Ruthenium catalyzed oxidative annulation with alkynes via cascade C-H/N-H bond functionalizations

Article abstract of DOI:10.1016/j.jorganchem.2014.02.014

Ruthenium(II) complexes catalyzed tandem C-H/N-H bonds functionalizations of 2-phenyl imidazole and its derivatives with alkynes were realized. This transformations allowed for rapid synthesis of isoquinoline derivatives under open-flask condition. Publis

Full text of DOI:10.1016/j.jorganchem.2014.02.014

Journal of Organometallic Chemistry 759 (2014) 33e36
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Ruthenium catalyzed oxidative annulation with alkynes via cascade
CeH/NeH bond functionalizations
*
Rui Wang , J.R. Falck
Department of Biochemistry, Division of Chemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ruthenium(II) complexes catalyzed tandem CeH/NeH bonds functionalizations of 2-phenyl imidazole
and its derivatives with alkynes were realized. This transformations allowed for rapid synthesis of iso-
quinoline derivatives under open-flask condition.
Received 30 November 2013
Received in revised form
11 February 2014
Published by Elsevier B.V.
Accepted 20 February 2014
Keywords:
Oxidative annulation
Isoquinolines
Ruthenium complex
Tandem reaction
2-Phenyl imidazole
1. Introduction
adducts, in sharp contrast to its pre-functionalized precursor syn-
thesis, which is more efficient. CeH functionalization has emerged
Isoquinoline, a heterocyclic aromatic compound, is actually a
structural isomer of quinoline. Firstly isolated in 1885, isoquino-
lines have more than four hundred members till now. Isoquinoline
alkaloids display an extensive range of biological activities such as
anti-malarial, anti-HIV, insect growth retarding anti-tumor, anti-
microbial, anti-leukemic, anti-bacterial, and treatment of Parkin-
son’s disease etc. [1] Considering its structural extensiveness and
biological activities, synthetic effort toward these transformation is
of great importance. As depicted in Scheme 1, considerable medi-
cal/natural molecules (i.e. Janus kinases inhibitor) possess the iso-
quinoline skeleton, which the core framework is the complex
hetero-aromatic part.
Although isoquinolines exist in numerous natural and medical
compounds, a long multi-step synthesis is required in classic
methods [2]. These methods included classic strategies: (i) Bis-
chlereNapieralski reaction; (ii) PicteteGams reaction; (iii) Pictete
Spengler reaction; (iv) PomeranzeFritsch reaction and most
recently, the novel pathways such as formations of C3eC4 and N2e
C3 and/or ring expansion of other ring systems. Another interesting
case is the CeH activation. It directly affords the corresponding
as a versatile tools for the construction of complex molecules. This
strategy is considerable valuable in view of atom-economy and
resource-sustainability over the past several decades [3].
Among this, transition metals catalyzed CeH bonds function-
alizations via oxidative annulations reactions have attracted sig-
nificant research interest, not only because these methods avoid
the multiple steps synthesis of the pre-activated precursors, but
also allow for an overall state-of-the-art molecules constructions,
which make them more valuable in modern organic synthesis.
Pioneering work disclosed by the research groups of Murai and
Satoh (Scheme 2, top) [4], Fagnou [5], and Jones [6] revealed that
rhodium catalysts enabled effective dehydrogenated annulation
reactions of alkynes through chelation assistance [7,8]. This have
set the stage for recently accomplishment of the rhodium catalyzed
isoquinoline synthesis [2f,9]. Notably, the use of inexpensive
ruthenium [3a,10] catalysts for oxidative annulations through
cleavages of CeH bonds have also been reported by Ackermann
et al. (Scheme 2, middle). Recently, the same research group dis-
closed unprecedented ruthenium-catalyzed direct annulations of
alkynes through the chemo- and regio-selective functionalizations
of both CeH and NeH bonds [11].
However, imidazole as an effective directing group and a
useful coupling partner in the tandem CeH/NeH bonds func-
tionalizations via oxidative annulations to construct isoquinoline
derivatives which broadly existing in natural and medical
* Corresponding author. Department of Biochemistry, Division of Chemistry,
University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
E-mail addresses: Rui.wang@UTSouthwestern.edu, shairwang@gmail.com
(R. Wang).
http://dx.doi.org/10.1016/j.jorganchem.2014.02.014
0022-328X/Published by Elsevier B.V.

