Ruthenium-Catalyzed Tandem Carbene/Alkyne Metathesis/N-H Insertion: Synthesis of Benzofused Six-Membered Azaheterocycles

Article abstract of DOI:10.1021/acs.orglett.0c00596

The Cp*RuCl-based catalyst enables expedient access to a variety of benzofused six-membered azaheterocycles from unprotected o-alkynylanilines and trimethylsilyldiazomethane through an unprecedent tandem carbene/alkyne metathesis/N-H insertion reaction. The transformation takes place under mild reaction conditions (room temperature, <15 min) and with excellent functional group tolerance. The synthetic utility of the final products and a mechanistic rationale are also discussed.

Full text of DOI:10.1021/acs.orglett.0c00596

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Letter
Ruthenium-Catalyzed Tandem Carbene/Alkyne Metathesis/N−H
Insertion: Synthesis of Benzofused Six-Membered Azaheterocycles
́
́
́
Damian Padín, Jesus A. Varela,* and Carlos Saa*
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ABSTRACT: The Cp*RuCl-based catalyst enables expedient access to a
variety of benzofused six-membered azaheterocycles from unprotected o-
alkynylanilines and trimethylsilyldiazomethane through an unprecedent
tandem carbene/alkyne metathesis/N−H insertion reaction. The trans-
formation takes place under mild reaction conditions (room temperature,
<15 min) and with excellent functional group tolerance. The synthetic utility
of the final products and a mechanistic rationale are also discussed.
andem processes involving catalytic metal carbenes have
proved to be useful strategies for the rapid generation of
carbamate, or sulfonamide,7,8 thus leading to less atom-
economical processes.
T
molecular complexity.1 In particular, the in situ generation of
metal vinyl carbenes through carbene/alkyne metathesis
(CAM) represents a versatile route for alkyne bifunctionaliza-
tion.2 These intermediates are known to react with olefins to
give dienes3 (Scheme 1a) or vinyl cyclopropa(e)nes4 (Scheme
We now report our efforts in the development of the first
tandem carbene/alkyne metathesis coupled to an intra-
molecular N−H insertion, leading to unprotected benzofused
six-membered azaheterocycles,9 which are privileged scaffolds
present in a myriad of bioactive compounds and natural
products (Figure 1).10,11
Scheme 1. Reactivity Pattern of Metal Vinyl Carbenes
Formed through CAM
o-Alkynylaniline 1a, an unprotected primary aromatic amine,
was synthesized and subjected to our previously reported
1b) with nucleophiles to afford ylide intermediates5 (Scheme
1c) or with C−H bonds to give new C−C bonds6 (Scheme
1d). However, as far as we know, a tandem CAM process
ending up in a N−H insertion reaction has never been
reported (Scheme 1e).
The development of such a tandem process is challenging.
The coexistence of two metal carbenes (a and b in Scheme 1)
in the reaction media may lead to competitive processes such
as dimerizations or unselective N−H insertions. In addition,
current methodologies for intramolecular N−H insertions
typically require the amine to be protected as an amide,
Figure 1. Selected bioactive compounds and natural products.
Received: February 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00596
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
conditions for aliphatic secondary amines (Table 1, entry 1).5f
Gratifyingly, 3-vinyldihydrobenzoxazine 2a was selectively
Scheme 2. Scope and Functional Group Tolerance for the
Tandem CAM/N−H Insertion of O-Tethered o-
a
Alkynylanilines
a
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from standard conditions
product/yield (%)
1
2
3
4
none
2a/77
cd
,
5 mol % Rh2(OAc)4 instead of Cp*RuCl(cod)
5 mol % Rh2(esp)2 instead of Cp*RuCl(cod)
[Cp*Ru(CH3CN)3]PF6 instead of
Cp*RuCl(cod)
3a/15
cd
,
3a/8
3a + 4a/n.d.
c
5
6
7
8
EtO2CCHN2 instead of TMSCHN2
[Cp*RuCl]4 instead of Cp*RuCl(cod)
THF/MeOH/iPrOH/CH3CN instead of DCM
7.5 mol % of Cp*RuCl(cod)/DCE reflux/
2 mmol scale
complex mixture
c
2a/60
2a + 5a/10−31
c
2a/73
a
Reaction conditions: 1a (0.2 mmol), TMSCHN2 (1.5 equiv), and
b
solvent (0.15 M) with the indicated catalyst at rt. Isolated yields.
