 °C). Under the developed conditions, the late
stage functionalization of analgesic niflumic acid (10ar) led
C
DOI: 10.1021/acs.orglett.7b02655
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
■
*
Rassias, G.; Larrosa, I. Chem. Sci. 2014, 5, 3509−3514. (e) Arroniz, C.;
Ironmonger, A.; Rassias, G.; Larrosa, I. Org. Lett. 2013, 15, 910−913.
E-mail: aechavarren@iciq.es.
ORCID
(f) Wu, Z.; Chen, S.; Hu, C.; Li, Z.; Xiang, H.; Zhou, X. ChemCatChem
2013, 5, 2839−2842. (g) Zhu, C.; Zhang, Y.; Kan, J.; Zhao, H.; Su, W.
Org. Lett. 2015, 17, 3418−3421. (h) Qin, X.; Li, Z.; Huang, Q.; Liu, H.;
Wu, D.; Guo, Q.; Lan, J.; Wang, R.; You. Angew. Chem., Int. Ed. 2015, 54,
Ruth Dorel: 0000-0002-8617-8648
Antonio M. Echavarren: 0000-0001-6808-3007
Notes
7
167−7170. (i) Huang, L.; Hackenberger, D.; Gooßen, L. J. Angew.
Chem., Int. Ed. 2015, 54, 12607−12611. (j) Pichette Drapeau, M.;
Gooßen, L. J. Chem. - Eur. J. 2016, 22, 18654−18677. (k) Simonetti, M.;
Cannas, D. M.; Panigrahi, A.; Kujawa, S.; Kryjewski, M.; Xie, P.; Larrosa,
I. Chem. - Eur. J. 2017, 23, 549−553. (l) Huang, L.; Weix, D. J. Org. Lett.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the European Research Council (Advanced Grant No.
21066), MINECO/FEDER, UE (CTQ2016-75960-P), MINE-
CO-Severo Ochoa Excellence Accreditation 2014-2018, SEV-
013-0319), and CERCA Program/Generalitat de Catalunya for
■
3
2
016, 18, 5432−5435. (m) Johnston, A. J. S.; Ling, K. B.; Sale, D.;
Lebrasseur, N.; Larrosa, I. Org. Lett. 2016, 18, 6094−6097. (n) Biafora,
A.; Krause, T.; Hackenberger, D.; Belitz, F.; Gooßen, L. J. Angew. Chem.,
Int. Ed. 2016, 55, 14752−14755. (o) Mei, R.; Zhu, C.; Ackermann, L.
Chem. Commun. 2016, 52, 13171−13174. (p) Mandal, R.; Sundararaju,
B. Org. Lett. 2017, 19, 2544−2547.
2
financial support. We also thank the ICIQ X-ray diffraction unit
and CELLEX-ICIQ HTE laboratory.
(
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D
DOI: 10.1021/acs.orglett.7b02655
Org. Lett. XXXX, XXX, XXX−XXX