34
R. Wang, J.R. Falck / Journal of Organometallic Chemistry 759 (2014) 33e36
accomplish such transformations [3a]. This may be due to several
reasons, which can be summarized as follows: first, ruthenium is
less expensive than rhodium; second, ruthenium complexes are air
stable in an open flask; third, with low loading the catalyst, the
transformation can be efficiently accomplished under relatively
mild conditions. With these advantages of ruthenium in mind, we
aim to develop an useful protocol to realize a valuable trans-
formation for the construction of natural products and/or medically
interesting molecules.
2. Experimental section
Considering the advantages of a ruthenium complex, and the
widely existence of isoquinoline derivatives in natural and
medical molecules, we chose 2-phenyl imidazole (1a) as one part
and diphenylacetylene (2a) as corresponding coupling partner in
the transformation of
reaction.
a tandem CeH/NeH bond activation
Scheme 1. Agents featuring core structure of isoquinoline.
As depicted in Table 1, we first investigated different oxidants
(entries 1e6). Copper acetate monohydrate (2.0 equivalent) affor-
ded 3a in 90% conversion and 84% yield (entry 1). A trace amount of
acetylene was not completely consumed. Silver oxide (2.0 equiva-
lent) combined with silver hexafluoroantimonate (30 mol%)
increased the conversion, but only led to 78% isolated yield (entry
2). Interestingly, when the loading in this reaction with p-benzo-
quinone (2.0 equivalent), we observed the best result, which is
obtained in quantitative conversion and 88% isolated yield (entry
3). Other oxidants such as tBuOOBz and DDQ did not provide
promising results (entries 4 and 5). To take into account the solvent
effects, suitable solvents were also screened. For example, when
DMF was replaced by methanol, only 60% conversion of this process
was detected (entry 6). In addition to solvents and oxidants
screening, we also tried to add suitable bases (CsOAc and NaOAc).
However, all these investigations led to negative results (entries 7
and 8). Notably, in control experiment, when the reaction was
conducted without loading of any oxidant, we still observed 60%
conversion (entry 9), which clearly demonstrated the importance
of the oxidant in the transformation. Reaction without addition of
ruthenium complex led to failure [13].
compounds has been investigated rarely (Scheme 2, bottom) [12].
Herein, we wish to reveal our preliminary results in this research
area. That is, ruthenium catalyst mediated oxidative annulations
of 2-phenyl imidazole with acetylene, which is depicted in
Scheme 2.
In all these cases, 2-phenyl imidazole are coupled with various
alkynes, and the corresponding oxidative annulation adducts were
obtained in moderate to good yield. This one pot synthesis of iso-
quinoline derivatives is absolutely valuable, not only because the
rapid construction of complex molecules via atom-economic strat-
egy, but also the structure-diversity achievement in the process.
Fromthe fundamental perspective of modern organic chemistry, the
reduced waste-generation transformations are of high importance.
A more straightforward synthetic strategy is highly appreciated,
instead of tedious procedures requiring pre-functionalized pre-
cursors such as classic halogen or boronic derivatives.
Ruthenium catalyst have recently gained interest in organic
community, which is largely due to its relative low price compared
with rhodium complex. Notably, ruthenium catalyzed cascade Ce
H/NeH bonds functionalizations have been investigated by Acker-
mann et al. in the past decades [3a,11]. To date, the directing groups
(DGs) are required in most of these reactions. Consequently, the
corresponding partners are generated at the ortho-position of the
DGs, with the assistance of transition metals (i.e., Pd, Rh and Cu) to
fulfill this transformation process [8]. Pd or Rh catalyzed trans-
formations either require harsh reaction conditions and/or use of a
high cost of metal [8aef,h,i]. Interestingly, ruthenium catalyzed Ce
H bond activation has emerged as an comprehensive strategy to
Table 1
Optimization conditions.a
Entry Oxidants and additives
Conversion (%)b Yield (%)c
1
2
3
4
5
Cu(OAc)2$H2O (2.0 equiv.)
Ag2O (2.0 equiv.), AgSbF6 (30 mol%)
BQ (2.0 equiv.)
90
100
100
100
100
84
78
88d
20
tBuOOBz (2.0 equiv.)
DDQ (2.0 equiv.)
<5
6
Cu(OAc)2$H2O (2.0 equiv.), MeOH
60
49
7
8
9
Cu(OAc)2$H2O (2.0 equiv.), CsOAc (2.0 equiv.) 60
Cu(OAc)2$H2O (2.0 equiv.), NaOAc (2.0 equiv.) 80
31
42
53
None oxidant
60
a
Conditions: 2-phenyl imidazoles 1a (0.2 mmol), alkynes 2a (0.3 mmol),
[Ru(p-cymene)Cl2] (10 mol%), oxidants (2.0 equiv.), DMF (2.0 mL), 130 ꢀC, 48 h.
b
Conversion based on isolated products.
Yields based on isolated yields.
Isolated yield.
c
d
Scheme 2. TMs catalyzed cascade CeH/NeH bonds activations.

