Organocatalytic, Organic Oxidant Promoted, Enamine C?H Oxidation/Cyclopropanation Reaction

Article abstract of DOI:10.1002/adsc.202100630

Herein, we demonstrate that organic, single-electron oxidant in the presence of diarylprolinol silylether type catalyst serves as a tool for the transformation of electron-rich enamines to iminium ions. These iminium ions take part in a subsequent Michael-initiated ring-closure (MIRC) reaction with in situ present nucleophile giving rise to overall cyclopropanation reaction of saturated aldehydes. Stereodefined cyclopropanes are obtained in high yields and selectivities. This one-pot transformation represents the additional example of saturated aldehydes being used in the coupled one-pot processes. (Figure presented.).

Full text of DOI:10.1002/adsc.202100630

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100630
Organocatalytic, Organic Oxidant Promoted, Enamine CÀ H
Oxidation/Cyclopropanation Reaction
a
b
c
Zdravko Džambaski, Aleksandra M. Bondžić, Ierasia Triandafillidi,
c
a,
Christoforos G. Kokotos, and Bojan P. Bondžić *
a
University of Belgrade-Institute of Chemistry, Technology and Metallurgy, Department of Chemistry
Njegoševa 12, 11000 Belgrade, Republic of Serbia
E-mail: bbondzic@chem.bg.ac.rs
b
Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11000
Belgrade, Serbia
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis
c
1
5771, Athens, Greece
Manuscript received: May 25, 2021; Revised manuscript received: June 20, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100630
Abstract: Herein, we demonstrate that organic, single-electron oxidant in the presence of diarylprolinol
silylether type catalyst serves as a tool for the transformation of electron-rich enamines to iminium ions. These
iminium ions take part in a subsequent Michael-initiated ring-closure (MIRC) reaction with in situ present
nucleophile giving rise to overall cyclopropanation reaction of saturated aldehydes. Stereodefined cyclo-
propanes are obtained in high yields and selectivities. This one-pot transformation represents the additional
example of saturated aldehydes being used in the coupled one-pot processes.
Keywords: CÀ H oxidation; Cyclopropanation; Diarylprolinols; Organocatalysis; One-pot reaction.
The strained cyclopropane scaffold is present in a
[1]
number of biologically relevant products; these
compounds exhibit a large spectrum of biological
activities, including enzyme inhibition, insecticidal,
antifungal, herbicidal, antibacterial, antitumor, and
[2]
antiviral activities.
Cyclopropane itself has been used as a general
[3]
anesthetic in the clinic since 1930, more recently
some derivatives have been found to have profound
biological activities such as BMS-505130, selective
Serotonine reuptake inhibitor (SRI), while some are
used as medicines, e.g., Cibenzoline, antiarrhythmic
drug, to name few (Figure 1).
The cyclopropane scaffolds are also important in
[4]
the synthesis of complex molecules and as templates Figure 1. Selected examples of bioactive molecules containing
for the construction of conformationally confined cyclopropane ring motif-
[5]
amino acids and peptides. Moreover, cyclopropanes
can undergo a variety of ring-opening reactions to
[6]
[9]
generate new molecular skeletons. Chemists have lyzed decomposition of diazo compounds and the
[7]
[10]
been long inspired in the synthesis of cyclopropanes,
using three principal methodologies, including the
Michael-initiated ring-closure (MIRC).
The importance of the cyclopropane structural motif
[8]
Simmons–Smith reaction, the transition-metal-cata- has inspired several research groups to apply various
organocatalytic methodologies in the synthesis of these
Adv. Synth. Catal. 2021, 363, 1–8
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scaffolds. Most of the reported organocatalyzed cyclo-
propanation strategies are based on the MIRC reaction
of pre-enolized or readily enolizable nucleophilic
species, such as α-bromo-malonates, bromonitrome-
thanes and sulfur ylides, with unsaturated substrates
(
e.g., enals, enones, and nitrostyrenes).
[11]
Tertiary amine catalysts have been used by Gaunt
in intermolecular enantioselective organocatalytic cy-
clopropanation reaction of enones via ammonium
[12]
ylides and by Connon in the cyclopropanation of a
variety of nitroolefins using dimethyl chloromalonate.