c
d
Incomplete consumption of 1a was observed. Slow addition of the
diazo compound over 1 h.
formed in 77% yield as a single Z stereoisomer12 in <10 min
of reaction at room temperature. A direct comparison between
the Cp*RuCl(cod) precatalyst and traditional Rh(II) catalysis
(Rh2(OAc)4, entry 2 and Rh2(esp)2, entry 3) highlights the
virtues of the half-sandwich ruthenium complex in promoting
CAM rather than direct N−H insertion. In fact, the reaction
proved to be very sensitive to the electronic nature of the
ruthenium precatalyst and the diazo compound as the use of
the cationic analog [Cp*Ru(CH3CN)3]PF6 (entry 4) or ethyl
diazoacetate (entry 5) gave rise to a mixture of the desilylated
product 4a together with minor amounts of the direct N−H
insertion product 3a and a complex mixture, respectively. The
use of the tetranuclear complex [Cp*RuCl]4 afforded a similar
result as Cp*RuCl(cod), but an incomplete consumption of 1a
was observed (entry 6), probably due to a faster deactivation of
the catalyst. The nature of the solvent also proved to be crucial
as the employment of more polar (protic and aprotic) solvents
led to low conversions (entry 7) and the formation of side
products of type 5a. Pleasingly, we discovered that it is possible
to scale up the reaction to 2 mmol and diminish the catalyst
loading from 10 to 7.5 mol % by using 1,2-dichloroethane as a
solvent at reflux (entry 8).
Having established the optimal reaction conditions for the
tandem CAM/N−H insertion reaction, we decided to explore
the scope and limitations of our methodology. First, O-
tethered o-alkynylanilines were tested (Scheme 2). The
cascade reaction tolerates any substitution pattern on the
aromatic ring, affording the corresponding 1,4-benzoxazines
2a−d from moderate to good yields. Substitution at the
propargylic position was also tolerated, albeit benzoxazine 2e
was obtained as a 1:1 mixture of diastereomers in 54% yield.13
Remarkably, the reaction proceeded with excellent chemo-
selectivity in the presence of a wide range of functional groups
such as halides (2g and 2h), ethers (2i), unprotected anilines
(2j), esters (2k), internal alkynes (2l), or terminal olefins
a
Conditions: Method A: 1 (0.2 mmol), TMSCHN2 (1.5 equiv),
CH2Cl2 (0.15 M), and Cp*RuCl(cod) (10 mol %) at rt for 10−15
min. Method B: Same conditions as method A but using 7.5 mol % of
Cp*RuCl(cod) and DCE as a solvent at reflux for 15 min.
(2m). Considering the slight excess of TMSCHN2 used for
this transformation, one might expect further evolution of the
final products 2 through N−H insertion of the resulting
secondary aniline, unselective N−H insertion with the primary
aniline 2j, CAM with the internal alkyne 2l, or metathesis/
cyclopropanation with the terminal olefin 2m; however, none
of these side reactions were detected in the analysis of the
crude mixtures.
The extension of the tandem CAM/N−H insertion to the
synthesis of other kinds of six-membered heterocycles was
subsequently analyzed (Scheme 3). To our delight, the
cyclization reaction allowed access to a variety of function-
alized tetrahydroquinoxalines (2n−p) and indoloquinoxalines
(2q), dihydrobenzothiazines (2r), or tetrahydroquinolines
(2s) from moderate to good yield. These results further
exemplify the excellent functional group tolerance toward
carbamates, sulfonamides, heteroaromatic systems, thioethers,
or silylethers. Curiously, these results are in striking contrast
with our previous experience with secondary benzylamines in
the tandem CAM/ylide rearrangement, where N-, S-, or C-
tethered o-alkynylamines were not tolerated.5f
According to precedent literature and the experimental
observations, a tentative mechanism was proposed (Scheme
4). The Cp*RuCl(cod) precatalyst would react with the diazo
compound to generate a ruthenium carbene that readily
coordinates to the o-alkynylaniline 1 (I). A chemo- and
B
https://dx.doi.org/10.1021/acs.orglett.0c00596
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
The presence of a versatile unprotected allylaniline
functionality in the cyclized products 2 led us to explore
some manipulations to prove their synthetic utility as potential
building blocks for organic synthesis (Scheme 5). First, the
Scheme 3. Scope and Functional Group Tolerance for the
Tandem CAM/N−H Insertion of Carbon- and Heteroatom-
a
Tethered o-Alkynylanilines
a
Scheme 5. Derivatization of Benzoxazine 2a
a
Conditions: (i) 1a (0.2 mmol), TMSCHN2 (1.5 equiv), Cp*RuCl-
(cod) (10 mol %) in CH2Cl2 (0.15 M) at rt for 10 min, then, the
corresponding allyl bromide (RCH = CH−CH2Br) was added (1.5
equiv) and stirred for 6−12 h. (ii) 2a (1 mmol), TBAF (1.5 equiv) in
THF (0.5 M) at reflux for 15 h.
