Assembly of Tetrahydroquinolines and 2-Benzazepines by Pd-Catalyzed Cycloadditions Involving the Activation of C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.1c01594

Cycloaddition reactions are among the most practical strategies to assemble cyclic products; however, they usually require the presence of reactive functional groups in the reactants. Here, we report a palladium-catalyzed formal (4 + 2) cycloaddition that

Full text of DOI:10.1021/acs.orglett.1c01594

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Letter
Assembly of Tetrahydroquinolines and 2‑Benzazepines by Pd-
Catalyzed Cycloadditions Involving the Activation of C(sp3)−H
Bonds
Xandro Vidal, José Luis Mascarenas,* and Moisés Gulías*
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ABSTRACT: Cycloaddition reactions are among the most
practical strategies to assemble cyclic products; however, they
usually require the presence of reactive functional groups in the
reactants. Here, we report a palladium-catalyzed formal (4 + 2)
cycloaddition that involves the activation of C(sp3)−H bonds and
provides a direct, unconventional entry to tetrahydroquinoline
skeletons. The reaction utilizes amidotolyl precursors and allenes
as annulation partners, and is catalyzed by Pd(II) precursors in
combination with specific N-acetylated amino acid ligands. The
reactivity can be extended to ortho-methyl benzylamides, which provide for the assembly of appealing tetrahydro-2-benzazepines in a
formal (5 + 2) annulation process.
problematic than in the case of substrates with sp2 reacting
zaheterocycles form the scaffold of many drugs, agro-
Achemicals, dyes, and fragrances and can be found in many carbons. Indeed, while a vast array of different types of
annulations (especially formal cycloadditions) involving the
activation of aromatic C(sp2)−H bonds have been described,
mechanistically related processes based on the activation of sp3
C−H bonds are very scarce.6
Herein, we report the first examples of transition metal
formal (4 + 2) annulations involving ortho-methylanilides,
using allenes as two-carbon partners (Scheme 1C). Impor-
tantly, we also demonstrate that the reaction, which is
catalyzed by Pd(II) species, can be extended to benzylamides,
providing for the direct assembly of azepines in a formal (5 +
2) cycloaddition approach.
natural products. Therefore, the assembly of these skeletons in
a sustainable and atom economical fashion remains a primary
goal in modern organic synthesis. In this context, one of the
more appealing synthetic strategies to build these type of rings
consists of the use of metal-catalyzed cycloadditions involving
the direct activation of C−H bonds.1,2 This is exemplified by
the synthesis of indoles from anilides through a formal (3 + 2)
oxidative cycloaddition (Scheme 1A).3 The reaction involves
an initial C(sp2)−H activation to form metallacycle A,
followed by migratory insertion of the unsaturated partner
and reductive elimination (Scheme 1A). One could envision a
similar annulation to build tetrahydroquinolines (THQs)
instead of indoles, which is a central scaffold in many bioactive
alkaloids; however this would require the use of 3-carbon
cycloaddition partners, which are not obvious to identify
(Scheme 1B, left arrow).4 An alternative, more attractive
disconnection for THQ skeletons could be based on a (4 + 2)
instead a (3 + 3) disconnection, like that shown in Scheme 1B
(right arrow), as this would entail the use of common 2-carbon
unsaturated partners. Moreover, as 4-atom components, ortho-
methylanilines are very appealing because of their availability.
However, synthetic reactions that fulfill this retrosynthetic
analysis, enabling a formal (4 + 2) cycloaddition between ortho
methylanilides and unsaturated partners, are unknown.
Performing this transformation using transition metal catalysis
is challenging, not only because of the well-known difficulties
associated with the activation of sp3 C−H bonds5 but also
because the subsequent steps (migratory insertion into the
C(sp3)−metal bond and reductive elimination) are also more
As previously established,7 the presence of strong electron-
withdrawing groups at the nitrogen is key for successful C−H
functionalization reactions in amino aromatic substrates.