α,β-unsaturated aldehydes have been very exten-
sively studied in this type of transformation. To date,
there have been several successful examples of organo-
catalyzed asymmetric cyclopropanation reactions of
α,β-unsaturated aldehydes catalyzed by secondary
amine catalysts using various nucleophilic compo-
[13]
[14]
nents. MacMillan and Arvidsson used stabilized
sulfur ylides with dihydroindole based organocatalysts
to obtain cyclopropane products in high yields and
selectivities. Diaril-prolinol TMS ether catalyst 1
known as Jørgensen–Hayashi catalyst has found the
widest application in the cyclopropanation reaction of
Scheme 1. Proposed reaction pathway, organocatalyzed enam-
ine oxidation/cyclopropanation reaction. (A) Enamine oxidation
catalysis, (B) Iminium catalysis.
[15]
[16]
α,β-unsaturated aldehydes. Cordova
and Wang
[17]
[18]
used bromomalonates, Cordova
and Yan
used
[19]
bromonitromethane, Ye used chloro-acetophenones
[20]
while Rios used the benzyl chlorides in conjunction subsequent reaction of the in situ formed imine species
[21]
with this catalyst. Figueiredo and Campagne used with readily enolizable nucleophile present in the
Jørgensen-Hayashi catalyst in cyclopropanation of α- reaction mixture (tandem process) or subsequently
substituted enals with bromomalonate, while added in the reaction mixture (one-pot procedure)
[22]
Rueping used the same catalyst and bromomalonate would establish full enamine oxidation/cyclopropana-
in allylic alcohol MnO oxidation/cyclopropanation tion procedure (Scheme 1). There is neither a cascade
2
sequence of α,β-unsaturated alcohols.
nor one-pot process that allowed this transformation to
It is apparent that most of the development in this date to the best of our knowledge. In order to
field has relied on the use of α,β-unsaturated aldehydes efficiently develop the postulated reaction, several
and secondary amine organocatalysts operating under a issues should be addressed. Due to the subtle depend-
well-known LUMO lowering aminocatalysis mecha- ence of reaction yields and selectivity to reaction
nism (Path B, Scheme 1).
conditions, the oxidant and resulting byproducts should
That is quite understandable since until recently, not interfere with the subsequent reaction. Accord-
iminium catalysis relied exclusively on the use of α,β- ingly, the reaction medium should be compatible with
unsaturated aldehydes. Reversal of enamine’s reactiv- both the oxidation and cyclopropanation reaction to
ity and their transformation from electron-rich, electro- enable the achievement of high reaction efficiencies
philic species into electron-deficient iminium ions and selectivities in the each step of the process.
acting as a nucleophilic species requires in situ
oxidation of enamines (Path A, Scheme 1). Hayashi
It is known that 2,3-dichloro-5,6-dicyano-1,4-ben-
zoquinone (DDQ) very efficiently oxidizes saturated
[23]
[
24]
and Wang
single electron oxidizing agents in their seminal Hayashi catalyst 1 in THF as a solvent.
publications. Subsequently, several additional reports catalyst 1 has been very extensively used in organo-
have accomplished this using organic aldehydes to enals in the presence of Jørgensen-
[23]
Also,
[25]
[15–22]
have appeared, and our group recently reported on catalyzed cyclopropanation reactions.
the enantioselective organocatalytic enamine oxida- this in mind, it appeared that at the very beginning we
tion/Diels- Alder reaction.
Having all
[26]
had a perfect match of reactivity for both steps of the
The design plan for the organocatalyzed enamine reaction with the single catalyst.
oxidation/cyclopropanation reaction was to use enoliz-
Our investigation started by testing DDQ oxidation
able aldehyde in combination with secondary amine of 3-phenylpropanal in the presence of the catalyst 1,
catalyst and organic single electron transfer (SET) bromomalonate as nucleophile and tertiary amine base.
oxidant in the first step of the reaction. Enamine However, we were unable to obtain the desired product
oxidation to the corresponding iminium ion and in good yields due to the formation of byproducts and
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incomplete conversion of starting material. Oxidation Table 1. Optimization of reaction conditions in enamine
reaction to α,β-unsaturated aldehyde proceeded well, oxidation/cyclopropanation sequence.
however, subsequent conversion of intermediary imi-
nium ion was very sluggish in most cases (see
supporting information, table S1 for details). Next, we
turned our attention to chloroacetophenones, previ-
[19]
ously used by Ye in cyclopropanation reaction.
