Copper(I)-Catalyzed Intramolecular Cyclization of o-Propargyloxy Diketopiperazines to Access Diverse Diazabicyclic and Spiro-Diketopiperazinochromanes

Article abstract of DOI:10.1002/adsc.202100432

In this report, two distinctive intramolecular cyclizations of o-propargyloxy diketopiperazines (achieved from a one-pot Ugi post-transformation) is achieved via a copper(I)-catalyzed intramolecular reaction of azomethine ylide and alkyne moiety. The presence of internal alkyne in the starting materials directed the reaction towards through [3+2]-cycloaddition, while terminal alkyne led to a spirocyclization reaction between azomethine ylide and terminal unsaturated C?C bond. This method offering an opportunity for the synthesis of challenging Diazabicyclics and Spiro-Diketopiperazinochromanes in high yields with exclusive diastereoselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.202100432

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doi.org/10.1002/adsc.202100432
Copper(I)-Catalyzed Intramolecular Cyclization of
o-Propargyloxy Diketopiperazines to Access Diverse Diazabicyclic
and Spiro-Diketopiperazinochromanes
Bita Manavi,a Hossein Zahedian Tejeneki,a Frank Rominger,b Mahsa Armaghan,c
Walter Frank,c Hamid Reza Bijanzadeh,d and Saeed Balalaiea, e,*
a
Peptide Chemistry Research Institute, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran,
Tel: +98-21-23064226
Fax: +98-21-22889403
E-mail: balalaie@kntu.ac.ir
b
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg
Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225
c
Düsseldorf, Germany
d
Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Tehran,
Iran
e
Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
Manuscript received: April 6, 2021; Revised manuscript received: June 26, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100432
preferred in many cases based on their unique
advantages including that they are readily available,
Abstract: In this report, two distinctive intramolec-
ular cyclizations of o-propargyloxy diketopipera-
zines (achieved from a one-pot Ugi post-trans-
formation) is achieved via a copper(I)-catalyzed
cost-effective, and the fact that they have low
toxicity.[2] In this context, metal-catalyzed cycloaddi-
tion reactions of unsaturated CÀ C bonds with dipolar
intramolecular reaction of azomethine ylide and
species in general, and azomethine ylides in particular,
alkyne moiety. The presence of internal alkyne in
have been developed into striking and integral trans-
the starting materials directed the reaction towards
formations for the synthesis of complex N-hetero-
through [3+2]-cycloaddition, while terminal alkyne
cycles, especially when they are performed in an
led to a spirocyclization reaction between azome-
intramolecular setting.[3]
thine ylide and terminal unsaturated CÀ C bond.
Considering the significance of azomethine ylides,
there are a variety of methods for in situ preparation of
these intermediates. However, the formation of these
This method offering an opportunity for the syn-
thesis of challenging Diazabicyclics and Spiro-
Diketopiperazinochromanes in high yields with
dipolar species is mostly limited to the carboxylative
exclusive diastereoselectivity.
condensation of aldehydes with amino acids or amino
esters. Moreover, most of the cycloaddition reactions
of azomethine ylides and dienophiles involve sub-
Keywords: Copper; Cyclization; Cycloaddition; Het-
erocycles; Homogeneous catalyst; Multicomponent
reactions
strates encompassing electron-withdrawing groups
(EWGs) to the unsaturated CÀ C bond.[3] In this project,
we successfully present a new generation of azome-
thine ylide surrogates (Scheme 1). These intermediates
were subsequently incorporated in an intramolecular
Over the past decades, there has been significant
[3+2]-cycloaddition reaction with an inactive triple
progress in the Lewis acid-catalyzed cycloaddition CÀ C bond. Recently, Ugi post-transformation reactions
reaction and it has become the method of choice for have proved to be a powerful synthetic method for the
the rapid synthesis of complex structural building synthesis of a wide range of carbocycles, heterocycles,
blocks using simple raw materials with high atom and bridge rings that are not easily accessible by
economy in a single step.[1] One of the most important traditional synthetic routes through careful selection
factors in these formations is the selection of a proper starting materials.[4] Inspired by prior reports, we
metal catalyst. Nowadays, earth-abundant metals are envisaged that an intramolecular [3+2]-cycloaddition
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azinochromanes. Both reactions happen in a single step
with 100% atom utilization.
