Titanium-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime Ethers

Article abstract of DOI:10.1002/anie.201909151

The Ti^IV-mediated synthesis of spirocyclic NH-azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich-type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2-aliphatic dianion equivalent, inserting into the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired N-heterocyclic four-membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH-azetidines in a single step.

Full text of DOI:10.1002/anie.201909151

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Ti-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime
Ethers
Authors: Nicole Erin Behnke, Kaitlyn Lovato, Muhammed Yousufuddin,
and László Kürti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201909151
Angew. Chem. 10.1002/ange.201909151
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10.1002/anie.201909151
Angewandte Chemie International Edition
COMMUNICATION
Ti-Mediated Synthesis of Spirocyclic NH-Azetidines from Oxime
Ethers
Nicole Erin Behnke[a], Kaitlyn Lovato[a], Muhammed Yousufuddin[b], and László Kürti*[a]
(CalBlock) and Ximelagatran (Exanta) both possess an
Abstract: The Ti(IV)-mediated synthesis of spirocyclic NH-azetidines
azetidine moiety (Figure 1).[4] Additionally, Penaresidin A, a
from oxime ethers with an alkyl Grignard reagent or terminal olefin
natural product isolated from a marine sponge, has an NH-
azetidine moiety and has been observed to possess actomyosin
ligand-exchange coupling partner is described. Through a proposed
Kulinkovich-type mechanism,
a titanacyclopropane intermediate
ATPase-activation activity, further exemplifying the importance of
this structural motif.[5] Given the utility of the azetidine ring and the
previously unreported 1-azaspiro[3.5]nonane NH-azetidine
structures (Scheme 1C), we set out to identify a new method that
would provide synthetic access to these types of molecules.
Currently, many synthetic methods exist to access a variety
of N-protected azetidine scaffolds.[6] For example, NR-azetidines
can be synthesized from 1,3-halo compounds or 1,3-diol
derivatives via double alkylation of a primary amine (Scheme 1,
A1).[7] Substituted azetidines can also be synthesized via various
[2+2] cycloadditions, including the reaction of aldimines with ethyl
2,3-butadienoate under Lewis basic conditions (Scheme 1, A2).[7-
forms that can act as a 1,2-dialkyl anion equivalent and inserts into
the 1,2-dielectrophilc oxime ether to ultimately give rise to the desired
N-heterocyclic four-membered ring. This transformation proceeds in
moderate yield to furnish previously unreported and structurally
diverse NH-azetidines in a single step.
The synthesis of substituted azetidines has become an emerging
interest to synthetic chemists as these small nitrogen
heterocycles display promising and significant biological activity
and efficacy in active pharmaceutical ingredients.[1] For example,
the 2-arylazetidine scaffold has been shown to display similar
binding affinity for the nicotinic acetylcholine receptor (nAChR)
compared to known nAChR agonists (e.g. nicotine and carbachol),
which are promising therapeutic leads for conditions such as
Parkinson’s disease, Tourette’s syndrome, attention deficit
disorder etc.[2] The bioisosteric replacement of a larger nitrogen
heterocycle (i.e. piperidine) with its four-membered counterpart
was shown to improve the potency and stability of a serotonin
receptor subtype 2C (5-HT2C) agonist (Figure 1).[3] It is also worth
noting that the marketed pharmaceuticals Azelnidipine
8]
NH-azetidines have been successfully synthesized from pre-
functionalized starting materials (i.e. 2-azetidinones and
malonimides) via reduction using LiAlH4 (Scheme 1, A3).[9]
However, few ring substituents can survive these harsh
conditions. Despite significant advances in this field, a simple and
direct synthesis of spirocyclic NH-azetidines has remained
A. Typical Approaches to Azetidines
Base
(1)
(2)
LG
LG
R
NH2
N
LG = I, Br, OTs, Etc.
