Preparation of aryloxetanes and arylazetidines by use of an alkyl-aryl suzuki coupling

Article abstract of DOI:10.1021/ol8011327

(Chemical Equation Presented) The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.

Full text of DOI:10.1021/ol8011327

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3259-3262
Preparation of Aryloxetanes and
Arylazetidines by Use of an Alkyl-Aryl
Suzuki Coupling
Matthew A. J. Duncton,* M. Angels Estiarte, Darlene Tan, Carl Kaub,
Donogh J. R. O’Mahony, Russell J. Johnson, Matthew Cox, William T. Edwards,
Min Wan, John Kincaid, and Michael G. Kelly
EVotec (USA), Two Corporate DriVe, South San Francisco, California 94080
mattduncton@yahoo.com
Received May 16, 2008
ABSTRACT
The oxetan-3-yl and azetidin-3-yl substituents have previously been identified as privileged motifs within medicinal chemistry. An efficient
approach to installing these two modules into aromatic systems, using a nickel-mediated alkyl-aryl Suzuki coupling, is presented.
The introduction of privileged modules with low molecular
weight and hydrophilic character into compounds with
biological activity is an ongoing challenge within modern
medicinal chemistry. The oxetan-3-yl substituent was re-
cently disclosed as one such privileged motif, with demon-
strated benefits for property-guided drug discovery and a
remarkable ability to alter the pharmacological character of
biologically active molecules.1 For instance, oxetanes can
act as a metabolically stable bioisostere of the tert-butyl
group. Additionally, oxetanes possess an exquisite ability to
reduce the octanol/water partition or distribution coefficient
of final compounds (log P and log D), which can be useful
for reducing biological side effects (e.g., phospholipidosis,
i-hERG potassium channel activity).1 Since an increase in
log P, as estimated by calculated methods (clog P), has also
been correlated to a number of detrimental events within the
drug discovery process,2 a module that can reduce this
parameter is potentially attractive for the medicinal chemist.
As part of a study aimed at examining drug-like pharma-
cophores, we initiated synthetic investigations for the
introduction of oxetanes into aromatic and heteroaromatic
systems.3 Our aim was to find a robust process that would
complement the existing protocols for oxetane incorporation.
Particularly, our attention turned to inclusion of the oxetan-
3-yl unit itself into aromatic systems (Figure 1).
Figure 1. Oxetan-3-yl substituted with an aryl group.
(3) For examples of medicinally active oxetan-3-yl derivatives published
prior to 2006, see: (a) Gibson, K. H.; Walter, E. R. H. GB 1976-51196. (b)
Edwards, P. N.; Girodeau, J. M. M. M. EP 1989-313384. (c) Kuramoto,
Y.; Okuhira, M.; Yatsunami, T. EP 1990-106007. (d) Belley, M. L.; Leger,
S.; Roy, P.; Xiang, Y. B.; Labelle, M.; Guay, D. EP 1991-309306. (e)
Crawley, G. C.; Dowell, R. I.; Edwards, P. N.; Foster, S. J.; McMillan,
R. M.; Walker, E. R. H.; Waterson, D. J. Med. Chem. 1992, 35, 2600. (f)
Vaillancourt, V. A.; Larsen, S. D.; Nair, S. K. WO 2001070706. (g) Homa,
F. L.; Wathen, M. W.; Hopkins, T. A.; Thomsen, D. R. WO 2002006513.
(h) Wathen, M. W.; Wathen, L. K. WO 2004019933. (i) Wathen, M. W.;
Wathen, L. K. WO 2004019940. (j) Allen, D. G.; Coe, D. M.; Cook, C. M.;
Cooper, A. W. J.; Dowle, M. D.; Edlin, C. D.; Hamblin, J. N.; Johnson,
M. R.; Jones, P. S.; Lindvall, M. K.; Mitchell, C. J.; Redgrave, A. J. WO
2004056823. (k) Watanuki, S.; Koga, Y.; Moritomo, H.; Tsukamoto, I.;
Kaga, D.; Okuda, T.; Hirayama, F.; Moritani, Y.; Takasaki, J. WO
2005009971.