a
Conditions: Method A: 1 (0.2 mmol), TMSCHN2 (1.5 equiv),
CH2Cl2 (0.15 M), and Cp*RuCl(cod) (10 mol %) at rt for 10−15
min. Method B: The same conditions as method A but using 7.5 mol
% of Cp*RuCl(cod) and DCE as the solvent at reflux for 15 min. No
full conversion of o-alkynylaniline 1q was observed.
mild conditions required for the cyclization enabled the one-
pot/base-free allylation of the secondary aniline 2a to afford
the corresponding bis-allylaniline 6a and 6b in good overall
yield. On the contrary, the desilylation of 2a could be
performed to render the terminal olefin 4a in 70% yield.
To conclude, we have developed the first tandem CAM/N−
H insertion reaction to afford unprotected and functionalized
benzofused six-membered azaheterocycles. The reaction
proceeded under very mild conditions and high chemo-
selectivity thanks to a fast CAM process catalyzed by a half-
sandwich ruthenium complex.
b
Scheme 4. Mechanistic Hypothesis
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00596.
Experimental procedures including characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
́
́
Jesus A. Varela − Centro Singular de Investigacion en Quimica
́
Bioloxica e Materiais Moleculares (CiQUS), Departamento de
́
́
Quimica Organica, Universidade de Santiago de Compostela
15782 Santiago de Compostela, Spain; orcid.org/0000-
0001-8499-4257; Email: jesus.varela@usc.es
́
́
́
Carlos Saa − Centro Singular de Investigacion en Quimica
́
Bioloxica e Materiais Moleculares (CiQUS), Departamento de
́
́
Quimica Organica, Universidade de Santiago de Compostela
15782 Santiago de Compostela, Spain; orcid.org/0000-
0003-3213-4604; Email: carlos.saa@usc.es
stereoselective CAM process would generate vinyl carbene II
that would then react with the aniline through two alternative
routes. In route A, a concerted N−H insertion process would
directly give rise to the observed product 2. In route B, the
mild electrophilic ruthenium vinyl carbene would induce a
nucleophilic attack by the aniline to give an ylide intermediate
III, which after a regioselective proton transfer would release 2.
In this stage of our investigations, we were not able to
unequivocally determine whether the N−H insertion step
occurs in a concerted or stepwise manner.14,15
Author
́
́
́
Damian Padín − Centro Singular de Investigacion en Quimica
Bioloxica e Materiais Moleculares (CiQUS), Departamento de
Quimica Organica, Universidade de Santiago de Compostela
15782 Santiago de Compostela, Spain; orcid.org/0000-
0002-3841-727X
́
́
́
Complete contact information is available at:
C
https://dx.doi.org/10.1021/acs.orglett.0c00596
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
́
́
́
Mace, A.; Berree, F.; Carboni, B.; Derien, S. One-Step Synthesis of
Strained Bicyclic Carboxylic and Boronic Amino Esters via
Ruthenium-Catalysed Tandem Carbene Addition/Cyclopropanation
https://pubs.acs.org/10.1021/acs.orglett.0c00596
Author Contributions
̀
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All authors have given approval to the final version of the
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has received financial support from MINECO
(project CTQ2017-87939R and ORFEO-CINQA network
RED2018-102387-T), the Xunta de Galicia (project ED431C
́
2018/04 and Centro singular de investigacion de Galicia
accreditation 2019-2022, ED431G 2019/03), and the Euro-
pean Union (European Regional Development Fund −
ERDF). D.P. thanks MEC for a predoctoral FPU fellowship
(FPU15/02132).
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