R
O
Ts
Me
NH
O
O
R
N
HO
Lewis Base
LiAlH4
EtO2C
O
O
R
H
N
NH
EtO2C
H
N
O
Ts
O
O
O
H
N
O
S
N
R’
R’
R’
O
O
NH
R
R
R
(3)
or
O
NH
NH
NH
N
HN
O
O
NH2
B. Kulinkovich Reaction: Formation of Cyclopropanols and Cyclopropylamines
HN
Cl
H2N
OH
R
OH
R’’
O
N
HO
Ti(Oi-Pr)3X
R’’
(4)
(5)
(6)
MgBr
OR’
OR’
HO
R
R
Serotonin receptor
subtype 2C agonist
Azelnidipine
antihypertensive
Ximelagatran
anticoagulant
Penaresidin A
actomyosin
ATPase-activator
C5H9MgBr
Ti(Oi-Pr)3X
O
OH
R’’
R
R’’
Figure 1. Biologically active compounds with azetidine rings.
NR’2
O
R
Ti(Oi-Pr)3X
R’’
MgBr
NR’2
R
[a]
N.E. Behnke+, K. Lovato+, Prof. Dr. L. Kürti
Department of Chemistry
R’’
X = Me, Oi-Pr, Cl
Rice University
6500 Main Street, Houston, TX, 77030 (USA)
E-mail: kurti.laszlo@rice.edu
C. This work: Formation of Spirocyclic Azetidines from Oxime Ethers
R’
OR
N
[b]
[+]
Dr. M. Yousufuddin
Ti-Complex
HN
R‘
Life and Health Sciences Department
The University of North Texas at Dallas
7400 University Hills Boulevard, Dallas, TX, 75241 (USA)
These authors contributed equally to this work.
MgBr
Oxime
ether
2-substituted-
1-azaspiro[3.5]nonane
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Methods for the synthesis of azetidines.
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10.1002/anie.201909151
Angewandte Chemie International Edition
COMMUNICATION
elusive. Given our group’s interest in electrophilic amination and
heterocycle synthesis, we initiated our study by investigating the
possibility of converting oxime ethers into NH-azetidines in a
single step.[10]
We became attracted to the idea that the mechanism of the
Kulinkovich reaction could be employed to synthesize the desired
1-azaspiro[3.5]nonane heterocyclic scaffolds.[11] The standard
Kulinkovich reaction utilizes esters and a Grignard reagent to
azetidines have been previously reported. Therefore, we
confirmed the structure of HCl salt 8 using single-crystal X-ray
crystallography. Additionally, since these NH-azetidines were
observed to decompose over time, conversion to the more stable
HCl salts was a viable solution for long term storage and stability.
Table 1. Optimization of NH-azetidine formation from oxime ethers and
Grignard reagents.
synthesize cyclopropanols through
a
titanacyclopropane
intermediate (Scheme 1, B4).[12] Several variations of this reaction
exist, including ligand exchange with olefins and reactions of
amides and nitriles with a Grignard coupling partner to form
cyclopropanols and cyclopropyl amines (Scheme 1, B5-6)).[13] For
this study, we decided to focus on the process that incorporates
the Grignard reagent into the final product. We proposed that O-
alkyl oximes, which possess a leaving group on the imine nitrogen
and differ electronically from the usual starting materials used to
synthesize cyclopropanols and cyclopropyl amines, would be
ideal substrates for this Kulinkovich-type synthesis of NH-
azetidines.
Entry[a]
R1
R2
Metal (equiv)
Temp
(C)
Solvent
Yield
Using cyclohexane oxime ethers and primary alkyl Grignard
reagents, we began the optimization process under similar
conditions utilized in traditional Kulinkovich reactions (Table 1).
To our delight, a preliminary proof-of-concept experiment (Table
1, entry 1) successfully formed spirocyclic NH-azetidine 3 in 14%
isolated yield. Our initial screens focused on modifying the nature
of the leaving group. With bulkier leaving groups (Table 1, entry 1
vs 2-4), only trace quantities or none of the desired product were
observed. To investigate the requirement of a leaving group, the
unsubstituted oxime was tested as a control and, as predicted, did
not yield the corresponding azetidine in measurable quantities
(Table 1, entry 5). Moving forward, the least hindered methyl
group was used as the ideal oxime O-substituent. During the
optimization studies, it was discovered that raising the
temperature from 0 °C to room temperature improved the
efficiency of the reaction (Table 1, entry 2 vs 6).