(1) Wuitschik, G.; Rogers-Evans, M.; Mu¨ller, K.; Fischer, H.; Wagner,
B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem., Int. Ed. 2006,
45, 7736.
(2) Leeson, P. D.; Springthorpe, B. Nat. ReV. Drug Disc. 2007, 6, 881,
and references cited therein.
10.1021/ol8011327 CCC: $40.75
Published on Web 07/09/2008
2008 American Chemical Society

Methods to prepare aryloxetanes include the addition of
aryllithium reagents to oxetan-3-one, followed by reductive-
deoxygenation,1 and the cyclization of 2-aryl-1,3 diols.4,5 We
sought a more general alternative to existing techniques and
were drawn to the possibility of an alkyl-aryl Suzuki
coupling,6 since it presented a convergent substitute to
previous methodology. The development of such reactions
has received considerable attention in contemporary organic
synthesis, and among the most accomplished methods for
undertaking this transformation is a series of nickel-mediated
reactions developed by Fu.7 In this paper we show that a
Fu-variant of the Suzuki coupling can be used to introduce
both oxetan-3-yl and azetidin-3-yl substiuents into aromatic
and heteroaromatic systems. Additionally, we show that the
majority of isolated oxetan-3-yl products do not conjugate
glutathione when examined in an in vitro screen for reactive
metabolites.
Table 1. Alkyl-Aryl Suzuki Coupling To Install the
Oxetan-3-yl Substituent into Aryl Systems
Our initial experiments at introducing the oxetan-3-yl
group examined reactions between 3-iodooxetane8 and an
appropriate arylboronic acid using a catalyst derived from
nickel(II) iodide and trans-2-aminocyclohexanol (Table 1).
These conditions were employed since Gonza´lez-Bobes and
Fu had demonstrated that the reactants required no special
handling and that microwave irradiation could be used to
accelerate the coupling process, giving rise to the Suzuki
products rapidly.7b The use of such a method would therefore
have obvious attractions for those working in an industrial
environment, where ease of synthesis can be a major
influence on the desirability to pursue a given transformation.
To our delight, we found that the Suzuki coupling proceeded
smoothly when 2 equiv of the boronic acid was used,9 giving
rise to 3-aryloxetanes in moderate-to-good yield. In some
cases a major byproduct was also produced (vide infra).
Additionally, a small quantity of biaryl, arising from homo-
coupling of the boronic acid starting material, was also
obtained in most examples. As can be seen from Table 1,
the reaction tolerated a number of common functional groups
such as alkyl, trifluoromethyl, ether, thioether, ester, nitrile,
tertiary amine, ketone, chloro, and fluoro. Additionally,
ortho-, meta-, and para-substituted boronic acids could be
coupled efficiently (entries 1-12). We also used the reaction
to prepare 3-(3-bromophenyl)oxetane (entry 13). The prepa-
ration of this compound is significant, as it demonstrates that
selectivity in coupling can be accomplished between iodoal-
a Isolated yield from reaction with ArB(OH)2 (2.0 equiv), NiI2 (0.06
equiv), trans-2-aminocyclohexanol hydrochloride (0.06 equiv), 3-iodoox-
etane (1.0 equiv), NaHMDS (2.0 equiv), and iPrOH; 80 °C, µwave, 20 min.
b Desired oxetane product as methyl ester (18% yield) also isolated.
c Acetophenone (22%) also isolated.
(4) (a) Searles, S.; Hummel, D. G.; Nukina, S.; Throckmorton, P. E.
J. Am. Chem. Soc. 1960, 82, 2928. (b) Castro, B.; Selve, C. Tetrahedron
Lett. 1973, 45, 4459. (c) Picard, P.; Leclercq, D.; Bats, J. P.; Moulines, J.