R. Wang, J.R. Falck / Journal of Organometallic Chemistry 759 (2014) 33e36
35
bonds activations are more preferred comparing with tedious pre-
activated strategy. In view of the sustainability chemistry, this one
is valuable, although the later one can be easily realized under
similar reaction condition.
3. Results and discussion
Based upon the preceding results and known transition metal-
catalyzed CeH bond activation/annulation reactions that have
been achieved [14], a plausible mechanism to account for the cur-
rent catalytic process was postulated (Scheme 4).
Ackermann et al. disclosed the pioneering mechanistic studies.
In view of these facts, we assumed a catalytic cycle. The ruthenium
catalyzed oxidative annulation to proceed via CeH/NeH bonds
ruthenation to provide the five-member ring intermediate I, alkyne
insertion to generate II, and subsequent reductive elimination to
afford the isoquinoline 3a. The corresponding Ru(0), is then
oxidized by benzoquinone to Ru(II) to complete this transformation
(Scheme 4).
Scheme 3. Substrates scopes.a aConditions: imidazoles
(0.3 mmol), [Ru(p-cymene)Cl2] (10 mol%), BQ (2.0 equiv.), DMF (2.0 mL), 130 ꢀC, 48 h. b
Isolated yield. Based on NOESY experiments. No direct evidence was detected base
on NOESY experiment, see supporting information.
1 (0.2 mmol), alkynes 2
c
d
With the optimized reaction conditions in hand, we next
expanded the substrates scope as shown in Scheme 3. First, sym-
metric alkynes provided desired product in moderate isolated
yields. That is, diphenylacetylene (3a), dimethyl acetylene-
dicarboxylate (3b) and dipropylacetylene (3c), all of these al-
kynes, whether aryl alkyne (3a) or alkyl alkynes (3b, 3c), proceeded
successfully under standard conditions to afford the corresponding
dehydro-coupling products in moderate to good yields. Generally,
electron-withdrawing groups such as phenyl acetylene (3a) pro-
vided better yield than electron-donating group (i.e., 3c). Second,
asymmetric acetylenes afforded complicated results (3d, 3e, 3f and
3g). The dehydrogenative coupling product (3d) can be obtained in
86% isolated yield. The regioselectivity was confirmed by corre-
sponding NOESY NMR spectral evidence. Not surprisingly, ethyl
phenyl acetylenecarboxylate afforded coupled product (3e) with
similar regioselectivity, but only in 74% isolated yield. However, the
assignment of regiochemistry by the NOESY experiment was not
obvious, thus the stereochemistry was postulated as shown in
Scheme 3. Phenyl propylacetylene only provided the corresponding
isoquinoline (3f) in 47% yield. The NOESY spectrum directly indi-
cated that there were several kinds of cross-peaks from NOE in-
teractions between the protons of alkyl group and the protons in
the benzene group of the 2-phenyl imidazole. Phenyl butylacety-
lene gave the corresponding isoquinoline (3g) in 50% yield, a
similar NOESY experiment confirmed the stereochemistry.
4. Conclusion
In conclusion, we have developed the ruthenium catalyzed
oxidative annulation reactions of alkynes with 2-phenyl imidazole,
which provided efficient access to various isoquinolines. The
valuable of this inexpensive catalytic process is represented by its
remarkably high chemo- and regioselectivity. Based on relevant
mechanistic studies on this CeH/NeH bonds functionalizations
process, the current transformations afford evidence for a rate-
limiting CeH bond metalation, a striking difference to known
rhodium catalyzed isoquinoline syntheses [8aef]. Furthermore, it is
noteworthy that the ruthenium catalyst converts electron-deficient
alkynes with increased efficacy and leads to improved isolated
yields. Further applications of ruthenium catalyzed oxidative CeH
bond functionalizations are ongoing in our laboratories, and will be
reported in due course.
Interestingly, one intelligible case was also investigated (Eq. (1)).
The cascade reaction was realized via catalytic ruthenium complex
under standard reaction conditions. The estimated bond dissocia-
tion energies of C(aryl)eH bond and C(aryl)eBr bond are 472 kJ/mol
and 336 kJ/mol, respectively. This intuitively indicates that the
cleavage of C(aryl)eBr bond is expected. Actually, upon completion
of the reaction, we examined the crude product via LC-MS, sur-
prisingly, no characteristic bromo-containing compound was
detected. That is, the competition between the hydrogen and
bromo is dominated by the strong bond. After purification, the
dominant process afforded coupling product 3h in 60% isolated
yield. This case straightforward indicated that the direct CeH/NeH
Scheme 4. Plausible mechanism pathway.

36
R. Wang, J.R. Falck / Journal of Organometallic Chemistry 759 (2014) 33e36
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