Rh(III)-Catalyzed [5 + 2] Oxidative Annulation of Cyclic Arylguanidines and Alkynes to 1,3-Benzodiazepines. A Striking Mechanistic Proposal from DFT

Article abstract of DOI:10.1021/acs.orglett.9b00354

A novel and mild Rh(III)-catalyzed [5 + 2] oxidative annulation between cyclic arylguanidines and alkynes efficiently affords 1,3-benzodiazepines (pentacyclic guanidines). The use of O₂ as the sole oxidant in place of commonly used metal oxidants such as AgOAc clearly improves the efficiency of the oxidative annulation process. The mechanism of the cycloaddition most likely involves the formation of an eight-membered rhodacycle. DFT calculations support a striking mechanistic proposal for the [5 + 2] oxidative annulation.

Full text of DOI:10.1021/acs.orglett.9b00354

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed [5 + 2] Oxidative Annulation of Cyclic
Arylguanidines and Alkynes to 1,3-Benzodiazepines. A Striking
Mechanistic Proposal from DFT
́
́ ́ ́
Nuria Martínez-Yanez, Jaime Suarez, Ana Cajaraville, Jesus A. Varela, and Carlos Saa*
̃
́
́
́
Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares (CiQUS), Departamento de Química Organica,
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
S
* Supporting Information
ABSTRACT: A novel and mild Rh(III)-catalyzed [5 + 2]
oxidative annulation between cyclic arylguanidines and alkynes
efficiently affords 1,3-benzodiazepines (pentacyclic guanidines).
The use of O2 as the sole oxidant in place of commonly used
metal oxidants such as AgOAc clearly improves the efficiency of
the oxidative annulation process. The mechanism of the
cycloaddition most likely involves the formation of an eight-
membered rhodacycle. DFT calculations support a striking
mechanistic proposal for the [5 + 2] oxidative annulation.
activation/alkyne insertion sequence that gives rise to the
enzodiazepines are an important class of benzo-fused
1
Bmedium-sized dinitrogenated heterocycles, and they are corresponding azaheterocycles via reductive elimination, which
the key structural motifs in many active pharmaceuticals.2
overall can be considered as formal [3 + 2] or [4 + 2] oxidative
annulations.6 However, the formation of eight-membered
These compounds comprise several structural derivatives, but
metallacycle intermediates is energetically more unfavorable,
and this has undoubtedly restricted the direct access to seven-
membered azaheterocycles. To the best of our knowledge, only
two reports on the direct Pd-catalyzed [5 + 2] cycloaddition
between nitrogen-containing preorganized substrates and
alkynes to form 1-benzazepine derivatives have been
published.7 On the other hand, we recently discovered that
1,3-dimethyl-1,3-diphenylguanidine 1a (i.e., linear arylguani-
dines) easily undergo catalytic C−H activation/alkyne
insertion processes to form the eight-membered rhodacycle
3, which could be isolated and characterized by X-ray
diffraction.8 In a catalytic process involving 3-hexyne 2a, the
corresponding metallacyclic intermediate 3 evolved via β-
elimination to 1,4-dihydroquinazolin-2-amine 4aa, which is the
product of a [5 + 1] oxidative annulation between the linear
arylguanidine and the alkyne (Scheme 1, eq 1).8 We envisaged
that the use of partially and/or fully cyclic arylguanidines 1
would modify the conformational/coordination abilities of
rhodacycle intermediates 3 to favor the crucial reductive
elimination step to give the desired seven-membered hetero-
cycle. Herein, we report the straightforward formation of the
seven-membered benzimidazo-1,3-benzodiazepines 5 by a
novel Rh(III)-catalyzed [5 + 2] oxidative annulation of fully
cyclic arylguanidines 1 with alkynes 2 (Scheme 1, eq 2).9 It is
noteworthy that in the C−H activation event two nitrogen
atoms of the chelate-directing guanidine group were integrated
in the final 1,3-benzodiazepine core.