Initially, the screening studies were focus on syn-
thesis of the o-propargyloxy diketopiperazine 6a. We
focused on the preparation of bifunctional precursor
1a using the synthetic procedure for the formation of
o-propargyloxybenzaldehyde mentioned in supporting
information.[10] As outlined in Scheme 3, subjecting o-
propargyloxy benzaldehyde 1a, aniline 2a, propiolic
acid 3, and cyclohexyl isocyanide 4a to stirring in
ethanol for 24 h at room temperature produced the
desired Ugi product with 87% yield after workup.
Scheme 1. Generation of azomethine ylide from 2,5- diketopi-
perazine.
reaction can be a viable Ugi post-transformation Next, with this Ugi adduct in hand, we conducted the
strategy to provide a capable method to access reaction for the generation of o-propargyloxy diketopi-
diazabicyclic skeletons.[5,6]
perazine 6a in the presence of PPh3 as the catalyst in
°
Bridged heterocycles have always been of para- ethanol as solvent at 60 C for 16 h, and the product
mount importance in the field of medicinal chemistry was obtained in 55% isolated yield.[5b,e] Afterwards, we
since they have been used as key structures in routes to attempted a one-pot procedure for the synthesis of
access a variety of pharmaceutical agents.[7] Drug diketopiperazine without the isolation of the Ugi
targets containing bridged heterocycles and their product. We carried out the reaction without evaporat-
unbridged counterparts often have similar physiochem- ing and changing the solvent of the Ugi reaction. The
ical properties, while the rigid bridged structures can one-pot procedure worked perfectly and improved the
cause additional potency and target selectivity.[8] overall yield to 89%.
Diazabicyclics are a well-known class of bridged
Furthermore, we used the o-propargyloxy diketopi-
heterocycles that have the subject of interest among perazine 6a as a model substrate in different conditions
bioactive compounds including antibiotics, antitumor for further transformations. We began by probing the
agents, antibacterial agents, and some other critical possible reactions by using different catalysts and
biologically active compounds.[9] As a result, there is bases. We achieved neither products in the absence of
an increasing demand for the development of more base nor catalyst, thus we realized that the presence of
convenient and operationally simple processes for the both of them is crucial for the development of further
synthesis of compounds containing fused diazabicyclic transformations. Treating 6a with a variety of Lewis
scaffolds (Scheme 2).
acid catalysts and bases revealed that applying CuBr
Herein, we introduce an efficient strategy for in situ and a base partner such as KOtBu (2 eq.) in
formations of azomethine ylide from C(sp3)À H of α- acetonitrile results in diazabicyclic compound 7a
amide in 2,5- diketopiperazines. The mentioned (Table 1, entry 1). Screening the reaction in different
diketopiperazines are synthesized via Ugi post-trans- temperatures, revealed that the optimum temperature
°
formation reaction.
for this step was 60 C within 30 min (Table 1, entries
Afterwards, the [3+2]-cycloaddition reaction of 2–7). In the next stage, the reaction was subjected to
these azomethine ylide intermediates with an internal several solvents for further optimization. It was
alkyne residue results in the diastereoselective syn- observed that only toluene rendered the product in a
thesis of 3,8-diazabicyclo[3.2.1] oct-6-en-2-ones. Ad- yield higher than that of acetonitrile (Table 1, entry 8).
ditionally, we demonstrate that the presence of terminal Moreover, while using other catalysts such as InCl3,
alkyne moiety on the o-propargyloxy diketopiperazines AgNO3, AgOTf, Cu2O, Cu(OAc)2, Pd(OAc)2,
would direct the reaction toward a regioselective PdCl2(PPh3)2, and PdCl2 did not form the desired
spirocyclization to afford a series of spiro-diketopiper- product 7a, In(OTf)3 and CuI successfully produced
Scheme 2. Selective synthesis of azabicyclic and spiro com-
Scheme 3. One-pot synthesis of o-propargyloxy diketopipera-
pounds.
zine.
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Table 1. Optimization of the reaction conditions.