Based on the experience from our previous work we
expected that the organocatalized, DDQ oxidation step
should not interfere with the enantioselectivity of the
[26]
subsequent reaction. In line with that, chiral catlyst
1
that has already shown excelent reactivity in DDQ
[23]
[a]
[b]
[c]
oxidation reactions and excellent enantioselectivities Entry
in cyclopropanation reaction of α,β-unsaturated
aldehydes was tested. We attempted reaction in the
presence of 20 mol% of catalyst 1, 1 equiv. DDQ, 1
Cat. Base (equiv.) solvent Time (h)
Yield
(%)
[19]
[d]
1
2
3
4
5
6
7
8
9
1
1
1
1
2
3
4
1
2
1
2
1
2
Et N (1)
THF
THF
THF
THF
THF
THF
2+36
2+36.
2+36
2+36
2+36
2+36
11
35
3
Et N (1)
3
equivalent of the Et N and 3 equivalents of the
[e]
3
Et N (3)
75
70
61
/
45
51
26
21
53
38
3
chloroacetophenone 7. However, oxidation reaction
proceeds very slowly in the presence of the base and
after 2 h 50% conversion was observed, and 11% of
final product was isolated (Table 1, Entry 1). Next, we
tested stepwise addition of reagents and allowed
oxidation reaction of 3-phenylpropanal in the presence
of catalyst and DDQ in THF to proceed for 2 h (until
full conversion to enal), then 1 equiv. of the base was
added and then 3 equivalents of chloroacetophenone,
we observed conversion to desired cyclopropane in
Et N (3)
3
Et N (3)
3
Et N (3)
3
Et N (3)
Toluene 2+36
Toluene 2+36
3
Et N (3)
3
Et N (3)
CH Cl2
24+36
24+36
2+36
2+36
3
2
0
Et N (3)
CH Cl2
3
2
1
1
DIPEA(3)
DIPEA(3)
THF
THF
1
2
[
a]
Reaction conditions unless otherwise indicated: 3-aryl
propanal derivative (0.25 mmol), catalyst (0.05 mmol), Oxi-
dant (0.25 mmol), and THF (1 mL) stirred at room temper-
3
5% yield (Table 1, Entry 2).
Since during the reaction 1 equivalent of DDQH is
2
formed, possessing 2 acidic protons, we hypothesized
that 2 equivalents of the base would be required to
neutralize these protons and one additional equivalent
to promote the reaction. Next, we tested the stepwise
oxidation/cyclopropanation by adding 3 equivalents of
ature for 2 h. Subsequently, Et N (1.5 mmol) and Chloroace-
3
tophenone derivative were added and the reaction mixture
was stirred for a designated period of time. See the
Supporting Information for details;
Oxidation time plus cyclization time;
Isolated yield after column chromatography;
All reagents added at the outset;
Enantiomeric excess was determined on chiral phase HPLC
to be 96% (see SI). DIPEA: Ethyldiisopropylamine; VG:
voluminous group.
[
b]
c]
[
Et N and chloroacetophenone after oxidation was
[d]
[e]
3
complete and indeed isolated 75% of the desired
product in very high diastereoselectivity of >95/5 and
excellent enantioselectivity of 96% (Table 1, Entry 3).
Since this stepwise procedure gave a satisfactory
result, we next tested several organocatalysts 2–4.