the most interesting are the 1,4-benzodiazepines, which have
attracted significant synthetic effort due to their broad range of
clinical applications in the treatment of anxiety, insomnia,
agitation, seizures, or muscle spasms.3 Other structural
isomers, such as 1,3-benzodiazepines, are less well-known
despite the fact that these molecules have a wide range of
medicinal applications4 (Figure 1). Accordingly, sustainable
catalytic routes for the construction of the 1,3-benzodiazepine
core are in high demand.5
Transition-metal-catalyzed C−H functionalization is nowa-
days considered to be a powerful synthetic sustainable strategy
for a direct access to five- and six-membered azaheterocycles.6
Typically, the process of heteroannulation of nitrogen-
chelating substrates with alkynes involves the formation of
six- and seven-membered metallacycles through a C−H
Received: January 28, 2019
Figure 1. Bioactive 1,3-benzodiazepines.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00354
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Organic Letters
Letter
Scheme 1. Rh(III)-Catalyzed [5 + 1] and [5 + 2] Oxidative
Annulations of Arylguanidines with Alkynes
Table 1. Rh(III)-Catalyzed [5 + 2] Oxidative Annulation of
Cyclic Arylguanidine 1c with Alkynes 2 to 1,3-
Benzodiazepines 5
ab
,
entry
R1
R2
product
yield (%)
1
2
3
4
5
6
7
8
Et
Et
5ca
5cb
5cc
5 cd
5ce
5cf
5cg
5ch
5ci
60 (85)
51 (82)
47 (81)
88 (93)
70
57 (84)
52 (81)
82 (82)
51
n-Pr
n-Bu
Ph
4-MeOPh
4-MePh
4-CF3Ph
2-thiophene-yl
4-BrPh
n-Pr
n-Bu
Ph
4-MeOPh
4-MePh
4-CF3Ph
2-thiophene-yl
4-BrPh
9
10
11
12
4-ClPh
3-BrPh
Me
4-ClPh
3-BrPh
Ph
5cj
5ck
43
36 (87)
66 (75)
5cl:5cl’ (1.5:1)
The partially cyclic N-methyl-N-phenyl-1H-benzo[d]-
imidazol-2-amine 1b reacted sluggishly to give 4ba in a low
18% yield (Scheme 2, eq 1), with most of the 1b recovered.10
a
Conditions A: 1c (0.3 mmol), 2 (0.33 mmol), [RhCp*Cl2]2 (0.0075
mmol), AgOAc (0.63 mmol) in MeOH (3 mL), 80 °C, air, 24 h.
Conditions B: 1c (0.3 mmol), 2 (0.33 mmol), [RhCp*Cl2]2 (0.0075
mmol), in MeOH (3 mL), O2, 80 °C, 24 h. Yields obtained under
conditions B are shown in parentheses.
b
Scheme 2. Rh(III)-Catalyzed Oxidative Annulations of
Partially Cyclic and Fully Cyclic Arylguanidines (1b, 1c)
with Alkynes
under both sets of conditions (entry 4). The molecular
structure of 5cd was elucidated by X-ray crystallography.
Electron-rich and electron-poor arylalkynes were all tolerated,
with insignificant variations in the cycloadditions. Thus, 4-
methoxy-, 4-methyl-, and 4-trifluoromethylarylalkynes 2e−g
gave rise to 1,3-benzodiazepines 5ce−cg in very good yields
(entries 5−7). The case of heteroarylalkyne 2h was particulary
efficient, and this gave rise to the thiophene-yl derivative 5ch in
high yield (entry 8). Halogenated arylalkynes were also well
tolerated, which may lead to future cross-coupling manipu-
lations. For example, 4-Br-, 4-Cl-, and 3-Br-arylalkyne
derivatives 2i−k gave moderate to good yields of the
corresponding halogenated 1,3-benzodiazepines 5ci−ck (en-
tries 9−11). Curiously, the [5 + 2] cycloaddition proved to be
non-regioselectivein contrast to the regioselective [5 + 1]
cycloaddition with linear arylguanidines.8 Thus, the alkyne 1-
(propynyl)benzene 2l, bearing Csp2 and Csp3 substituents, gave
rise to a mixture of regioisomers 5cl and 5cl′ (1.5:1) in a 75%
combined yield (entry 12).
