Synthesis of 3,3-Diarylazetidines by Calcium(II)-Catalyzed Friedel-Crafts Reaction of Azetidinols with Unexpected Cbz Enhanced Reactivity

Article abstract of DOI:10.1021/acs.orglett.8b03745

Azetidines are valuable motifs that readily access under explored chemical space for drug discovery. 3,3-Diarylazetidines are prepared in high yield from N-Cbz azetidinols in a calcium(II)-catalyzed Friedel-Crafts alkylation of (hetero)aromatics and phenols, including complex phenols such as β-estradiol. Electron poor phenols undergo O-alkylation. The product azetidines can be derivatized to drug-like compounds through the azetidine nitrogen and the aromatic groups. The N-Cbz group is crucial to reactivity by providing stabilization of an intermediate carbocation on the four-membered ring.

Full text of DOI:10.1021/acs.orglett.8b03745

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 3,3-Diarylazetidines by Calcium(II)-Catalyzed Friedel−
Crafts Reaction of Azetidinols with Unexpected Cbz Enhanced
Reactivity
Camille Denis,†,‡,∥ Maryne A. J. Dubois,†,∥ Anne Sophie Voisin-Chiret,‡ Ronan Bureau,‡
Chulho Choi,§ James J. Mousseau,§ and James A. Bull*,†
†Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London
W12 0BZ, U.K.
‡
́
Normandie Univ, UNICAEN, EA 4258, CERMN (Centre d’Etudes et de Recherche sur le Medicament de Normandie) - FR
CNRS INC3M, Caen, France
§Pfizer Global Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Azetidines are valuable motifs that readily
access under explored chemical space for drug discovery.
3,3-Diarylazetidines are prepared in high yield from N-Cbz
azetidinols in a calcium(II)-catalyzed Friedel−Crafts alkyla-
tion of (hetero)aromatics and phenols, including complex
phenols such as β-estradiol. Electron poor phenols undergo O-
alkylation. The product azetidines can be derivatized to drug-
like compounds through the azetidine nitrogen and the
aromatic groups. The N-Cbz group is crucial to reactivity by
providing stabilization of an intermediate carbocation on the four-membered ring.
aturated nitrogen heterocycles are among the most
Sabundant pharmacophores in pharmaceutical products,
dominated by five- and six-membered rings.1 In marked
contrast, 4-membered azetidines are much less explored, despite
offering attractive physicochemical properties for drug discovery
being low molecular weight and polar structures with defined 3D
vectors for substituents.2 The development of new synthetic
methods for azetidine synthesis3 can readily access new
biologically relevant chemical space for exploitation by
medicinal chemists.4 Recent years have seen high profile
examples of azetidines in biologically active compounds,
including antimalarial BRD9185,5 and azelnidipine, an anti-
hypertensive containing an azetidine ether (Figure 1a).6 New
azetidine motifs have recently been targeted as screening
compounds and bioisosteres, including fused and spirocyclic
derivatives.7,8
Diarylmethanes and related derivatives display a wide range of
important biological activity.9 We are recently interested in
small ring derivatives as alternative linking groups for diaryl-
methane and diarylketone motifs, to mask potentially
Figure 1. Bioactive azetidine structures and targeted 3,3-diary-
lazetidines.
metabolically vulnerable sites (Figure 1b).10 We reported the
first examples of 3,3-diaryloxetanes, formed through a mild
lithium-catalyzed Friedel−Crafts reaction of oxetan-3-ols with
found in biologically active compounds in the patent literature,11
phenols.
and a prolylcarboxypeptidase (PrCP) inhibitor (Figure 1c).12
We envisaged the application of 3,3-diarylazetidines to
maintain the polar functional group, and to provide an
additional vector for functionalization through the nitrogen
atom. 3,3-Diarylazetidines are relatively little studied but can be
Received: November 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03745
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
These 3,3-diarylazetidines also provide interesting scaffold
structures, enable increased F(sp3), and reduce planarity
without the introduction of a chiral center. Limited prior
methods to access these motifs are lengthy and low yielding.
These include a cyclization strategy,13 and previous Friedel−
Crafts approaches employing excess AlCl3 or TfOH, limiting the
functional group compatibility.11a,b Here we describe a rapid and
divergent synthesis of 3,3-diarylazetidines. A calcium catalyst
generates azetidine carbocations from 3-arylazetidin-3-ols under
mild conditions. The reaction is compatible with functionalized
substrates and a wide range of electron-rich aromatic and
heteroaromatic nucleophiles. The choice of the N-Cbz group
was shown to be crucial, being uniquely effective in enhancing
the reactivity.
equivalents of phenol from five to three maintained the excellent
yield and provided the optimal conditions (entry 5). Toluene
and heptane were shown to also be very suitable solvents
(entries 6 and 7), but dichloromethane was chosen for reasons
of improved substrate solubility. The reaction using o-cresol as a
nucleophile could be scaled to 4.0 mmol preserving a high yield
of 2a (1.5 g, 93% yield, Scheme 1).