Next, the nature of the metal complex and its loading were
evaluated. Investigating a variety of ligands on the Ti(IV) species
did not significantly improve the outcome and even restricted the
reaction pathway in several instances (Table 1, entries 7-9). With
another Group(IV) metal complex, the oxime ether did not react
(Table 1, entry 10). Instead, a stoichiometric amount of the
inexpensive and easy-to-handle[14] Ti(Oi-Pr)4 was chosen and this
produced 40% of azetidine 4 (Table 1, entry 11). All attempts to
render this process catalytic were unsuccessful (Table 1, entry
12). Using a mixed ethereal system (Et2O/THF) by adding Et2O to
the THF solution of the Grignard reagent resulted in improved
yield (Table 1, entry 11 vs 13-14). Increasing the temperature to
40 C did not improve the yield of the reaction (Table 1, entry 15).
Without extensive literature on the isolation of NH-azetidines, a
significant challenge arose in screening of workup and
chromatography conditions for these four-membered polar and
somewhat unstable 2o amines[15] (see Supporting Information for
details). Overall, the optimization screens revealed that the
formation of an NH-azetidine from an oxime ether in combination
with 2.5 equivalents of the Grignard reagent and a stoichiometric
amount of Ti(Oi-Pr)4 proceeds best over a period of 6 hours at
ambient temperature (Table 1, entry 16).
Using the optimized reaction conditions, the scope of NH-
azetidine formation from oxime ethers (5) and primary Grignard
reagents with hydrogens in the beta-position (6) was examined
(Scheme 2). The scale-up of azetidine 4 from 1.0 to 2.5 mmol
proceeded well with a slight increase in the isolated yield (51% to
53%). To create product diversity, the length of the aliphatic chain
and electronic properties of the phenyl ring of the Grignard
reagent were modified to synthesize spirocyclic azetidines 8-11 in
good yield. To the best of our knowledge, none of these NH-
1
Me
i-Pr
t-Bu
Bn
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
Ph
Ti(Oi-Pr)3Cl (1)
Ti(Oi-Pr)3Cl (1)
Ti(Oi-Pr)3Cl (1)
Ti(Oi-Pr)3Cl (1)
Ti(Oi-Pr)3Cl (1)
Ti(Oi-Pr)3Cl (1)
TiCl4 (1)
0
0
0
0
0
rt
rt
rt
rt
rt
rt
rt
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Et2O
14%
trace
trace
none
trace
13%
none
18%
trace
none
40%
none
2
3
4
5
OH
i-Pr
Me
Me
Me
Me
Me
Me
6
7
8
Ph
Ti(OBu)4 (1)
9
Ph
Ti(OMe)4 (1)
Zr(OEt)4 (1)
10
11
12
Ph
Ph
Ti(Oi-Pr)4 (1)
Ph
Ti(Oi-Pr)4
(0.01)
13
14
15
16
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ti(Oi-Pr)4 (1)
Ti(Oi-Pr)4 (1)
Ti(Oi-Pr)4 (1)
Ti(Oi-Pr)4 (1)
rt
DME
MTBE
Et2O
20%[b]
32%[b]
33%[b]
51%[c]
rt
40
rt
Et2O
[a] The reactions were performed on a 0.5 mmol scale and 0.1 M concentration
relative to the oxime ether and quenched with water unless otherwise stated. [b]
NMR yield based on 0.1 mmol dibromomethane internal standard. [c] Reaction
performed on a 1.0 mmol scale for 6 hours, quenched with 15% aqueous citric
acid, and purified with a NH3/MeOH solvent additive.
To further investigate the scope of the method, substitutions
were made on the cyclohexane oxime in the beta- and gamma-
positions (Scheme 2: 12-16). Unfortunately, substitutions at the
alpha-position were not well-tolerated presumably due to the
steric hindrance surrounding the bulky 5-membered heterocyclic
intermediate proposed in the mechanism (Scheme 3: 26).
Spirocyclic azetidine 12, prepared from
a beta-substituted
cyclohexane oxime ether, was isolated in good yield as a 1:1
mixture of diastereomers. The yield of azetidine 13 was lower than
comparable products and was hypothesized to be a result of steric
hindrance depending on the flexibility of the methylene linker
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10.1002/anie.201909151
Angewandte Chemie International Edition
COMMUNICATION
between the azetidine ring and the phenyl group. To test this
prediction, a shorter-chain Grignard reagent was utilized and the
yield increased to 46% as the conformational flexibility was
removed (Scheme 2: 13 vs 14). Increasing the bulkiness of the
gamma-substituent on the oxime provided azetidine 15 in
moderate yield. The transformation was also successful when
ring resulted in a slightly lower yield of the desired product
(Scheme 2: 17-18). Lastly, we were happy to see that non-
spirocyclic azetidines (compounds 19-20) could also be prepared
in moderate yield.