Other cyclic arylguanidines were also tested (Figure 2). The
substituted 2-(methylindolyl)guanidine 1d also reacted
smoothly to give the 1,3-benzodiazepine 5dd in good yield
(80%). Both electron-rich and electron-poor para-substituted
indolyl units were well tolerated since indolyl guanidines 1e
and 1f gave the 1,3-benzodiazepines 5ed and 5fd in excellent
yields.13 Gratifyingly, the 2-(indol-1-yl)-1,3-benzimidazole
derivative 1i also underwent the [5 + 2] oxidative annulation14
to give the indolo-1,3-benzodiazepine 5ia in fairly good yield.
The starting indole 1i could be prepared in moderate yields
from the readily available 2-(N-phenyl)-1,3-benzimidazole 1k
in a Rh(III)-catalyzed [3 + 2] oxidative cycloaddition with 3-
hexyne (Scheme 3).8,15 To our delight, the above indolo-1,3-
benzodiazepine 5ia (which was characterized by X-ray
Gratifyingly, when the fully cyclic 2-(indolin-1-yl)-1H-benzo-
[d]imidazole 1c was heated in MeOH at 80 °C (conditions A),
a smooth conversion gave the benzimidazo-1,3-benzodiazepine
5ca in a respectable 60% yield (Scheme 2, eq 2). To our
delight, the yield of the reaction could be improved to 85%
when O2 was used as the sole oxidant (conditions B).11
We proceeded to test the scope and limitations of the new
[5 + 2] annulation using cyclic arylguanidine 1c as the
substrate under both sets of oxidative conditions.12 In general,
reactions performed using O2 as the sole oxidant (conditions
B) gave better yields (Table 1). Thus, other internal aliphatic
alkynes, namely 4-octyne 2b and 5-decyne 2c, gave the
corresponding 1,3-benzodiazepines 5cb−cc in high yields
(entries 2 and 3). Interestingly, unlike the cycloaddition with
linear arylguanidines,8 aromatic alkynes 2d−k reacted
smoothly to give the corresponding 4,5-diarylated 1,3-
benzodiazepines 5cd−ck. In the case of diphenylacetylene
2d, excellent yields of 1,3-benzodiazepine 5cd were obtained
B
DOI: 10.1021/acs.orglett.9b00354
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group would trigger the required tautomerism between the
nitrogen atoms (L- to X-type ligand) to facilitate the reductive
elimination step. In fact, the 2-(indolin-1-yl)-1-methyl-1H-
benzo[d]imidazole 1j failed to react under optimized
conditions with total recovery of the starting material.