Therefore, we started our investigation by examining the
reactivity of 1,1,1-trifluoro-N-(o-tolyl)methanesulfonamide
(1a, Table 1). As partners we paid attention to allenes,
owing to their successful performance in previous cyclo-
additions involving the activation of C(sp2)−H bonds.8
Using commercially available allene 5-vinylidenenonane
(2a), we observed no reaction in the presence of 10 mol %
of palladium acetate, and copper acetate as oxidant (in toluene
Received: May 10, 2021
Published: June 24, 2021
https://doi.org/10.1021/acs.orglett.1c01594
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5323−5328
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desired tetrahydroquinoline product 3aa in a promising 25%
yield (based on allene), as a single regioisomer (entries 1 and
2). We tested other amino acid ligands, bearing different
amino-protecting groups, discovering that N-acetyl-L-valine
(Ac-Val-OH) produces the best results (3aa formed in 60%
yield, entry 8). Other oxidants, including benzoquinone or
silver carbonate, are clearly inferior to copper acetate (26% and
20% yield respectively). It is possible to use substrates with
other electron-withdrawing groups at the nitrogen than triflyl,
such as mesyl and nosyl, albeit the reactions are less efficient
(entries 9−10). Interestingly, the reaction also works using the
environmentally friendly solvent methyl-THF (54% yield),
which even allowed it to proceed at lower temperature (85
°C). Decreasing the amount of Cu(OAc)2 and Cs2CO3 to 1
equiv resulted in the product being obtained in 61% yield
(entry 14), while with a lesser amount of palladium salt,
conversions were not complete. Finally, we found that a slow
addition of allene over a 4 h period led to an increase in yield
up to 71% (entry 16).
Scheme 1. Metal-Catalyzed Annulations To Give
Azaheterocycles
With the optimized conditions in hand, we investigated the
scope of the reaction using different types of allene partners
(Scheme 2). Similar to 2a, the 1,1-disubstituted allene
vinylidenecyclohexane (2b) worked in good yield (61%).
Symmetrical 1,3-disubstituted allenes such nona-4,5-diene (2c)
also led to the quinoline product 3ac in 61% yield. Gratifyingly
nonsymmetrical 1,3-allenes 2d and 2e led to the expected
products, with excellent regio- and diastereoselectivities and an
up to 76% yield. Furthermore, while ethyl 2,3-butadienoate did
not work, probably because of the presence of an electron-
withdrawing group, electron-rich monosubstituted allenes like
cyclohexylallene (2f) or the aryl-substituted derivative 2g
produced the cycloadducts 3af and 3ag as mixtures of E/Z
isomers. Remarkably, trisubstituted allenes are also valid
at 105 °C). In line with previous reports on the role of
monoprotected amino acids accelerating the rate of Pd-
mediated C−H activations,9 we found that using 40 mol % of
Boc-protected valine as ligand promotes the formation of the
a
Table 1. Selected Optimization Results
b
Entry
R
Solvent
Temp
Ligand L
Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Tf (1a)
Tf
Tf
Tf
Tf
Tf
Tf
Tf
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-Xylene
THF
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
105 °C
85 °C
−
<5%
25%
42%
55%
55%
37%
52%
60%
39%
33%
49%
53%
54%
61%
56%
71%
Boc-Val-OH
Ac-Gly-OH
Ac-Ala-OH
Ac-Leu-OH
Formyl-Val-OH
Pro-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ac-Val-OH
Ms (1a′)
Ns (1a″)
Tf
Tf
Tf
Tf
Tf
Tf
c
2-Me THF
2-Me THF
2-Me THF
2-Me THF
d
85 °C
85 °C
85 °C
de
,
df
,
a
b
Conditions: 0.333 mmol of 1a, 0.167 mmol of allene 2a, 2 mL of solvent, under air, 2 equiv of Cu(OAc)2·H2O, 1.5 equiv of Cs2CO3, 16 h. Yields
c
calculated based on 2a. Calculated by using an internal standard (entries 1−11). Isolated yields (entries 12−16). Reaction performed in sealed
tube. 1 equiv of Cu(OAc)2·H2O and 1 equiv of Cs2CO3. 0.167 mmol of 1a, 0.167 mmol of allene 2a. Slow addition over 1 h of 0.167 mmol of
allene 2a in 1.5 mL of 2-Me THF to the reaction.
d
e
f
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a
Scheme 2. Scope of the Formal (4 + 2) Cycloaddition of ortho-Anilides and Allenes
a
Conditions: 0.333 mmol of 1, 0.167 mmol of allene 2, 2 mL of Me-THF, under air, 16 h. Regioisomeric ratios >20:1 and E/Z ratios >20:1, unless
b
otherwise stated. Yield after a gram-scale experiment.
cycloaddition partners, and therefore products 3ah, 3ai, and
3aj were obtained (42−73% yields).10
reactions (3la−3na, 52−67% yield). Finally, as expected, the
reaction is general for other allenes, as demonstrated with
substrate 1f and product 3fh.