Entry[a] Cat. (mol%)
Solvent T ( C) Base
Yield
°
1
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
CuBr (20)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
r.t.
70
60
50
60
60
KOtBu 29
2[b]
3
KOtBu 55
KOtBu 39
KOtBu 59
KOtBu 48
KOtBu 53
KOtBu 47
KOtBu 89
KOtBu 47
KOtBu 38
KOtBu 95
KOtBu 48
4
5
6[c]
7[d]
8
Toluene 60
9
In(OTf)3 (10) Toluene 60
10
11
12
13
CuI (20)
Toluene 60
Toluene 60
Toluene 60
Toluene 60
CuBr (10)
CuBr (5)
CuBr (20)
NaH
24
[a] The model reaction set up with 0.2 mmol of 6a in the
presence of 2 eq. base.
[b] The reaction carried out for 24 h.
[c] The reaction carried out for 20 min.
[d] The reaction carried out for 40 min.
Scheme 4. Substrates scope for synthesis of 3,8-diazabicyclo
[3.2.1] oct-6-en-2-ones 7a–h.
the expected product 7a; however, these catalysts
failed to further enhance the yield of the reaction in
comparison to CuBr (Table 1, entries 9 and 10).
Consequently, CuBr was chosen as the best catalyst for substituents in both aromatic rings Ar1 and Ar2. All
1
the model reaction. Carrying out the reaction using products were characterized by H NMR, 13C NMR,
°
10 mol% of CuBr at 60 C in toluene as solvent, and HRMS spectral analysis. In addition, X-ray
improved the reaction yield to 95% (Table 1, entry 11) diffraction analysis of the product 7a has confirmed
but in the presence of 5 mol% of CuBr, the reaction the structure of these compounds.
yield was decreased to 48% (Table 1, entry 13).
To our surprise, removing the Ar2 aromatic ring in
Screening different organic and inorganic bases such compound 6i caused the emerging of a serendipitous
as Et3N, DBU, NaOAc, and Cs2CO3 failed to provide reaction in the standard reaction condition. We realized
any results, and the only other base partner that proved that using a terminal alkyne containing compound 6i,
to be successful was indeed NaH; however, NaH also failed to produce the expected structure 7i, and
failed to improve the yield of the reaction in structure 8a was detected as the sole product in 88%
comparison to KOtBu (Table 1, entry 13). Finally, isolated yield with exclusive chemoselectivity. The
based on these pieces of information, the best result spiro-diketopiperazinochromanes 8a was identified
(95% yield) was achieved in the presence of CuBr based on 1H NMR, 13C NMR, HRMS spectral analysis,
(10 mol%) as the catalyst, KOtBu (2 eq.) as the base, and
°
and toluene as the solvent at 60 C in a period of
30 min.
With the optimal conditions in hand, we then (Scheme 5), and spiro-diketopiperazinochromane 8a
explored this in situ copper-catalyzed [3+2]-cyclo- was synthesized without any specific side product.
X-ray diffraction analysis. In this case, the reaction
proceeds through selective 6-exo-dig spirocyclization
addition and representative results shown below
Resting on these observations, the substrate scope
(Scheme 4). All of the products were obtained in good of the copper-catalyzed cyclization of terminal alkyne
to excellent yields in a completely diastereoselective containing ortho-propargyloxy diketopiperazines for
manner. This reaction showed generality and functional the synthesis of new spiro-diketopiperazinochromanes
group tolerance. The protocol was found to be efficient was explored and representative results are shown in
to both electron-withdrawing and electron-donating Scheme 6. All of the products were obtained in good
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were all compatible under the standard condition.
Moreover, both electron-donating and electron-with-
drawing substitutions on the aryl group of amines
worked quite well. By using aliphatic amine in the
synthesis of starting materials, the reaction became a
complex mixture of products. Notably, in addition to
the cyclohexyl group in R1 position, CH2CO2Et also
worked very well. But in the presence of the t-butyl
group in the R1 position, the rection does not lead to
the desired product.
