Mild Intramolecular Ring Opening of Oxetanes

Article abstract of DOI:10.1021/acs.orglett.9b03810

Oxetanes have been increasingly used as stable motifs in medicinal chemistry as well as versatile synthetic intermediates. Herein, an intramolecular ring opening of oxetane carboxamides with mild nucleophiles, such as nitrogen heterocycles, is presented. The reaction proceeds under metal-free basic conditions which is highly unusual in ring opening reactions of oxetanes. Amide formation and oxetane ring opening/cyclization in a one-pot approach affords high levels of molecular complexity in a single step from simple, readily available substrates.

Full text of DOI:10.1021/acs.orglett.9b03810

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mild Intramolecular Ring Opening of Oxetanes
Lindsey G. DeRatt, Edward C. Lawson, Chao-Yuan Wang, and Scott D. Kuduk*
Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States
S
* Supporting Information
ABSTRACT: Oxetanes have been increasingly used as stable
motifs in medicinal chemistry as well as versatile synthetic
intermediates. Herein, an intramolecular ring opening of
oxetane carboxamides with mild nucleophiles, such as
nitrogen heterocycles, is presented. The reaction proceeds
under metal-free basic conditions which is highly unusual in
ring opening reactions of oxetanes. Amide formation and
oxetane ring opening/cyclization in a one-pot approach
affords high levels of molecular complexity in a single step from simple, readily available substrates.
n recent years, oxetanes have received significant attention
from the pharmaceutical industry as stable motifs in
emerged utilizing oxetanes to furnish valuable compounds via
ring opening reactions.1a,2 Furthermore, Jacobsen6 and Sun7
have reported asymmetric ring opening of oxetanes using
chiral cobalt complexes or phosphoric acids, respectively, as
the catalyst (Scheme 1).
I
medicinal chemistry that can be employed to modulate the
physicochemical properties of a drug candidate (Figure 1).1
Scheme 1. Intramolecular Ring Opening of Oxetanes
Figure 1. Oxetane use by medicinal and synthetic communities.
In seeming contradiction with the stability required of the
oxetane ring in medicinal chemistry applications, the
reactivity of oxetanes and their propensity to undergo a
variety of synthetic transformations via ring opening have led
to their use by the synthetic community in generating
complex scaffolds.2
The susceptibility of oxetanes to ring opening can be
traced back to the inherent ring strain of the four-membered
ring. Oxetane has similar ring strain (106 kJ/mol) as
compared to oxirane (112 kJ/mol),3 and both undergo
acid-catalyzed hydrolysis by sulfuric or perchloric acid in
aqueous dioxane at similar rates.4 However, the rates of
hydrolysis under alkaline conditions differ greatly between the
two with oxetane being hydrolyzed 3 orders of magnitude
slower than oxirane. A few theoretical studies have been
carried out in an attempt to explain this reactivity difference
resulting in several possible explanations.5 Consequently, the
ring opening of oxetanes typically require activation with
As part of a recent medicinal chemistry program, efforts
were pursued to access a route toward target scaffold 6.8
Surprisingly, when mild basic conditions were employed to
alkylate the N-hydroxyamide 5 with 3-iodooxetane, facile
cyclization to afford the oxadiazepanone 7 was observed
(Scheme 2). This result was quite intriguing when compared
Scheme 2. Preliminary Ring Opening of Oxetane Result
̈
Lewis or Bronsted acids or elevated temperatures (Scheme
2).1a,2
Though readily accessible via commercial reagents,
oxetanes were largely neglected by the synthetic community.
However, over the past decade new methodologies have
Received: October 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03810
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to commonly reported conditions to open the oxetane ring.
As noted previously, most methods use harsh conditions with
metal additives9 or proceed under acidic conditions.10
Interestingly, to the best of our knowledge, there has not
been a report of intramolecular ring opening of oxetanes
under basic conditions with mild heterocyclic nucleophiles
such as pyrazoles. Inspired by this result and attracted to the
molecular complexity generated from simple starting materi-
als, we sought to further develop and expand this reaction.
The results of this work are presented herein.