Running the reaction of 1a in the presence of D2O or
Ac(d3)-OD under standard conditions revealed no deuterium
incorporation in neither the starting material nor the product,
which suggests the C−H activation step is irreversible (eq 1).
The use of allenes as reaction partners is key for the success
of the annulation. Alkynes, like diphenylacetylene, were
essentially unreactive, while alkenes, such as ethyl acrylate,
failed to give the cycloadducts, providing just traces of
products resulting from addition/β-hydride elimination pro-
cesses (olefination).11 This success with allenes is likely
associated with several factors: (1) they are not as coordinating
as alkynes, and thereby avoid the saturation of the metal
coordination sphere to give nonactive complexes; (2) they
favor the migratory insertion step owing to the formation of π-
allyl intermediates; (3) they also facilitate the reductive
elimination step because of the presence of an extra
coordinating handle (double bond).12
We then explored the scope regarding the ortho-methyl
anilides, by testing substrates 1b−1n, most of which were
prepared by triflation of commercially available substrates.
Precursors 1b and 1c with substituents ortho to the methyl
group gave the corresponding products 3ba and 3ca in 69%
and 50% yield, respectively. Substrates equipped with
substituents meta to the methyl group such as phenyl or
methoxy, or even with halogens (chloro, bromide), also led to
moderate yields (3da−3ga), exhibiting better performance for
the electron-rich substrates. The reaction is also compatible
with substituents para to the methyl group (chloro, methyl
ester, methoxy and phenyl), to give the expected products
(3ha−3ka, 50−69% yield). Aryl-disubstituted substrates such
1l and 1m, as well as naphthyl anilide 1n, also led to effective
We also measured the primary kinetic isotopic effect carrying
out a competition between 1a and the deuterated analogue 1a-
d3. When the competition experiments were carried out in the
same vessel, we obtained a kH/kD ≈ 7.3. Using parallel
experiments, the resulting value was 2.7. From both experi-
ments we can conclude that the C−H bond cleavage is the
turnover limiting step (eq 2).13
At this stage, we wondered whether it would be possible to
use ortho-methyl benzylamides instead of anilides as annulation
precursors. In these substrates the amide directing group is
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further apart from the methyl substituent, and therefore the
required C(sp3)−H bond activation was not warranted. The
annulation is synthetically relevant, as it could allow the
formation of seven-membered tetrahydro-2-benzazepines,
through a novel type of formal (5 + 2) annulation.
Scheme 4. Preliminary Results on a (5 + 2) Enantioselective
Annulation
a
The route requires use of ortho disubstituted benzylamide
precursors, to avoid the activation of the C(sp2)−H of the
aromatic ring (see the Supporting Information). The reaction
works well (Scheme 3) and even leads to better yields than
Scheme 3. Scope of the (5 + 2) Formal Cycloaddition of
a
ortho-Methylbenzylamides and Allenes
a
2 equiv of allene.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01594.
Experimental procedures and spectroscopic data for new
compounds; X-ray data for 3fa and for 6 (PDF)
Accession Codes
a
CCDC 2025994 and 2026002 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Conditions: 0.167 mmol of 1a, 0.333 mmol of allene 2a, 2 equiv of
Cu(OAc)2·H2O, 2 mL of toluene, 15 equiv of DMSO, 1.5 equiv of
Cs2CO3, under air, 16 h. Racemic Ac-Val-OH was used.
b
that of the homologous anilides. The annulations were better
performed using N-acetyl-L-valine as an amino acid ligand and
toluene as solvent, at 105 °C. It is also beneficial to use 2 equiv
of allene and of copper acetate. Several interesting azepine
products (5aa−5da) were obtained from readily available
starting materials in good to excellent yields (61−90% yield).
