Schreiner's Thiourea Promoted [2+2] Cycloaddition of Captodative Azetidinones and Nitroolefins

Article abstract of DOI:10.1002/ejoc.201601524

Strained, captodative benzylideneazetidinones were demonstrated to function as potent reaction partners in thermal [2+2] cycloadditions with nitro alkenes. The relief of strain during the cycloaddition could be leveraged to secure kinetic and thermodynamic stability for the aminonitrocyclobutane ring. Accordingly, this mild and robust procedure could be used to simplify the synthesis of azaspiro[3.3]heptanes, a motif that serves as a rigid piperidine bioisostere.

Full text of DOI:10.1002/ejoc.201601524

A Journal of
Accepted Article
Title: Schreiner's Thiourea Promoted [2+2] Cycloaddition of
Captodative Azetidinones and Nitroolefins
Authors: Zoltán Dobi, Tamás Holczbauer, and Tibor Soos
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601524
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601524
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
Schreiner’s Thiourea Promoted [2+2] Cycloaddition of
Captodative Azetidinones and Nitroolefins
Zoltán Dobi, Tamás Holczbauer and Tibor Soós*
Abstract: Strained, captodative benzylidene-azetidinones are
demonstrated to function as potent reaction partners in thermal [2+2]
cycloaddition with nitro alkenes. The relief of strain during the
cycloaddition could be leveraged to secure the kinetic and
thermodynamic stability for the amino-nitro-cyclobutane ring.
Accordingly, this mild and robust procedure can be used to simplify
the synthesis of aza-spiro[3.3]heptanes, a motif that serves as a rigid
piperidine bioisostere.
In recent years, development of nonclassical bioisosters with
strained ring systems have been evolved as a prominent tactical
approach in drug discovery and development.[1] By inserting
these structural motifs in drug candidates, several
pharmacological properties have been beneficially altered and
Figure 1. Methods for the preparation of aza-spiro[3.3]heptanes.
the challenge of narrowing intellectual property space has also
been eased.[2]
Recently, we have reported that the angle strain of four-
membered heterocyclic ketones could be exploited in the
development of direct cross-ketol and aldol reactions, providing
new class of constrained building blocks.[5] As exemplified, the
commercially available azetidinone 1 (Figure 2), as an inherently
bifunctional synthetic module, could function as a linchpin
element in an iterative double-aldol sequence without the need
of preformed enols.
As saturated heterocycles, such as piperidines, morpholines
and piperazines are often encountered in drugs, significant
research efforts have been pursued to create their structurally
rigid surrogates.[3] These activities have implied a range of
synthetic advances, including the invention of novel
methodologies and strategies to incorporate these scaffolds into
elaborated molecules. A particular class of substructure, that is
of interest to medicinal chemists, is the aza-spiro[3.3]heptanes
which can serve as a piperidine analog. The synthetic strategies
for construction of these spirocyclic counterparts are scarce and
exclusively rely upon the formation of the azetidine ring from
cyclobutane derivatives (Figure 1. routes a,b).[4] Surprisingly,
there has been no report about the obvious alternative approach
that would proceed via cyclobutane ring formation of an
azetidine derivative. Herein, we report the realization of this
alternative ring formation that was based on the unique reactivity
of a captodative benzylidine azetidinone. A complementary
motivation underlying this synthetic study was to investigate the
effect of strain on chemical reactivity of four membered
heterocyles.
Figure 2. The Effect of Strain Release on Chemical Reactivity of
Azetidinone 1.
Following these findings, we became intrigued whether the
strain-driven reactivity[6] of four-membered heterocyclic ketones
could have been extended by incorporating an exo-olefin
functionality. More specifically, we aimed to investigate the 2-
benzylidene derivatives of azetidinone 1 that might function as a
reactive captodative olefin.[7] This initiative obviously posed the
following questions. First of all, can such captodative
compounds be readily synthetized? What will be the
consequence of ring strain on the reactivity? Finally, can these
derivatives be exploited in building potentially useful structures
to expand the reach of interesting structural patterns?
Z. Dobi, T. Holczbauer, T. Soós
Institute of Organic Chemistry, Research Centre for Natural
Sciences, Hungarian Academy of Sciences
P.O. Box 286, 1519 Budapest (Hungary)
E-mail: soos.tibor@ttk.mta.hu
To deal with the first question, the synthesis of the
captodative olefin 2a was attempted following a straightforward
three-step aldol condensation protocol developed by Masuda.[8]
The synthesis began with the direct cross-aldol reaction of
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
azetidinone 1 and benzaldehyde without added catalyst. As we
have reported earlier, one could only isolate the anti-aldol
adduct because the isolation of the syn product was hampered
by its tendency to undergo rapid syn-anti isomerization.[5] While
at first glance, one might have thought that aldol adduct 3a could
have been directly converted to the condensation product 2a, no
formation of the captodative olefin was observed because the
retro-aldol reaction outperformed the water elimination reaction
under the requisite forcing reaction conditions. Thus, the anti-
aldol adduct 3a was acetylated to facilitate the subsequent
elimination procedure. The thermal elimination of 4a was then
carried out in neat upon rapid thermal treatment (185°C, 2 min).