Using Cs2CO3 as base in DMF at 70 °C, 14 fully converted
to the cyclized product 15 within 1 h (entry 1).12 For a
homogeneous reaction, DBU was also a suitable base for this
transformation providing quantitative conversion to the
cyclized product (entry 2). The temperature could be
reduced to 50 °C and the reactivity maintained, although
slightly longer reaction times were required (entry 3).
Interestingly, when 14 was treated under Lewis acid conditions,
an entirely different ring opened product was obtained and trace
desired product 15 was observed (entry 4).13
Attracted by the resemblance of these building blocks to
motifs commonly found in medicinal chemistry, evaluation of
this oxetane ring opening reaction was of high interest. Thus,
it was envisioned that a system such as 10 would maintain
enough geometrical constraint to enable a facile ring opening
and furnish biologically relevant scaffolds11 with a resultant
hydroxymethyl group as a synthetic handle for further
functionalization (Scheme 3). Based on the preliminary
With the cyclization reaction proceeding exceptionally well
under basic conditions, a one-pot transformation was
explored to achieve amide bond formation and cyclization
in a single flask. Toward this end, conditions were
optimized12 to furnish 15 in 97% yield in the one-pot
reaction starting from indazole carboxylic acid 16 (Scheme
4).
Scheme 4. Development of One-Pot Approach
Scheme 3. General Proposed Reaction
With the one-pot conditions established, the scope of the
nucleophile in the ring opening was studied (Table 2).
Imidazole nucleophiles (entries 1−2) afforded the cyclized
product in moderate yields, primarily due to an incomplete
amide coupling. However, the benzimidazole (entry 3) was
an effective substrate in this transformation affording the
product in 73% yield. Additionally, pyrazoles (entries 4−5)
and indazoles (entries 6−8) formed the corresponding
piperazinone rings in high yields (76−97%). Triazole was
also a competent nucleophile in the reaction, forming product
24 in 74% yield (entry 9). Furthermore, the pyridone reacted
smoothly under the standard reaction conditions providing
25 in 77% yield (entry 10). Notably, indoles 26 and 27 were
formed in remarkably high yields, 98% and 91%, respectively,
despite the low nucleophilicity of indoles. The indole
substrate was also chosen to study the substituent effect on
the reaction. Adding an electron-donating group did not
affect the yield of the reaction. However, the reaction rate
was lowered, requiring longer reaction times to fully convert
to the cyclized product (entry 13). Incorporation of an
electron-withdrawing group resulted in a facile reaction with
high yields (entry 14).
result above, this reaction could avoid the use of metals and
harsh conditions with an array of heterocyclic nucleophiles
being tolerated. Overall, it would constitute an efficient
method, with the advantage of using readily available oxetanyl
amines 9, to form the lactam 11 as compared to preparation
of the requisite amino alcohol 12 and proceeding through a
stepwise approach via manipulation of protecting and leaving
groups. In effect, the oxetane serves as both the leaving and
protecting group to provide the unprotected primary hydroxyl
after cyclization.
To study this type of oxetane ring opening and ensure it
could be extended beyond the oxadiazepanone, the indazole
substrate 14 was prepared in a single step and subjected to a
number of conditions to promote cyclization (Table 1).
Seeking to expand the nucleophile component beyond
heterocyclic nitrogens, other heteroatom nucleophiles were
investigated in the one-pot amidation/cyclization sequence
(Table 3). For the formation of larger ring systems,
sulfonamide, phenol, and thiophenol were all suitable
nucleophiles to open the oxetane ring, furnishing diazepa-
nones, oxazepanones, and thiazepanones, respectively, in high
yields (entries 1−3). Other seven-membered ring systems
could be obtained using the 7-substituted carboxylic acid as
the substrate (entries 4−5). An additional methylene could
be incorporated between the nitrogen and the oxetane,
affording product 35 in 87% yield (entry 6). The eight-
membered ring 36 was generated in 72% yield as shown in
entry 7, albeit elevated temperatures were required to cyclize
Table 1. Optimization of Oxetane Ring Opening
Conditions
entry
T (°C)
additive
solvent
conversion to 15
1
2
3
4
70
70
50
0
Cs2CO3
DBU
DBU
DMF
DMF
DMF
THF
>99%
>99%
>99%
trace
BF3·OEt2
B
DOI: 10.1021/acs.orglett.9b03810
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Organic Letters
Letter
a
Table 2. One-Pot Formation of Six-Membered Rings
Table 3. One-Pot Reaction To Form Larger Ring Systems
and N-Substitution Effect
a
a
Standard conditions: amine (1.2 equiv), HATU (1.2 equiv), Et3N
b
(2.0 equiv), DMF, rt and then DBU (3.0 equiv), 70 °C. CDI as
coupling agent. Cs2CO3 as base. 100 °C.
c
d
Figure 2. Control substrates for cyclization reaction.
also be envisioned to access other valuable scaffolds.