Substitution in the α-position to the amino group (5ea, 87%)
are also tolerated. The reaction can also be performed with
allenes other than 2a, illustrated with the formation of 5ch
(61%).14
We have also made a preliminary exploration of a kinetic
resolution with substrates 4e and 4f. After a brief screening of
ligands, we found out that with Boc-L-Leu-NHOMe, using
standard reaction conditions at 60 °C, the cycloadduct 5fa was
produced with a promising 90:10 enantiomeric ratio (Scheme
4).15,16 This result indicates that we can generate optically
active tetrahydrobenzazepine skeletons in only three steps
from commercially available starting materials and warrants
further studies to optimize the process.
In conclusion, we have developed a palladium-catalyzed
annulation between ortho-methyl anilides or benzylamides and
allenes involving the activation of benzylic methyl groups. The
technology represents a substantial addition to the yet very
scarce arsenal of metal cycloaddition tools lying on the
activation of C(sp3)−H bonds. The approach allows a
straightforward assembly of highly substituted tetrahydroqui-
noline or benzazepine skeletons from inexpensive and readily
available starting materials.
AUTHOR INFORMATION
Corresponding Authors
■
Moisés Gulías − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain; orcid.org/0000-0001-8093-2454;
Email: moises.gulias@usc.es
José Luis Mascarenas − Centro Singular de Investigación en
̃
Química Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain; orcid.org/0000-0002-7789-700X;
Email: joseluis.mascarenas@usc.es
Author
Xandro Vidal − Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares (CIQUS) and
Departamento de Química Orgánica, Universidade de
Santiago de Compostela, 15782 Santiago de Compostela,
Spain; orcid.org/0000-0003-0963-1506
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01594
Notes
The authors declare no competing financial interest.
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Activation. J. Am. Chem. Soc. 2011, 133, 3264−3267. (d) Chan, C.-
M.; Zhou, Z.; Yu, W.-Y. Rhodium-Catalyzed Oxidative Cycloaddition
of N-tert-Butoxycarbonylhydrazones with Alkynes for the Synthesis of
Functionalized Pyrroles via C(sp3)−H Bond Functionalization. Adv.
Synth. Catal. 2016, 358, 4067. (e) Archambeau, A.; Rovis, T.
Rhodium(III)-Catalyzed Allylic C(sp3)−H Activation of Alkenyl
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ACKNOWLEDGMENTS
■
This work has received financial support from Spanish grants
(SAF2016-76689-R, PID2019-108624RB-I00, CTQ2016-
77047-P, PID2019-110385GB-I00, and FPU fellowship to
X.V.), the Consellería de Cultura, Educación e Ordenación
Universitaria (ED431C 2017/19, 2015-CP082 and Centro
Singular de Investigación de Galicia accreditation 2019-2022,
ED431G 2019/03), the European Regional Development
Fund (ERDF), and the European Research Council (Advanced
Grant No. 340055). The orfeo-cinqa network CTQ2016-
81797-REDC is also kindly acknowledged.
Mascarenas, J. L.; Gulías, M. Palladium-Catalyzed Formal (4 + 2)
̃
Cycloaddition between Alkyl Amides and Dienes Initiated by the
Activation of C(sp3)−H Bonds. ACS Catal. 2020, 10, 3425−3430.
(g) Park, H.; Yu, J.-Q. Palladium-Catalyzed [3 + 2] Cycloaddition via
Twofold 1,3-C(sp3)-H Activation. J. Am. Chem. Soc. 2020, 142,
16552−16556. (h) Zhang, Z.-Z.; Han, Y.-Q.; Zhan, B.-B.; Wang, S.;
Shi, B.-F. Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed
Multiple C(sp3)−H Activation Strategy. Angew. Chem., Int. Ed. 2017,
56, 13145−13149.
(7) The presence of the triflate increases the acidity of the NH
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palladium remains electrophilic enough to promote C−H activation.
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(13) See the Supporting Information for a mechanistic proposal for
this reaction.
(14) For a derivatization of 5ch see the Supporting Information.
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(16) The absolute configuration of 5ea and 5fa was not determined.
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