(Figure 3). This interesting diketo compound 5 could decompose
even further to glycine derivative 6 in the EtOH/AcOH mixture.
After multiple iterations of reaction conditions, we found that one
equivalent of AcOH in acetonitrile efficiently promoted the
elimination as a single olefinic product 2a yielded without side
product formations. From the structure of captodative olefin 2a
determined by X-ray crystallography,[9] it was concluded that the
elimination proceeded in
a stereoselective trans manner.
Experiments that probe the scope of aromatic aldehydes in
captodative olefin formation reaction are also summarized in
Table 1. As hoped, an array of electron-rich and electron-poor
aldehydes can effectively serve as starting materials in this
procedure. Most importantly, all elimination reaction steps were
stereoselective, robust and scalable. Finally, it is noteworthy that
utilization of aliphatic aldehydes as starting materials are not
tolerated in this procedure, as the resulting captodative
derivative proved to be unstable.
Table 1. Synthesis of captodative olefins 2a–h.
Ac
O
R
O
N
O
N
O
N
O
N
Aldehyde
(1-3 equiv)
AcO
H (1
ACN
equi
v)
R
R
AcCl, TEA
H
25-40°C, 2 d,
iPrOH
25°C, 1 d
0-25°C, 4 h
Toluene
H
OH
1
Ph
4a-h
Ph
2a-h
3a-h
Ph
Ph
Ph
Ph
Ph
Ph
R
aldol product
acetate
captodative olefin
3a (62%) (dr = 4:1)
4a (72%)
2a (89%)
3b (78%) (dr = 4:1)
3c (63%) (dr = 1.2:1)
3d (80%) (dr = 1.1:1)
4b (30%)
4c (58%)
4d (69%)
2b (87%)
2c (89%)
2d (92%)
3e (81%) (dr = 2:1)
3f (87%) (dr = 2:1)
3g (65%) (dr = 1.5:1)
3h (49%) (dr = 6:1)
4e (56%)
4f (27%)
4g (71%)
4h (30%)
2e (96%)
2f (83%)
2g (93%)
2h (91%)
Figure 3. Exploring the reactivity of captodative olefin 2a.
Next, we have conducted some preliminary experiments to
ascertain the ambident nature of the captodative olefin 2a. In an
initial trial, the reaction of captodative olefin with thiophenol was
probed. Gratifyingly, highly selective reaction occurred and the
sense of regioselectivity reflected the dominant directivity of the
amino functionality. It is worth mentioning that the degradation of
captodative olefin during its preparation, as highlighted in Figure
3, seems to follow this type of reactivity. We next examined a
reaction with a more acidic sulphur compound, the thioacetic
acid with 2a. Interestingly, this nucleophile also underwent a
selective addition reaction, however, the reaction occurred with
different regioselectivity. In the presence of stronger acid, the
amino group seems to be protonated and the captodative olefin
functioned not as an enamine, but as a Michael acceptor.
This procedure, developed by Matsuda, did afford the
desired captodative olefin 2a, however, it proved to be less
robust and reproducible in our hand despite repeated attempts.
The poor and non-reproducible yields were presumed to be due
to the decomposition of the vulnerable captodative olefin 2a
under the harsh condition, therefore, an alternative, mild
procedure had to be developed. After a few elimination attempts
at ambient temperature, it became evident that the elimination
process could only be promoted by acids, but not by bases.
Several observations are of note: When a small amount of acetic
acid was added to the starting material, an autocatalytic
elimination occurred that could be completely inhibited by
triethylamine. Another interesting feature is the solvent
dependence of reaction rate and outcome. The reaction rate is
largely decelerated in apolar solvents such as hexanes, toluene,
ethyl acetate. In acetic acid, however, decomposition of the
captodative olefin 2a to a ring opened derivative 5 was observed
Having established the acid modulated ambident reactivity
of the captodative system, we also sought to utilize azetidinone
alkene derivatives 2a–h for gaining access to spirocyclic
structures. Given their dominant enamine character, we
envisioned installing nitro alkenes to captodative olefins 2a–h in
a [2+2] reaction to form cyclobutane[10] derivatives. While
common enamines could form amino-nitro cyclobutanes, those
compounds are notoriously unstable.[11] They are either in
thermal equilibrium with the corresponding enamine and nitro
alkene or undergo ring opening in the presence of water (Figure
4).[11e] Nevertheless, we hypothesized that the inherent angle-
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
strain of azetidinones could be leveraged to secure kinetic and
thermodynamic stability for the amino-nitro-cyclobutane ring.