In an effort to gain an insight into the selectivity of the
reaction between guanidines 1b (partially cyclic) and 1c (fully
cyclic) with alkyne 2a to form [5 + 2] cycloadducts, i.e.,
benzodiazepines 5, or [5 + 1] cycloadducts, i.e., quinazolines 4,
DFT calculations17 were performed starting with the key eight-
membered rhodacycles I18 which lie 14.1 (1b, blue line) and
9.9 (1c, red line) kcal mol−1 below the free energy of the
corresponding starting materials (Figure 3). To our surprise,
calculations showed that the formation of [5 + 2] cyclo-
adducts, i.e., benzodiazepines 5, occurs by an initial
decoordination of the imidazole moiety from the metal center
to complex II, followed by a nucleophilic attack of the iminic
nitrogen to the Csp2−Rh bond to afford protonated Rh(I)-
coordinated benzodiazepines III (ΔG⧧ = 20.9 and 11.5 kcal
mol−1, ΔG° = 6.6 and −0.1 kcal mol−1) rather than the
expected direct reductive elimination from I (ΔG⧧ = 29.5 and
26.4 kcal mol−1, ΔG° = 12.2 and 10.2 kcal mol−1).19 Exergonic
deprotonation and reoxidation of the Rh(I) to Rh(III) with
AgOAc would give the final benzodiazepines 5ba and 5ca
(ΔG° = −21.5 and −16.2 kcal mol−1) for the overall
transformations. On the other hand, formation of [5 + 1]
cycloadducts,20 i.e., quinazolines 4, starts with coordination of
acetate to the eight-membered cationic rhodacycles I to give
neutral complexes IV (ΔG° = 4.9 and 11.5 kcal mol−1), which
after acetate-assisted β-hydride elimination afford allene
intermediates V (ΔG⧧ = 11.1 and 3.9 kcal mol−1, ΔG° = 7.2
and 1.4 kcal mol−1). Protonation of V by the acetic acid ligand
affords the cationic π-allyl Rh (III) species VI after acetate
release (ΔG⧧ = 7.6 and 7.8, ΔG° = −15.4 and −15.6 kcal
mol−1), where Rh(III) is stabilized by an agostic interaction
involving a Csp3−H bond of the ethyl substituent. Finally,
nucleophilic attack of the iminic nitrogen to the π-allyl moiety
(ΔG⧧ = 21.3 and 21.1 kcal mol−1) followed by exergonic
deprotonation and reoxidation of the Rh(I) to Rh(III) by
Figure 2. Rh(III)-catalyzed oxidative annulations of other cyclic
arylguanidines. (a) Conditions A: 1 (0.3 mmol), 2 (0.33 mmol),
[RhCp*Cl2]2 (0.0075 mmol), AgOAc (0.63 mmol) in MeOH (3
mL), 80 °C, air, 24 h. Conditions B: 1 (0.3 mmol), 2 (0.33 mmol),
[RhCp*Cl2]2 (0.0075 mmol), in MeOH (3 mL), O2, 80 °C, 24 h. (b)
Yields obtained under conditions B are shown in parentheses.
Scheme 3. Rh(III)-Catalyzed [3 + 2] and Tandem [3 + 2]/
[5 + 2] Oxidative Annulations of N-Phenylbenzimidazole 1k
diffraction) could also be obtained from the linear
benzimidazole 1k in a cascade process involving tandem [3
+ 2]/[5 + 2] oxidative annulations16 with 2a (Scheme 3).
At the outset, the cyclic arylguanidine substrates were
selected to favor the crucial reductive elimination step over the
β-elimination found for the eight-membered rhodacycle
intermediates derived from the linear arylguanidines.8 We
believe that the presence of the NH in the benzimidazole
Figure 3. Free energy profile for the formation either of benzodiazepines 5ba and 5ca or quinazolines 4ba and 4ca20 from eight-membered
rhodacycles I. Energies are relative to catalytic active species Cp*Rh(OAc)2 combined with those of the relevant substrates. The phenyl ring of the
benzimidazole moiety is omitted for clarity.
C
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AgOAc affords the quinazolines 4ba and 4ca (ΔG° = −24.9
and −18.8 kcal mol−1) for the overall processes.
skeleton is smoothly assembled by a remarkable cascade
process involving [3 + 2]/[5 + 2] oxidative annulations of
linear benzimidazole 1k with alkyne 2a. A striking mechanistic
rationale for the [5 + 2] oxidative annulation is proposed on
the basis of DFT calculations. Redox reactions of the
indoline−benzodiazepines have been successfully achieved.
Further applications of this novel oxidative process are
currently being explored in our laboratory.