Catalyst 2 under the same conditions gave 70% yield
of the desired product. This catalyst is known to (Table 1, Entries 11 and 12). Since the combination of
efficiently promote oxidation of aldehydes to enals catalyst 1 and DDQ in THF with the subsequent
[
23b] and it very efficiently catalyzed the cyclo- addition of Et N as a base gave the best results, these
3
propanation step (Table 1, Entry 4). Catalyst 3 gave conditions were chosen to test this transformation‘s
1% yield of the desired product (Table 1, Entry 5) scope. Pent-4-enals possessing electron-donating or
6
while catalyst 4 did not promote reaction (Table 1, electron-withdrawing substituents were tested in com-
Entry 6). Since catalysts 1 gave the best results, it was bination with unsubstituted or 4’-substituted 2-chlor-
tested in different solvents, in toluene oxidation oacetophenones. 3-phenyl propanal was efficiently
reaction proceeds efficiently; however, the MIRC step oxidized and reacted smoothly with tested 2-chloroace-
doesn’t proceed as efficiently, giving lower yields tophenones to give desired products in good yields and
compared to THF (Table 1, Entries 7 and 8). The excellent enantioselectivities (Table 2, Entries 1–3). 3-
oxidation step is very slow and sluggish in CH Cl2 (p-tolyl)propanal with electron-donating Me-substitu-
2
giving low yields of the desired final product as a ent gave good yields of desired cyclopropanation
consequence (Table 1, Entries 9 and 10). Finally, in the products (Table 2, Entries 4–6). 3-phenylpropanals
presence of DIPEA, the final product is obtained in with electron-withdrawing substituents i.e., 4-Fluoro,
lower yield compared to the use of Et N as a base 4-CF 4-Br or 3,4-dichloro substituted, also reacted
3
3,
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Table 2. Scope of organocatalyzed asymmetric enamine oxida- these cases. Aldehydes such as 3-benzyloxypropanal
tion/cyclopropanation reaction of 3-aryl propanals.
and 7-phenylhept-4-enal are also not suitable substrates
for DDQ oxidation in the presence of secondary amine
[23b]
catalysts.
The presence of an extended π system or
other stabilizing group seems to be a prerequisite for
reaction to progress. Stereoconfiguration of synthe-
sized formyl cyclopropanes was determined by com-
paring NMR spectra of our compounds with the
compounds of known configuration from the
1
2
[a]
[b]
[c]
Entry Ar
Ar
Yield (%) d.r.
e.e.
%)
[19]
literature.
(
Pent-4-enal derivatives 9 undergo oxidation reac-
1
2
3
4
5
6
7
8
9
1
C H5
C H5
4-ClC H4 69(8b)
75(8a)
>95/5 96
>95/5 97
tion since they possess an extended π system that can
6
6
[23, 26]
C H5
stabilize charge and/or radical intermediate.
DDQ
6
6
C H5
6
4-FC H4
66(8c)
71(8d)
>95/5 n.d.
>95/5 n.d.
>95/5 n.d.
>95/5 n.d.
>95/5 92
>95/5 95
>95/5 99
>95/5 96
>95/5 95
>95/5 99
>95/5 n.d.
>95/5 n.d.
>95/5 n.d.
>95/5 95
>95/5 94
>95/5 99
>95/5 n.d.
>95/5 n.d.
>95/5 n.d.
6
promoted oxidation of pent-4-enal substrates in the
presence of amine catalyst produces α,β,γ,δ,-unsatu-
rated iminium ion 12. This type of iminium ion system
may undergo 1,4 or 1,6 conjugate addition reactions;
however, 1,4 addition is the prevalent mode of
reactivity in the presence of diphenyl prolinol silyl
6
4-MeC H4
6
C H5
4-MeC H4
4-MeC H4
4-FC H4
4-FC H4
4-ClC H4 70(8e)
4-FC H4 62(8f)
6
6
6
6
C H5
69(8g)
6
6
4-ClC H4 73(8h)
4-FC H4
6
6
60(8i)
68(8j)
6
4-FC H4
6
[27]
ether type catalyst 1. We tested 5-substituted pent-4-
0
4-CF C H
4-CF C H
4-CF C H
4-BrC H4
4-BrC H4
4-BrC H4
C H5
3
6
4
4
4
6
enals 9 in our reaction setup using optimized reaction
conditions with catalyst 1 (Table 3). Aromatic groups
with either E- or Z-configuration Ph substituted E-
olefinic substrate reacted with 2-chloroacetophenone to
yield 68% of two isomers 10 and 11 in 85/15 ratio
(Table 3, Entry 1) at the double bond were used as
substituents at the 5- position of pent-4-enal substrates.