Table 2. Solvent screening for [2+2] cycloaddition of benzylidene-azetidinone
and nitrostyrene
The envisioned [2+2] reaction was first examined using the
representative captodative olefin 2a and nitroalkene 9a as
coupling partners, along with p-nitrophenol as hydrogen donor
catalyst.[12] Gratifyingly, the desired spirocyclic product 10aa was
observed as a sole product with all-trans cyclobutane ring at
room temperature with good conversion. To our delight, the
cyclobutane ring of 10aa proved to be stable; no decomposition
was observed during its isolation indicating that the strain relief
upon cycloaddition drives the thermodymanics of the reaction.
As the strained captodative olefin is a vulnerable entity, these
reactions had to be performed at ambient temperature with the
rigorous exclusion of O or S nucleophiles, such as alcohols,
aromatic an aliphatic thiols. Even the stabilizer of the chloroform,
the ethanol, had to be removed for successful reaction. An
attempt to extend the heterocyclic part of the strained
captodative alkenes was also probed, however, the thia analog
2i failed to react with nitroolefin 9a.
Entry
Solvent
DMSO
dr[a]
12:1
Yield[b]
70
1
2
3
4
5
6
7
8
Toluene
Chloroform
THF
3.5:1
2.3:1
>20:1
2.25:1
>20:1
11:1
65
74
32
Ethyl acetate
Acetonitrile
Acetone
DMF
68
48
72
>20:1
28
[a] The diastereomeric ratio in the crude reaction product was determined by
1H NMR. [b] Isolated yields of diastereomers.
Using the optimized catalytic conditions, the scope of the
cycloaddition was investigated. The scope of the captodative
olefins that can be reacted in [2+2] addition is illustrated in Table
3 (10aa–10hb). Monosubstituted phenyl derivatives bearing
electron-donating groups worked smoothly, however, electron
withdrawing group substituted derivatives, as expected, tend to
give lower yields. Experiments that probe the scope of the
nitroalkene component is summarized in Table 3 (10ac–10az).
These studies revealed that [2+2] cycloaddition reaction with the
representative olefin 2a works with aromatic or aliphatic
nitroalkenes and their structural and electronic modification had
an anticipated effect on reactions’ efficiency. Enhancement of
the steric demand of the nitroalkene deleteriously affected the
yields, as exemplified in the formation of (10ao, 10ad). The
presence of the electron withdrawing groups on the aromatic
rings of β-nitrostyrenes exerted auspicious influence on the
reactions’ efficiency, especially when they were in ortho or para
positions (10ab, 10db, 10hb, 10ai). However, the para-nitro
substituted β-nitrostyrene reacted distinctly; two unidentified side
products were also formed, that lowered the yield. The β-
nitrostyrenes with electron rich aromatic rings have a tempered
electrophilic reactivity that resulted in lower yields in the
cycloadditions (10al, 10as). As a proof for versatility and
generality of this methodology, we have found that aliphatic
nitroalkenes are suitable substrates (10ax, 10ay, 10az). It is
worth noting that the cycloaddition reaction tolerated various
high-value functionalities such as acetylene, bromo and iodo
substitutents that provide additional opportunities for further
diversification.
Figure 4. Formation and decomposition of cyclobutanes generated in a [2+2]
cycloaddition reaction.
Despite p-nitrophenol being an efficient catalyst, further
screens for an improved catalyst were pursued.[9] This search
eventually identified Schreiner’s thiourea[13] as the most efficient
promoter. In cases of phenolic catalyst or acetic acid, the
isolated yields were significantly lower, because the captodative
olefin 2a suffered decomposition in their presence. Chiral
hydrogen donating catalysts were also probed, however, no
chiral induction was observed.[9] As revealed in a subsequent
solvent screening (Table 2), this unique [2+2] addition can be
easily accomplished in a wide range of aprotic solvents. The
best
yield
was
achieved
in
chloroform,
but
the
diastereoselectivity was modest. A reaction conducted in toluene
gave a lower yield; however, the product precipitated out from
that solvent which can be a tradeoff for practicality. The optimal
solvent was the acetone, because the reaction proceeded in this
solvent with high yield and diastereoselectivity.
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
Table 3. Scope of [2+2] cycloadditions between captodative olefins 2a–h and
nitroalkenes 9a–z.
[a] The diastereomeric ratio in the crude reaction product was determined by 1H
NMR. [b] Isolated yields of diastereomers. [c] The catalyst was changed to p-
nitro-phenol.