Scheme 1. Scope of Phenol Derivatives and Heteroaromatics
as Nucleophiles
Catalytic functionalization of π-activated alcohols has under-
gone considerable development in recent years.14,15 However,
carbocation formation on small four-membered rings is
challenging due to the existing ring strain and increased barrier
to planarization. In targeting 3,3-diarylazetidines, we also
required selective coordination of a catalyst to an azetidinol
hydroxyl group over the Lewis basic N-functionality. Initially, we
examined N-Boc azetidinols bearing a 4-methoxyphenyl group
using catalytic amounts of various Lewis acids and phenols such
as o-cresol as nucleophiles. The system was unreactive using
lithium triflimide, which was previously successful for
oxetanols,10 calcium triflimide,15a and iron chloride,16 indicating
significantly reduced reactivity of this substrate compared to the
oxetane derivatives. Remarkably, effective catalysis was enabled
by changing to the N-Cbz azetidinol. With this substrate,
lithium, calcium, and iron catalysts were all successful using
azetidinol 1 (Table 1, entries 1−3), with a dramatic increase in
reactivity.
Table 1. Selected Optimization Studies for Friedel−Crafts
Arylation of Azetidinol 1 with o-Cresol
b
equiv of
yield 2a/2a′
a
entry
1
cat. (mol %)
o-cresol
solvent
CH2Cl2
(%)
Li(NTf2)/Bu4NPF6
(11/5.5)
5
45/1
2
3
FeCl3 (5/−)
Ca(NTf2)2/Bu4NPF6
(5/5)
5
5
CH2Cl2
CH2Cl2
75/4
92/6
4
5
Ca(NTf2)2 (5)
Ca(NTf2)2/Bu4NPF6
(5/5)
5
3
CH2Cl2
CH2Cl2
0
94/5
6
7
Ca(NTf2)2/Bu4NPF6
(5/5)
Ca(NTf2)2/Bu4NPF6
(5/5)
3
3
PhMe
96/3
91/4
a
Reaction conditions: 1 (0.50 mmol), Ca(NTf2)2 (5 mol %),
heptane
Bu4NPF6 (5 mol %), CH2Cl2 (0.5 M), 40 °C, 2 h. Different
a
b
temperatures or times indicated in parentheses where appropriate.
Using 0.25 mmol of 1. Yield determined by 1H NMR spectroscopy
using 1,3,5-trimethoxybenzene as internal standard.
b
c
4.0 mmol scale. 0.25 mmol scale.
Using Ca(NTf2)2 with a Bu4NPF6 additive afforded para- and
ortho-substituted products 2a and 2a′ in 92% and 6% yield
respectively, which could be separated by column chromatog-
raphy (entry 3). The Bu4NPF6 additive was crucial, with no
reaction in its absence (entry 4), likely due to anion metathesis
providing a more Lewis acidic catalyst.14d,15a Decreasing the
A wide range of aromatic and heteroaromatic nucleophiles
were then investigated (Scheme 1). Phenol itself gave para/
ortho products 2b and 2b′ in 77% and 22% yields respectively,
which were readily separable by flash chromatography. ortho-
Substituted (iPr and Ph) and disubstituted (Me) phenols
afforded 3,3-diarylazetidines 2c, 2d, and 2e selectively in 86% to
B
DOI: 10.1021/acs.orglett.8b03745
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89% yields. 3-Ethylphenol gave the 6-substituted product 2f in
70% yield as a major regioisomer, due to minimization of the
steric clash from the ethyl group (Scheme 1B). Resorcinol
underwent reaction at the 4-position, forming 2g in 76% yield.