These calculations described above show the preference for
the [5 + 2] over the [5 + 1] cycloaddition pathway for the fully
cyclic guanidine 1c to benzodiazepine 5ca (ΔΔG⧧ is 9.2 kcal
mol−1), while the opposite is observed from the partially cyclic
guanidine 1b to quinazoline 4ba (ΔΔG⧧ is 1.2 kcal mol−1).
These findings are in complete agreement with the
experimental results found. We believe that the rigidity/
planarity of the indolyl moiety in 1c (as compared to the linear
1b) enables the formation of complex II with an appropriate
spatial disposition between the reactive centers (0.54 Å closer
for fully cyclic than partially cyclic II due to the planarity
imposed by the indolyl ring, 15.4° against 42.4°) that are prone
to undergo the formation of the seven-membered heterocycle
(Figure 4).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00354.
Detailed experimental procedures and compound
characterization data (PDF)
Computational details, Cartesian coordinates, imaginary
frequencies, and absolute energies in hartrees for all
optimized geometries (PDF)
Accession Codes
CCDC 1873637−1873638 contain the supplementary crys-
tallographic 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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: carlos.saa@usc.es.
ORCID
́
Jesus A. Varela: 0000-0001-8499-4257
Figure 4. Calculated geometries for intermediates II in guanidine 1b
(partially cyclic) and 1c (fully cyclic).
́
Carlos Saa: 0000-0003-3213-4604
Notes
Redox reactions of indoline-1,3-benzodiazepines 5 were
performed to get a straightforward access to N-doped aromatic
scaffolds containing [4n+2]πe− with potential electrolumines-
cent properties.21 Treatment of 5cd with MnO2 at 80 °C
promotes the oxidation of the indoline moiety to give the
indole-1,3-benzodiazepine 6cd in excellent yield (Scheme 4).22
Careful hydrogenation of 5cd in MeOH(H2 4 atm, 60 °C)
affected only to the enamine unit to give the dihydro-1,3-
benzodiazepine 7cd in fairly good yield.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has received financial support from MINECO
(projects CTQ2014-59015R, CTQ2017-87939R, and
ORFEO-CINQA network CTQ2016-81797-REDC), the
Xunta de Galicia (projects GRC2014/032, ED431C 2018/
́
04, and Centro singular de investigacion de Galicia
accreditation 2016−2019, ED431G/09), and the European
Union (European Regional Development Fund - ERDF).
N.M.-Y. thanks MINECO and Xunta de Galicia for a
predoctoral contract. We are also grateful to the CESGA
(Xunta de Galicia) for computational time.
Scheme 4. Oxidation and Reduction of Benzodiazepine 5cd
DEDICATION
■
́
́
Dedicated to Professor Jose M. Saa on the occasion of his 70th
birthday.
In summary, we have successfully developed a new and
efficient rhodium-catalyzed [5 + 2] oxidative cycloaddition
between fully cyclic arylguanidines and alkynes to give 1,3-
benzodiazepines. The use of O2 as the sole oxidant in place of
commonly used metal oxidants like AgOAc clearly improves
the efficiency of the oxidative annulation process. The reaction
tolerates functional groups in both the guanidine and alkyne
partners and provides an easy access to relevant pentacyclic
guanidine derivatives. In addition, an indolobenzazepine
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(16) For a tandem Rh-catalyzed [3 + 2]/[5 + 2] annulation to
indeno[1,7-cd]azepines, see: Yang, Y.; Zhou, M.-B.; Ouyang, X.-H.;
Pi, R.; Song, R.-J.; Li, J.-H. Angew. Chem., Int. Ed. 2015, 54, 6595−
6599.
(17) These calculations were performed using AgOAc as oxidant to
visualize the different selectivity found for guanidines 1b ([5 + 1]
cycloadducts) and 1c ([5 + 2] cycloadducts). In fact, when O2 is used
as oxidant, only guanidine 1c reacts to afford [5 + 2] cycloadduct
E
DOI: 10.1021/acs.orglett.9b00354
Org. Lett. XXXX, XXX, XXX−XXX