Synthesis 1981, 550. (d) Robinson, P. L.; Barry, C. N.; Kelly, J. W.; Evans,
S. A. J. Am. Chem. Soc. 1985, 107, 5210. (e) Katritzky, A. R.; Fan, W.; Li,
kane- and arylbromide-containing starting materials. Previ-
ously, only selectivity between bromo- and chloro-alkanes
had been illustrated, although the increased reactivity of
iodides over bromides had been noted.7b,c Additionally, 3-(3-
bromophenyl)oxetane contains a handle for further manipula-
tion via palladium-, nickel-, and copper-mediated processes
and is thus a valuable building block.
Next, we turned our attention to the introduction of the
oxetan-3-yl motif into heteroaromatic and bicyclic systems.
As can be seen from Table 2, mixed results were obtained.
Q. Youji Huaxue 1988, 8, 53
.
(5) For alternative synthesis of 3-aryloxetanes, see: (a) Yates, P.; Szabo,
A. G. Tetrahedron Lett. 1965, 37, 485. (b) Nerdel, F.; Kaminski, H.; Frank,
D. Tetrahedron Lett. 1967, 39, 4973. (c) Delmond, B.; Pommier, J. C.;
Valade, J. Tetrahedron Lett. 1969, 41, 2089. (d) Lewis, F. D.; Turro, N. J.
J. Am. Chem. Soc. 1970, 92, 311. (e) Delmond, B.; Pommier, J. C.; Valade,
J. J. Organomet. Chem. 1973, 47, 337
.
(6) For a review see: Netherton, M. R.; Fu, G. C. In Topics in
Organometallic Chemistry: Palladium in Organic Synthesis; Tsuji, J., Ed.;
Springer: New York, 2005; pp 85-108.
(7) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. (b)
Gonza´lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. (c)
Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602.
(8) Clark, S. L.; Polak, R. J.; Wojtowicz, J. A. US 1966-557376.
(9) Other conditions were not investigated.
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Org. Lett., Vol. 10, No. 15, 2008

to be the only cases where the oxetane product could be
obtained (entries 7-9). Almost all other reactions provided
a “deborylated” product in which the starting boronic acid
had been cleaved. At present, we do not have an explanation
as to why boronic acids directly linked to a heteroaromatic
nucleus seem reluctant to participate in the coupling process.
A number of reports have indicated that nickel-mediated
alkyl-heteroaryl Suzuki couplings are possible,7a,10 although
reduced efficiencies and higher catalyst loadings are some-
times a feature of such reactions.10a,b Additionally, all reports
to date have utilized a catalyst derived from Ni(COD)2 and
bathophenanthroline, rather than NiI2 and trans-2-aminocyclo-
hexanol.7a,10
Table 2. Alkyl-Aryl Suzuki Coupling To Install the
Oxetan-3-yl Substituent into Heteroaryl and Bicyclic Systems
As mentioned previously, for reactions that were success-
ful, two byproducts could usually be observed. First, a small
quantity of biaryl arising from homocoupling could be
isolated. In other examples, a further byproduct, tentatively
identified as the boroxine, was also obtained (Figure 2).
Figure 2. Proposed boroxine byproduct for selected reactions.
While the extent of biaryl coupling was small (<5%), the
boroxine byproduct could become quite substantial in a
number of cases (e.g., Table 1, entries 2 and 5; Table 3,
entry 1).
We also used the general principle of alkyl-aryl Suzuki
coupling to install a protected azetidine into numerous
aromatic nuclei (Table 3).11 The reactions proceeded un-
eventfully, with no significant cleavage of the N-tert-
butoxycarbonyl (Boc) protecting group.
Finally, a number of aryloxetane products were evalu-
ated in an in vitro screen for reactive metabolites by
incubating with human liver microsomes in the presence
of glutathione and nicotinamide adenine dinucleotide
phosphate (NADPH) cofactor. In just over half of the cases
investigated, no glutathione conjugates were observed
(Figure 3). As such experiments are commonly used as a
qualitative filter for the ability to form covalent adducts
upon bioactivation,12 our results provide additional evi-
dence that the oxetan-3-yl chemotype is attractive from a
medicinal chemistry perspective.13
a Isolated yield from reaction with ArB(OH)2 (2.0 equiv), NiI2 (0.06
equiv), trans-2-aminocyclohexanol hydrochloride (0.06 equiv), 3-iodoox-
etane (1.0 equiv), NaHMDS (2.0 equiv), and iPrOH; 80 °C, µwave, 20 min.
b Unidentified byproduct also obtained.