Dimethoxybenzene reacted similarly, without phenol function-
ality (2h), demonstrating enhanced reactivity in the Cbz-
azetidines versus the oxetane system. 4-Substituted phenols gave
the Friedel−Crafts products, substituting at the 2-position
(Scheme 1C). The reaction occurred in good yield (68% and
59%) for 4-methyl and 4-(methyl acetate) substrates (2i and 2j),
the latter providing a substructure related to compounds
contained in a published patent application as a β2 adrenergic
receptor agonist, and muscarinic receptor antagonist.11b para-
Methoxy phenol gave the 2-substituted phenol product 2k, as
well as a small quantity of a dihydrobenzofuran (7% 2k′′, not
shown), formed via ring opening of azetidine 2k by the phenolic
OH. This contrasts with the oxetanes where the dihydrobenzo-
furan was the major product and the intermediate ortho-phenol
could not be detected. Pleasingly, complex phenols such as β-
estradiol were successful in the reaction, furnishing the desired
product 2l in 51% yield, and opening the possibility to apply this
reaction for late stage functionalization. In contrast, para-
substituted phenols bearing electron-withdrawing groups gave
azetidine-ether products 3a to 3c in 31−46% yield (Scheme
1D). Using acetaminophen (paracetamol) as a nucleophile also
afforded ether product 3d. These represent relatively rare
examples of phenol O-alkylation in Friedel−Crafts reactions.10c
3-Ether azetidines have been reported as potential ligands for
monoamine transporters and modulators of melanocortin
receptors involved in obesity and skin disorders.17,18
Scheme 3. Scope of Azetidinols
such, a variety of 3,3-diarylazetidines can be easily prepared
using different nucleophiles and preinstalled aryl groups with
appealing functionalities of interest for medicinal chemistry.
To show the applicability of this method to access drug-like
compounds, the potential to further functionalize azetidine 2a
was explored (Scheme 4).
Removal of the Cbz group by using H2 and Pd/C revealed the
NH-azetidine 19 in 74% yield, important for further
functionalization. This was derivatized through amide formation
Importantly for medicinal chemistry programs, heteroaro-
matic nucleophiles were successful (Scheme 1E). N-Methyl-
indole, 2-methylfuran, and 2-methylthiophene all successfully
gave 3,3-diarylazetidines 2m−2o in good yield by using
increased reaction temperatures and times.19 N-Methylpyrrole
was also suitable in this reaction, giving a separable mixture of
the 2- and 3-substituted pyrrole derivatives 2p and 2p′.
Scheme 4. Derivatization of 3,3-Diarylazetidines
Alternative 3-aryl-3-azetidinol substrates were readily pre-
pared using Grignard reagents formed by exchange from the aryl
halide (4−9, Scheme 2). It is worth noting that azetidinol 1 was
Scheme 2. Synthesis of Azetidinols
formed on scales of up to 38.5 mmol using a commercial
Grignard solution. The use of the organolithium reagents led to
deprotonation at the benzylic position of the Cbz group.
The azetidinol derivatives were then tested with various
nucleophiles (Scheme 3). Aromatics bearing OBn and OTIPS
groups were successful substrates and gave azetidines 10 and 11
in 85% and 57% yield respectively with o-cresol, with the
potential for deprotection and further elaboration. Catechol was
also shown to be a suitable nucleophile to give OBn derivative
12. Benzodioxole and trimethoxybenzene derivatives were also
successful (13 and 14). Furthermore, the ortho-methoxy phenyl
group was suitable in promoting the reaction (15). Importantly,
indole containing azetidine 16 was formed in high yield as well as
azetidines containing two nitrogen heteroaryls 17 and 18. As
C
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using EDC coupling to introduce a pyrrolidine amide 20 in 96%
yield. Pyrimidine 21 could be installed in high efficiency through
an SNAr reaction, both occurring selectively in the presence of
the unprotected phenol. The phenol itself provides a valuable
synthetic handle for functionalization. A second azetidine could
be readily installed by alkylation giving 22 in 63% yield. Phenol
2a was also converted to triflate 23 and used in a Suzuki−
Miyaura cross-coupling to afford 24, which is related to a
compound reported by AstraZeneca in a patent application
(Figure 1c).11a Finally, the phenol functionality was removed
from a mixture of azetidine 2b and 2b′ (80/20 ratio), and a
single phenyl-azetidine product 25 was obtained in 83% overall
yield by triflation followed by palladium catalyzed deoxygena-
tion.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.bull@imperial.ac.uk.
ORCID
Anne Sophie Voisin-Chiret: 0000-0001-5564-2244
James A. Bull: 0000-0003-3993-5818
Author Contributions
∥C.D. and M.A.J.D. contributed equally.
Notes
The authors declare no competing financial interest.
To probe the role of the Cbz group in enabling reactivity, we
applied the final conditions to azetidine derivatives with
different N-groups (Figure 2). Alternative carbamates with
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Royal Society [University
Research Fellowship, UF140161 (to J.A.B.), URF Appointed
Grant RG150444 and URF Enhancement Grant RGF\EA
\180031], EPSRC [CAF to J.A.B. (EP/J001538/1)], Pfizer and
Imperial College London for studentship funding (M.D), and
European Union in the framework of the ERDF-ESF operational
programme 2014−2020, Normandy County Council, and
́
̂
Canceropole Nord-Ouest for funding. Thanks is also given to
the National Mass Spectrometry Facility (NMSF) at Swansea
University.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03745.
■
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