1
1
4-ClC H4 77(8k)
4-FC H4 71(8l)
3
6
6
1
1
1
1
1
1
1
1
2
2
2
3
4
5
6
7
8
9
0
1
3
6
6
C H5
70(8m)
6
6
4-ClC H4 80(8n)
4-FC H4 71(8o)
6
6
6
6
64(8p)
6
3,4-diClC H3 C H5
6
3,4-diClC H3 4-ClC H4 82(8q)
3,4-diClC H3 4-FC H4 70(8r)
2-Naph
2-Naph
2-Naph
6
6
6
6
C H5
51(8s)
6
4-ClC H4 58(8t)
4-FC H4 50(8u)
Table 3. Scope of organocatalyzed asymmetric enamine CÀ H
6
6
activation/cyclopropanation reaction of Pent-4-enal derivatives.
Reaction conditions unless otherwise indicated: 3-aryl propanal
(0.25 mmol), catalyst (0.05 mmol), DDQ (0.5 mmol) in THF
(
1 mL) stirred at r.t. for 2 h. Subsequently, Et N (1.5 mmol)
3
and Chloroacetophenone derivative (1.5 mmol) were added
and stirred for a designated period of time. See the Supporting
Information for details.
[a]
[b]
[c]
Isolated yield after column chromatography;
Determined by 1H NMR spectroscopy;
Determined by chiral phase HPLC separation; n.d.=not
determined.
[a]
1
2
[b]
[c]
Entry
Ar
Ar
Yield (%)
10+11)
d.r.
Pent-4-enal derivatives 9 undergo oxidation reaction since they
possess an extended π system that can stabilize charge and/or
(
10/11
[
23,26]
radical intermediate.
DDQ promoted oxidation of pent-4-
1
2
3
4
5
E-Ph
E-Ph
E-Ph
Z-Ph
Z-Ph
Ph
4-ClC H4
4-FC H4
Ph
68 (10a+11a)
75 (10b+11b)
65 (10c+11c)
66 (10a+11a)
71 (10b+11b)
85/15
76/24
73/27
84/16
75/25
enal substrates in the presence of amine catalyst produces
α,β,γ,δ, unsaturated iminium ion 12. This type of iminium ion
6
6
4-ClC H4
6
very efficiently to give desired products in high yields
and excellent enantioselectivities (Table 2, Entries 7–
[a]
Reaction conditions unless otherwise indicated: pent-4-enal
derivative (0.25 mmol), catalyst (0.05 mmol), DDQ
1
8).
(0.5 mmol), and THF (1 mL) stirred at room temperature for
3-(naphthalen-2-yl)propanal possessing voluminous
2
h. Subsequently, Et N (1.5 mmol) and chloroacetophenone
3
naphtyl group was also a good substrate in this
reaction, although bit lower yields compared to other
substrates were obtained (Table 2, Entries 16–18).
Linear unsubstituted aliphatic aldehydes such as
hexanal and nonanal did not undergo the oxidation
reaction, and the starting material was recovered in
(1.5 mmol) were added, and the reaction mixture was stirred
for a designated period of time. See the Supporting
Information for details.
Isolated yield after column chromatography;
Determined by 1H NMR spectroscopy; VG: voluminous
group.
[
b]
c]
[
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2-chloro-4’-chloroacetophenone possessing elec-
There are several publications regarding derivatiza-
tron-withdrawing p-Cl substituents at phenyl ring also tions of chiral formylcyclopropane structures using
[29]
[30]
efficiently reacted with 9 upon oxidation, giving 75% NHC
or Ni
catalysis. We have performed a
yield and 76/24 ratio of diastereoisomers (Table 3, reaction with 3-phenylpropanal on a larger (1 g) scale
Entry 2). 2-chloro-4’-fluoroacetophenone reacted to (see SI for details) to show that reaction is viable on a
give 65% yield and 73/27 ratio od diastereoisomers preparative scale as well.
(Table 3, Entry 3). Ph substituted Z-olefin in reaction
When a solution of starting aldehydes was com-
with 2-chloroacetophenone gave rise to 84/16 ratio of bined with DDQ, we observed the immediate forma-
diastereoisomers; however, Z-olefin isomerizes to give tion of deep green to brown color that might indicate
the product of E-olefin reaction. Products were isolated charge transfer complex A (Scheme 2). Based on the
in 66% yield (Table 3, Entry 4).
above observations, we propose the plausible catalytic
The same Z-olefinic substrate reacts with 2-chloro- cycle for enamine oxidation/cyclopropanation reaction.