Based on the results depicted in Scheme 2, the formation of
azetidine diastereomers was dependent on the structure of the
oxime starting materials. In the case of symmetrical oxime ethers
with ring substitutions, single diastereomer products were
observed (Scheme 2: 13-16). For these examples, it is possible
that the observed diastereomers could be favored due to the
sterically encumbering 1,3-diaxial interactions presented by either
the methyl or phenyl group being in the axial position (see
Scheme 2: 15 for the three-dimensional structure of the favored
conformation). Unsymmetrical oxime ethers, on the other hand,
produced mixtures of azetidine diastereomers (Scheme 2: 12, 19-
20).
The proposed mechanistic pathway for the synthesis of NH-
azetidine 4 from oxime ether 24 and phenethyl Grignard reagent
is described in Scheme 3. Based on a Kulinkovich-type reaction,
the Ti(IV) complex first undergoes a double transmetalation with
the excess Grignard reagent to form dialkylated species 21.
Through
-hydride
elimination
of
ethylbenzene,
titanacyclopropane intermediate 23, which is considered a 1,2-
aliphatic dianion equivalent, is formed.[16] Coordination of this Ti-
complex with oxime ether 24, (i.e. a 1,2-dielectrophile equivalent)
occurs before insertion into the weaker terminal C-Ti bond. The
5-membered intermediate (26) breaks down through loss of a
methoxide to form a four-membered heterocyclic species 27.
Finally, an aqueous acidic quench cleaves the N-Ti bond and the
free NH-azetidine is released.
(2 equiv)
MgBr
(2 equiv)
i-PrOMgBr
Ph
Ph
Ti(Oi-Pr)2
Ti(Oi-Pr)4
Ph
21
Ph
4
HN
Ethylbenzene
aqueous
acidic
quench
Ph
Ph
(i-PrO)2Ti
(i-PrO)2Ti
22
23
Ph
L
NOMe
24
(i-PrO)2Ti
N
27
MeOMgBr
Scheme 2. Formation of NH-azetidines from Grignard reagents. [a] Ti(Oi-Pr)4
(1.0 mmol), Et2O (0.2 M), and oxime (1.0 mmol) were combined in a dry flask
under Ar before the dropwise addition of the alkyl Grignard reagent (2.5 mmol)
over 5 minutes at room temperature. Upon consumption of the oxime by TLC
(approximately 6 hours), the reaction was quenched with 15% aqueous citric
acid (30 mL) and stirred overnight at room temperature until colorless. The
aqueous layer was washed with hexanes (5 mL) and basified with 2 M NaOH
until pH 12. The basic aqueous layer was extracted with EtOAc (2  50 mL) and
the combined organic layers were dried over Na2SO4 and concentrated under
reduced pressure. Column chromatography in 10% EtOAc:hexanes + 2% of 7
N NH3 in MeOH produced the pure NH-azetidine. [b] Isolated as the free amine
and then converted to the corresponding salt using 2 M HCl in ether for X-ray
crystallography analysis.
(i-PrO)2
L
Ph
MeO
Ti
N
Ti(Oi-Pr)2
N
MeO
Ph
Ligand
L = Oi-Pr or
Ph-CH2-CH2-
26
25
Scheme 3. Proposed Kulinkovich-type mechanism for NH-azetidine formation.
To probe the proposed mechanism, reactions were
conducted using terminal olefins instead of Grignard reagents to
form the desired azetidines (Scheme 4). If this mechanism is
viable, ligand exchange should occur between the olefin and the
titanacyclopropane intermediate.[17] Indeed, the oxime ethers
were converted to the corresponding NH-azetidines with the
using a completely aliphatic Grignard reagent (Scheme 2: 16).
Next, the ring size of the oxime ether coupling partner was varied
and it was observed that any deviation from the six membered
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10.1002/anie.201909151
Angewandte Chemie International Edition
COMMUNICATION
olefins incorporated into the product with yields up to 42%
(Scheme 4: 4, 30-33). Interestingly, substitution on the 2-position
of the terminal olefin was tolerated to provide azetidine 32 in
moderate yield. These results signify that constructing further
variations in structural diversity of spirocyclic NH-azetidines is
possible via olefin exchange through the Kulinkovich-like
mechanism.