Although the oxetane group could generally be coupled
efficiently to heteroaromatic or bicyclic systems, whose
boronic acid resided on a benzenoid substructure (entries
1-6), the use of boronic acids connected to a heteroaromatic
ring were rarely successful (entries 7-12). Indeed, ben-
zothiophene, benzofuran, and pyrimidine examples seemed
In summary, our studies outline a new approach for
incorporating the oxetan-3-yl and azetidin-3-yl groups into
aromatic systems by use of a nickel-catalyzed alkyl-aryl
(10) (a) Malpass, J. R.; Handa, S.; White, R. Org. Lett. 2005, 7, 2759.
(b) White, R.; Malpass, J. R.; Handa, S.; Baker, R. S.; Broad, L. M.; Folly,
L.; Mogg, A. Bioorg. Med. Chem. 2006, 16, 5493. (c) Armstrong, A.;
Bhonoah, Y.; Shanahan, S. E. J. Org. Chem. 2007, 72, 8019.
(11) For a previous synthesis of protected arylazetidines using a
palladium-mediated (Negishi) coupling of aryl halides with (1-(tert-
butoxycarbonyl)azetidin-3-yl)zinc(II) iodide, see: (a) Billotte, S. Synlett
1998, 379.
(13) It should be noted that the glutathione incubation experiment did
not ascertain the degree to which compounds undergo phase I metabolism
or the site of conjugation to glutathione. Although we cannot rule out that
compounds prepared in this paper undergo metabolism at the oxetane group,
Rogers-Evans and Carreira have previously demonstrated that model
compounds containing an oxetan-3-yl moiety exhibit good metabolic
stability.1 Efforts to determine the position and extent of metabolism for
compounds in this paper are under investigation and should yield further
information as to any potential metabolic liability associated with the oxetan-
3-yl group.
(12) Kumar, S.; Kassahun, K.; Tschirret-Guth, R. A.; Mitra, K.; Baillie,
T. A. Curr. Opin. Drug DiscoVery 2008, 11, 43.
Org. Lett., Vol. 10, No. 15, 2008
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Table 3. Alkyl-Aryl Suzuki Coupling To Install the
Azetidin-3-yl Substituent
Figure 3. Screen for reactive metabolites by incubation with
glutathione in the presence of human liver microsomes and NADPH
cofactor. Observation of conjugates is used by many medicinal
chemists as a qualitative filter for reactive metabolites.12,13
We also demonstrate that a majority of model compounds
containing an oxetan-3-yl substituent do not conjugate
glutathione when incubated with human liver microsomes
in vitro. This result provides additional support for the
continued development of oxetanes within medicinal chem-
istry.
a Isolated yield from reaction with ArB(OH)2 (2.0 equiv), NiI2 (0.06
equiv), trans-2-aminocyclohexanol hydrochloride (0.06 equiv), 1-Boc-3-
iodoazetidine (1.0 equiv), NaHMDS (2.0 equiv), and iPrOH; 80 °C, µwave,
30 min.
Acknowledgment. We thank Andrew Calabrese and
Thomas Ryckmans of Pfizer, Sandwich (United Kingdom)
for insightful discussions around the oxetane motif and
clog P.
Suzuki coupling. We show that this technique can be used
on starting materials that would be of interest to practicing
medicinal chemists. Although our reaction conditions do have
limitations when used with certain heteroaromatic systems,
the reaction offers an attractive alternative to current
methodology for oxetane synthesis in particular.
Supporting Information Available: Detailed experimen-
tal procedures and copies of analytical data.This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8011327
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Org. Lett., Vol. 10, No. 15, 2008