Synthesis and indole coupling reactions of azetidine and oxetane sulfinate salts

Article abstract of DOI:10.1039/c5cc00975h

Aztidine and oxetane sulfinate salts are easily prepared from commercially available 3-iodoheterocycle precursors in a three-step sequence. They undergo smooth coupling reactions thereby providing an expedient route for the introduction of these four-membered heterocycles into indoles.

Full text of DOI:10.1039/c5cc00975h

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Synthesis and indole coupling reactions of
azetidine and oxetane sulfinate salts†
Cite this:DOI: 10.1039/c5cc00975h
Anne-Chloe M. A. Nassoy,a Piotr Raubob and Joseph P. A. Harrity*a
´
Received 2nd February 2015,
Accepted 23rd February 2015
DOI: 10.1039/c5cc00975h
www.rsc.org/chemcomm
Azetidine and oxetane sulfinate salts are easily prepared from compounds. Although this approach generated an intermediate
commercially available 3-iodoheterocycle precursors in a three- that was amenable to further elaboration via cross-coupling, the
step sequence. They undergo smooth coupling reactions thereby synthetic route proved to be rather linear.7 The potential for direct
providing an expedient route for the introduction of these four- incorporation of azetidines and oxetanes via cross-coupling seemed
membered heterocycles into indoles.
more attractive, and recent reports by Deng and Kuhakarn suggested
that direct coupling via the use of a sulfone linker could offer
The direct incorporation of small strained sp3-rich heterocycles an efficient means for achieving this goal.8 Moreover, this
into a range of molecular scaffolds has recently received approach would complement sulfone promoted cyclisation
significant attention as these fragments have the potential to and functionalization methodology developed by Bull and
offer favourable pharmacological properties whilst contributing co-workers that allows 2-(aryl-sulfonyl)oxetanes to be accessed
little to overall molecular weight.1 In this regard, oxetanes have from chloromethyl arylsulfides.9
generated considerable interest in the medicinal chemistry
We began our studies by exploring the sulfonylation of
sector because of their enhanced solubility and metabolic indoles for which we required the corresponding 3-sulfinate
stability relative to traditional linkers such as carbonyl and salts of azetidine and oxetane, respectively. These compounds
gem-dimethyl moieties.2 Azetidines are also of interest and have were accessed from the appropriate commercially available 3-iodo
the added capacity to diversify via the N-atom.3 From a synthetic heterocycles in 3 steps and in good overall yield. Notably, we found
standpoint, the incorporation of azetidines and oxetanes into the displacement of the pyridine group in the final step (2 - 3) to
aromatic scaffolds by cross-coupling has been realized by the use work well with sodium ethanethiolate, however, NaSBn was used in
of a number of transition metal catalysed processes. Negishi the synthesis of 3b because of the easier removal of organosulfur
coupling of azetidin-3-ylzinc iodide was reported by Billotte, by-products in this case. This process allowed the salts to be
while more recently Rombouts and Molander have demonstrated prepared on gram scale (see ESI†) (Scheme 1).
the Ag-promoted coupling of azetidine and oxetane-derived
We found that azetidine sulfinate salt 3a could be coupled to
trifluoroborates via the Minisci reaction.4 These small ring a range of indoles using the conditions reported by Kuhakarn
heterocycles can also be coupled as their corresponding alkyl (1.5 equiv. I2, MeOH, rt) over a period of 24 h,8b and the scope of
halides via transition metal catalysis or the Minisci reaction.5 this process is summarised in Scheme 2. Sulfonylation of indole
Finally, during the preparation of this manuscript, Baran
reported a four step synthesis of azetidine sulfinate salts, and
their subsequent employment in the direct alkylation of N-hetero-
aromatic compounds.6
Our own interests in this area have led to a cycloaddition
strategy for the incorporation of oxetanes into N-heteroaromatic
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF,
UK. E-mail: j.harrity@sheffield.ac.uk
b Research and Development, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG,
UK
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Synthesis of azetidine and oxetane sulfinate salts.
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As our objective was to introduce a versatile method for the
direct introduction of small heterocyclic rings, we decided to
employ this chemistry in the synthesis of an analogue of
atevirdine, a reverse transcriptase inhibitor that has been
studied for the treatment of HIV.10 As shown in Scheme 4, this
compound consists of indole and pyridine moieties that modulate
potency against reverse transcriptase. These fragments are linked by
a piperazine spacer unit. We envisaged that replacing the acylpiper-
azine fragment with an azetidine sulfone would allow us to devise a
short route to this class of compound that would permit the flexible
variation of the key heteroaromatic fragments. Indeed, we found that
4g could be prepared in near quantitative yield on 1 mmol scale, and
that the Boc group could be smoothly cleaved by treatment with TFA.
The amidation of 2-chloropyridine 7 proved to be quite challenging
but we found that the use of dppf as a ligand provided product 8 in
acceptable yield.11 Hence a simple atevirdine analogue was rapidly
assembled in a convergent route that offers the prospect for
significant variation of both key heteroaromatic units.
Finally, we have found that the regioselective incorporation
of small ring heterocycles at the C-3 position of indoles is also
possible by employing a sulfenylation12 followed by oxidation.
This strategy allows access to regioisomeric analogues of azetidines 4
in good overall yield (Scheme 5).
Scheme 2 Sulfonylation of indoles using azetidine 3a.
proceeded in excellent yield, and the coupling was found to be
compatible with substrates bearing a methyl group at nitrogen and
at the 3-position. A range of substituents were also tolerated at C-5,
although the chemistry was more effective for indoles bearing electron
donating groups (to give 4d,e,g) relative to electron deficient analogues
(4f,h). Finally, we found that the promoting effect of the MeO-group
was effective at all positions on the fused benzene ring (4g,i,j,k).
We next explored the compatibility of this chemistry with the
oxetane based sulfinate salt 3b and our results are summarised in
Scheme 3. We were pleased to find that the general trends
highlighted in the case of the azetidine sulfonylation could be
reproduced here. The reaction was found to work well with
electron rich indoles, although the free hydroxyl was not as well
tolerated in this case giving 5d in relatively modest yield.
Scheme 4 Synthesis of an atevirdine analogue.
Scheme 3 Sulfonylation of indoles using oxetane 3b.
Scheme 5 Sulfenylation of indoles followed by S-oxidation.
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We report a convenient strategy for the direct incorporation
of azetidines and oxetanes into indoles via the use of readily
available sodium sulfinate salts. The reactions proceed under
mild conditions, they are regioselective, and they allow access
to C-2 or C-3 sulfone linked products. The potential of this
chemistry for incorporation of the azetidines and oxetanes into
other heterocycles is underway and will be reported in due
course.
Communication
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We are grateful to AstraZeneca and The University of Sheffield
for financial support.
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