In conclusion, two routes for the Ti-mediated synthesis of
spirocyclic NH-azetidines from oxime ethers were evaluated. In
the first pathway, oxime ethers were converted to NH-azetidines
using primary Grignard reagents while the second pathway
utilized olefin ligand-exchange partners. With these methods a
diverse range of novel, previously unreported spirocyclic NH-
azetidines were prepared in moderate yield through a proposed
Kulinkovich-type mechanism.
Support from Rice University, the National Institutes of Health
(R01 GM-114609-04), the National Science Foundation
(CAREER:SusChEM CHE-1546097), the Robert A. Welch
Foundation (grant C-1764), Amgen (2014 Young Investigators’
Award for LK), Biotage (2015 Young Principal Investigator Award)
and the National Science Foundation Graduate Research
Fellowship (Grant No. 1842494, Award for KL) is greatly
appreciated.
Keywords: Azetidine • Titanium alkoxides • Olefins • Aliphatic
Grignard • Spirocycle
[1]
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Heterocycl. Compd. 2017, 53, 329-334.
[2]
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[4]
[5]
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[6]
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2008, pp. 3-34.
[8]
B. Marc R., R. Alistair D., S. Corinna S., in Functionalized Azetidines
Via Visible Light-Enabled Aza Paternò-Bꢀchi Reactions, 2019 (DOI:
10.26434/chemrxiv.7218272.v3)
Scheme 4. Formation of NH-azetidines from terminal olefins. [a] Terminal olefin
(1.05 mmol), Et2O (0.2 M), oxime (1.0 mmol), and Ti(Oi-Pr)4 (1.0 mmol) were
[9]
[10]
[11]
N. H. Cromwell, B. Phillips, Chem. Rev. 1979, 79, 331-358.
Z. Zhou, L. Kürti, Synlett 2019, 30, 1525-1535.
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Wolan, Y. Six, Tetrahedron 2010, 66, 15-61.
O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, Synthesis-
Stuttgart 1991, 234-234.
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Mendeleev Commun. 1993, 230-231.
Solid Ti(Oi-Pr)3Cl was observed to readily oxidize in air before
addition to the reaction. Liquid Ti(Oi-Pr)4 did not have this issue.
The observed decomposition product was the primary amine
resulting from ring-opening of the azetidine.
combined in
a dry flask under Ar before the dropwise addition of
Cyclopentylmagnesium bromide (C5H9MgBr, 2.5 equiv) over 5 minutes at room
temperature. Upon consumption of the oxime by TLC, the reaction was
quenched with 15% aqueous citric acid (30 mL) and stirred overnight until
colorless. Workup and purification conditions are identical to those described
for azetidine formation from Grignard reagents in Scheme 1.
[12]
[13]
Acknowledgements
[14]
[15]
We thank Mr. Tobias Wilczek and Mr. Christopher Paasch
(visiting students from the University of Cologne) for technical
assistance with preliminary experiments. Additionally, Priv.-Doz.
Dr. Martin Prechtl (University of Cologne) is recognized for
obtaining DAAD support (Project ID 57386699) for the visiting
students. The authors would also like to thank Mr. Brian Mercer
(Biotage) for helpful discussions regarding purification. Financial
[16]
[17]
O. G. Kulinkovich, A. de Meijere, Chem. Rev. 2000, 100, 2789-2834.
O. Kulinkovich, Eur. J. Org. Chem. 2004, 4517-4529.
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10.1002/anie.201909151
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Direct synthesis of NH-
Nicole Erin Behnke, Kaitlyn
Lovato, Muhammed
Yousufuddin, and László Kürti*
azetidines:
The
Ti(IV)-
of
mediated
synthesis
spirocyclic NH-azetidines from
oxime ethers with an alkyl
Grignard reagent or terminal
Page No. – Page No.
Ti-Mediated Synthesis of
Spirocyclic NH-Azetidines
from Oxime Ethers
olefin
ligand-exchange
coupling partner is described.
This transformation proceeds
in moderate yield to furnish
previously unreported and
structurally
diverse
NH-
azetidines in a single step.
This article is protected by copyright. All rights reserved.