Conclusions
In summary, the research above demonstrates the synthetic
utility of strained, azetidinone-based captodative olefins for
accessing aza-spirocyclic compounds. The captodative building
blocks are reached through a three-step, robust and scalable
procedure. We have demonstrated that the strained captodative
olefin has acid modulated ambident reactivity. Taking advantage
of strain-driven enhanced reactivity and the dominant enamine
character of 2a, we have accomplished the highly
diastereoselective [2+2] cycloaddition of cyclobutane ring. Given
the importance of the aza-spirocyclic motifs as rigid piperidine
bioisostere in medicinal chemistry, the lower yet serviceable
yields observed will likely be a welcome advance to chart highly
coveted region of chemical space in a concise manner. Further
explorations of the strain-driven reactivity of four-membered
heterocycles are underway in our laboratory.
Experimental Section
General procedure for the direct aldol reactions between 1-
Diphenylmethylazetidin-3-one (1) and benzaldehyde derivatives: 1
(2.0 mmol) was dissolved in 4 mL of isopropanol and a benzaldehyde
derivative (1-3 equiv.) was added. The mixture was stirred at 25-40 °C for
2 days then the solvent was evaporated. The residue was purified by
column chromatography (SiO2; hexane / ethyl acetate) to give aldol
products (3a–h).
General procedure for the acetylation of aldol adduct 3a–h: A
solution of 3a–h (2.0 mmol), triethylamine (4.0 equiv.) and abs. toluene
(9 mL) were cooled to 0 °C and acetyl chloride (3.5 equiv.) was added
dropwise. After 10 minutes the mixture was allowed to warm to room
temperature, stirred for another 4 hours then washed with 3 ml water, 3
ml saturated NaHCO3 solution and 3 ml brine. The organic phase was
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
dried over MgSO4 and the solvent was removed under reduced pressure.
The residue was purified by column chromatography (SiO2; hexanes /
ethyl acetate) to give 4a-h.
[5]
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General procedure for the elimination reactions: 4a–h (1.0 mmol)
was dissolved in 9 mL of acetonitrile and acetic acid (1.0 equiv) was
added. The mixture was stirred at room temperature for 24 hours then
diluted with 45 ml diethyl ether, washed with 2x12 mL of saturated
NaHCO3 solution and with 12 mL of brine. The organic phase was dried
over MgSO4 and the solvent was removed under reduced pressure. The
residue was purified by column chromatography (SiO2; hexanes / ethyl
acetate) to give 2a–h.
[8]
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For more details see the Supporting Information.
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General procedure for the [2+2] cycloadditions: 2a–h (0.8 mmol), 9a-
z (2.0 equiv.) and Schreiner’s catalyst (0.2 equiv.) were dissolved in 1.6
mL of acetone. The mixture was stirred at room temperature for 24 hours
then the solvent was evaporated at reduced pressure. The residue was
purified by column chromatography (SiO2; hexanes / ethyl acetate) to
give 10a-h_a-z.
General handling guide for the 1-azaspiro[3.3]heptane derivatives:
The products are rather stable solid molecules with high melting point.
However, in liquid phase they can decompose slowly, depending on the
solvent. Chloroform must be avoided unless for the NMR studies. The
best solvents to prevent decomposition are hexane and diethyl ether.
The product is sensitive to common (acidic) silica gel and basic alumina.
The chromatography needs to be carried out in neutral silica gel. Our
choice was the Biotage® SNAP KP-Sil (pH = 7.2), which was found to be
perfect solid phase to purify the crude product.
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Acknowledgements
Keywords: Organocatalysis
•
azetidine
•
cyclobutane
•
Spirocycle • [2 + 2] cycloaddition
[12] Without added H-bond donor additives no reaction occurred in
analogous organocatalytic processes, ref 11e, 11g
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10.1002/ejoc.201601524
European Journal of Organic Chemistry
SHORT COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
SHORT COMMUNICATION
NO2
R'
Strained, captodative benzylidene-
Zoltán Dobi, Tamás Holczbauer, Tibor
Soós*
R'
O
N
O
33 examples
azetidinones are demonstrated to
function as potent reaction partners
in thermal [2+2] cycloaddition with
nitro alkenes. The relief of strain
during the cycloaddition could be
leveraged to secure the kinetic and
thermodynamic stability for the
amino-nitro-cyclobutane ring.
Accordingly, this mild and robust
procedure can be used to simplify
the synthesis of aza-spiro[3.3]-
heptane bioisoteres.
R''
up to 78% yield
R''
Thiourea
N
Strain-relief
stability
Page No. – Page No.
NO2
Ph
Ph
Ph
Ph
Schreiner’s Thiourea Promoted
[2+2] Cycloaddition of Captodative
Azetidinones and Nitroolefins
Layout 2:
SHORT COMMUNICATION
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