To gain a deeper insight into the mechanism of this
spiro-cyclization for the synthesis of 8a product,
ortho-allenoxy benzaldehyde was synthesized[11] and
subjected to Ugi reaction. The corresponding Ugi
adduct was then incorporated in cyclization reaction in
the presence of PPh3 to provide compound 9. Finally,
this structure was subjected to the standard reaction
condition, but no product was detected (Scheme 7).
This experiment revealed that the reaction does not
proceed through the allenoxy intermediate 9.
Scheme 5. Cu(I)-Catalyzed serendipitous spirocyclization.
Based on the mentioned results and previous works,
a plausible pathway for these reactions is shown in
Scheme 8. In the presence of KOtBu, CuBr converted
to KBr (not soluble in toluene) and t-BuOCu which
acted as the catalysis of the reaction.[12] Initially, after
deprotonation of the acidic proton by KOtBu, the
carbanion intermediate I is generated. Afterwards, two
separate pathways can be possible depending on the R
group. On one hand, if R=Ar, the reaction proceeds
through the formation of azomethine ylide. The
generated azomethine ylide III can undergo [3+2]-
cycloaddition with the π bond of alkyne (through the
II intermediate) to generate intermediate IV. Finally,
after protodemetalation of this intermediate, the desired
diazabicyclic product is performed. On the other hand,
the spiro compound is synthesized through a spiro-
cyclization. If R=H, the enol type intermediate V is
formed. Then, the triple bond is activated, and
followed by the nucleophilic addition of carbon chiral
center to alkyne bond, that would result in the
intermediate VII. Finally, after hydrogen abstraction of
this intermediate, the spiro-diketopiperazinochromane
compound is achieved as the product (Scheme 8).
To demonstrate the synthetic potential of our
products, compounds 8a and 8e were treated with
phenylboronic acid for oxidative Heck reaction of
Scheme 6. Substrates scope for the synthesis of spiro-diketopi-
perazinochromanes.
to excellent yields with exclusive regioselective
spirocyclization. This reaction was successful in
tolerating various functional groups. Electron-with-
drawing substitutions on the aryl group of aldehydes
Scheme 7. Control experiment of the spiro cyclization by using
o-allenoxy diketopiperazine 9.
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Scheme 8. Proposed reaction mechanism for the synthesis of 7a and 8a.
geminal hydrogens of two exo-double bonds yields with exclusive diastereoselectivity. The starting
(Scheme 9).[5b] Among four geminal hydrogens in this materials for this cycloaddition reaction were synthe-
compound, only one of them participated in the sized in two steps by PPh3-mediated Ugi post-trans-
oxidative Heck reaction, and just 1 eq. phenyl group formation reaction. Furthermore, using different start-
was coupled in a completely chemo- and stereo- ing materials with the terminal triple bonds, we were
selective manner.
able to synthesis functionalized spiro-diketopiperazino-
In conclusion, we have reported an efficient route chromanes in the standard reaction condition. This
to achieve functionalized diazabicyclic compounds, via spiro-cyclization reaction occurs completely regiose-
copper-catalyzed intramolecular [3+2]-cycloaddition lective.
reaction of o-propargyloxy diketopiperazines in high
Experimental Section
General procedure for the synthesis of final prod-
ucts
A 10 ml Schlenk tube was flame-dried under vacuum, back-
filled with argon and cooled to room temperature using a
standard Schlenk line apparatus. The Schlenk tube was charged
with CuBr (2.8 mg, 10 mol%), t-BuOK (45 mg, 0.4 mmol,
2 eq.). The Schlenk tube was put under vacuum and backfilled
with argon. Afterwards dry toluene (2 mL) was added by
syringe under a flow of argon. O-propargyloxy diketopiperazine
(0.2 mmol, 1 eq.) was added. The Schlenk tube was sealed by a
screw cap and the resulting mixture was stirred for 30 min at
°
60 C. The crude reaction mixture was evaporated under
reduced pressure. The residue was purified via column
chromatography on silica gel (eluent: EtOAc/ n-Hexane=1/7)
Scheme 9. Selective oxidative Heck reaction of geminal hydro-
gen of compound 8a and 8e.
to afford the corresponding product after drying under vacuum.
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CCDC-2058480 and CCDC-2058951 contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
We thank the Alexander von Humboldt Foundation for the
Linkage Research Group Program.
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