Dihydrobenzodioxine 42 can be obtained using similar
basic conditions with 3-iodooxetane in 75% yield (Scheme
5), highlighting the carboxamide function is not essential in
promoting the cyclization.
a
Standard conditions: amine (1.2 equiv), HATU (1.2 equiv), Et3N
b
(2.0 equiv), DMF, rt then DBU (3.0 equiv), 70 °C. CDI as coupling
agent.
Scheme 5. One-Pot Alkylation Followed by Ring Opening
To Afford Dihydrobenzodioxines
completely. Lastly, in addition to methyl, an ethyl substituent
is tolerated on the aminooxetane (entry 8).
To gain a deeper understanding of the ring opening aspect
of this reaction, additional control substrates were subjected
to the reaction conditions (Figure 2). The amine 38 resulted
in no reaction under the basic cyclization conditions.
Additionally, incorporating a methylene spacer between the
heteroaromatic and amide functionality as demonstrated with
39 led to a loss of reactivity. Lastly, minimal reaction was
observed in substrate 40 that has removed the alkyl
substitution on the amide nitrogen. These results suggest
that the rigidity and conformation of the substrate are an
important factors for increased susceptibility of the oxetane to
undergo ring opening by such mild nucleophiles.
In summary, an intramolecular ring opening of oxetanes
under metal-free, basic conditions has been reported. A facile
intramolecular ring opening of this type under mild basic
conditions is largely unprecedented in the literature. In
addition, the scope of the nucleophile for this reaction is
extensive and a variety of biologically prevalent and
moderately complex ring systems can be generated from
readily available starting materials in a one-pot fashion in
high yields. Further studies on the ring opening reaction of
In an expansion of the amidation/cyclization sequence
under basic conditions, a one-pot alkylation/cyclization could
C
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53, 10699−10708. (d) Dussault, P. H.; Trullinger, T. K.; Noor-e-
Ain, F. Org. Lett. 2002, 4, 4591−4593.
oxetanes are currently underway and will be reported in due
course.
(11) (a) Furlotti, G.; Alisi, M. A.; Cazzolla, N.; Ceccacci, F.;
Garrone, B.; Gasperi, T.; La Bella, A.; Leonelli, F.; Loreto, M. A.;
ASSOCIATED CONTENT
* Supporting Information
■
́
Magaro, G.; Mangano, G.; Bettolo, R. M.; Masini, E.; Miceli, M.;
S
Migneco, L. M.; Vitiello, M. ChemMedChem 2018, 13, 1597−1607.
(b) Engers, J. L.; Rodriguez, A. L.; Konkol, L. C.; Morrison, R. D.;
Thompson, A. D.; Byers, F. W.; Blobaum, A. L.; Chang, S.; Venable,
D. F.; Loch, M. T.; Niswender, C. M.; Daniels, J. S.; Jones, C. K.;
Conn, P. J.; Lindsley, C. W.; Emmitte, K. A. J. Med. Chem. 2015, 58,
7485−7500.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03810.
Experimental procedures and spectral data for all new
compounds (PDF)
(12) See Supporting Information for optimization conditions.
(13) Huang, H.; Yang, W.; Chen, Z.; Lai, Z.; Sun, J. Chem. Sci.
2019, 10, 9586. The observed product likely forms from cyclization
of the carbonyl group.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: skuduk@its.jnj.com.
ORCID
Lindsey G. DeRatt: 0000-0002-0412-8111
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Ronghui Zhou and Kerem Bingol of
the Janssen R&D, Spring House analytical chemistry team for
assistance in characterizing final products. We would also like
to thank Scott Ballentine for assistance in obtaining HRMS
data.
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