’-chloroacetophenone to give E-olefin reaction prod- Upon condensation of the catalyst with the saturated
4
ucts, showing once again that isomerization of Z- aldehyde, enamine species I is formed. DDQ oxidizes
olefinic bond is occurring under these reaction con- enamine I to iminium ion II, which hydrolyzes to α,β-
ditions. Z-E olefin isomerization might indicate radical unsaturated aldehyde III. Upon addition of Et N,
3
cation intermediate and single electron transfer oxida- counter-ion change occurs, forming IV, which reacts
tion mechanism (Figure 2). Cis-Trans isomerization of with enolized 2-chloroacetophenone to form the inter-
[28]
allylic radicals is a well-known process.
mediate Michael addition adduct V. This adduct
cyclizes to give cyclopropane adduct VI. Upon
hydrolysis, the transient iminium species VI is con-
verted to product VII, the catalyst is released and
enters the new cycle. The first step of the reaction i.e.,
DDQ oxidation of the enamine is thought to proceed
via a single electron transfer from enamine to DDQ
[28]
(Figure 2). Resonance stabilized allylic radical cati-
on is formed, from which hydrogen transfer would
proceed to provide iminium ion. CÀ H bond dissocia-
tion energy in radical cation has significantly lower
Figure 2. Proposed mechanisms for DDQ oxidation of enam-
ines to iminium ions.
Scheme 2. Proposed catalytic cycle of DDQ promoted enamine oxidation/cyclopropanation reaction.
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energy than in starting material, allowing it to be References
abstracted by DDQ. In summary, we have demon-
strated the first example of an organocatalyzed one-pot
enamine oxidation/cyclopropanation reaction. In situ
oxidation of saturated aldehyde, in the presence of a
secondary amine catalyst and DDQ as an oxidant,
served as an effective system for the promotion of
swift conversion to α,β-unsaturated aldehyde, i.e.,
enamines to iminium ions. Subsequently, formed
transient iminium ion reacts with a nucleophile present
in the reaction mixture to undergo a Michael-initiated
ring closure reaction to provide cyclopropanation
product upon hydrolysis. This reversal of reactivity
from electron-rich enamine to electron-deficient imi-
nium ion served as a mechanistic foundation for our
reaction. Due to its operational simplicity and insensi-
tivity to traces of water or air in the reaction mixture,
this easily performed reaction setup can be of great use
to organic synthesis practitioners.
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4
493–4537; e) O. G. Kulinkovich, Cyclopropanes in
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2
[
2] For reviews see: a) A. De Meijere, Topics in Current
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[
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Experimental Section
Catalyst 1 (0.075 mmol) was added to a stirred solution of
aldehyde (0.5 mmol) in THF (1 ml) and allowed to stir for
2
000, 11, 645–732. Recent application:; c) S. C. De Pol,
1
5 minutes. Then DDQ (0.5 mmol) was added, and the solution
C. Zorn, C. D. Klein, O. Zerbe, O. Reiser, Angew. Chem.
Int. Ed. 2004, 43, 511–514; Angew. Chem. 2004, 116,
was stirred at room temperature until TLC showed full
conversion of starting aldehyde (typically 1–2 h). Subsequently,
5
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Acknowledgements
This work was financially supported by the Ministry of
Education, Science and Technological Development of the
Republic of Serbia (Grant No. 451-03-9/2021-14/200026). I. T.
would like to thank State Scholarships Foundation (IKY) for a
post-doctoral research scholarship funded by the “Supporting
Post-Doctoral Researchers-Call B” (MIS 5033021), action of
the Operational Programme “Human Resources Development,
Education and Lifelong Learning” and co-funded by the
European Social Fund (ESF) and Greek National Resources. C.
G. K. gratefully acknowledges the Hellenic Foundation for
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Organocatalytic, Organic Oxidant Promoted, Enamine CÀ H
Oxidation/Cyclopropanation Reaction
Adv. Synth. Catal. 2021, 363, 1–8
Z. Džambaski, A. M. Bondžić, I. Triandafillidi, C. G.
Kokotos, B. P. Bondžić*