Synthesis and Cycloaddition Reactions of Stabilized Münchnones

Article abstract of DOI:10.1002/ejoc.201600486

A family of stabilized münchnones bearing an acyl group at C4 have been prepared and studied in alkyne cycloaddition reactions. These reactions are highly regioselective, and the method represents a rapid and straightforward route to densely substituted pyrroles. Finally, the C4-stabilizing units can be further manipulated to furnish carboxylic acid and amide groups, or removed altogether to provide unsubstituted pyrroles.

Full text of DOI:10.1002/ejoc.201600486

DOI: 10.1002/ejoc.201600486
Communication
Cycloadditions
Synthesis and Cycloaddition Reactions of Stabilized
Münchnones
Taban K. K. Kakaawla,[a] Will C. Hartley,[a] and Joseph P. A. Harrity*[a]
Abstract: A family of stabilized münchnones bearing an acyl to densely substituted pyrroles. Finally, the C4-stabilizing units
group at C4 have been prepared and studied in alkyne cyclo- can be further manipulated to furnish carboxylic acid and
addition reactions. These reactions are highly regioselective, amide groups, or removed altogether to provide unsubstituted
and the method represents a rapid and straightforward route pyrroles.
Introduction
explore the scope of alkyne cycloaddition reactions of stabilized
münchnones, and report our results herein (Scheme 2).
Mesoionic compounds are five-membered dipolar heterocycles
that have a rich source of chemistry, in particular with respect
to reactivity and structure.[1] Amongst the many possible mem-
bers of this family of compounds, sydnones 1 are the most
generally studied due to their ease of synthesis and isolation.[2]
The closely related 1,3-oxazolium 5-oxides (münchnones) 2
have also attracted significant attention,[3] in particular in their
transformation to pyrroles by cycloaddition/retrocycloaddition
processes.[4] Generally speaking, however, münchnones are less
stable than sydnones, and they readily undergo hydrolysis to
the corresponding N-amido α-amino acids 3.[5] For this reason,
much of the chemistry of these compounds requires their em-
ployment in situ directly after formation (Scheme 1).
Scheme 2. Use of stabilized münchnones in the synthesis of pyrroles.
Scheme 1. Mesoionic heterocycles.
On the other hand, stabilized münchnones 4 bearing an acyl
group at C4 can be significantly more stable than their non-
acylated analogues, allowing them to be isolated, purified and
characterized by traditional methods.[6] A relatively narrow
range of C4-acyl substituents has been reported, with the tri-
fluoroacetyl group being the most commonly employed.[7]
Moreover, the potential of these compounds to function as pre-
cursors to the corresponding pyrroles by alkyne cycloadditions
has received scant attention,[6] and so the regioselectivity of
this process has not been established. We therefore set out to
Results and Discussion
The stabilized münchnones required for the regioselective
cycloaddition study were prepared by cyclodehydrative acyla-
tion reactions. Applying conditions reported by Kawase,[7] we
were able to generate 4-trifluoroacetylated münchnones 1a–d
bearing alkyl and aryl groups at the nitrogen atom. Although
acid anhydrides are commonly employed for the formation of
münchnones, isocyanates have not been exploited for this pur-
pose.[8] However, we were pleased to find that isocyanates bear-
ing Ts and trichloroacetyl groups performed quite well in this
regard to deliver a family of novel C4-imide-substituted münch-
nones 2a–e. Overall, compounds 1, 2 were found to be stable
and amenable to chromatographic purification (Scheme 3).
[a] Department of Chemistry, University of Sheffield
Brook Hill, Sheffield, S3 7HF, UK
E-mail: j.harrity@sheffield.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600486.
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performing the cycloaddition with an excess of a stoichiometric
mixture of phenylacetylene and 1-octyne resulted in the select-
ive incorporation of the aryl-substituted alkyne (Scheme 5).
Scheme 5. Relative reactivity of phenylacetylene and 1-octyne.
We next opted to explore the cycloaddition reaction of the
C4-imide-substituted münchnones and began with sulfonimide
2a and trichloroacetimide 2d, and using phenylacetylene as a
reactive alkyne. In the event, 2a generated pyrrole 11a in mod-
erate yield but excellent regioselectivity. Surprisingly, pyrrole
11b was also isolated, in which the imide had undergone ap-
parent cleavage. Nonetheless, we were able to minimize loss of
the imide group by reducing the reaction time and tempera-
ture, which allowed us to isolate the pyrrole 11a in high yield.
With respect to substrate 2d, cycloaddition with phenyl-
acetylene also produced two pyrrole products. In this case
amide 12b was the predominant product when the reaction
mixture was heated in xylenes over 6 h. We were able to im-
prove the yield of this product by extending the reaction time
to 21 h.
Having optimized the conditions for the cycloaddition of
münchnones 2, we explored the scope of this process. Pyrroles
13–15 and 17–19 were formed in moderate to high yields and
with excellent regiocontrol. However, once again, alkyl-substi-
tuted alkynes were less effective; for example, compound 16
was produced in significantly lower yield.
We were pleased to note that the reaction regioselectivities
are uniformly high across all substrates examined. Interestingly,
the incorporation of the stabilizing groups does not appear to
play a significant role with respect to regiochemistry, and the
trends observed here reflect the known regiochemical alkyne
insertion patterns of arylacetylenes, whereby the initial cyclo-
addition takes place to connect the substituted alkyne carbon
atom to the münchnone C4 position.[10]
Scheme 3. Synthesis of stabilized münchnones.
With a selection of mesoionic compounds in hand, we
turned our attention to the alkyne cycloaddition reactions of
these compounds. We began our studies by exploring the re-
activity of 4-trifluoroacetylated substrates, and our results are
shown in Scheme 4. Münchnones 1a–d underwent efficient re-
action with phenylacetylene after heating in xylenes to give the
corresponding pyrroles 3–6 in good yields. Moreover, we were
delighted to find that the products were generated as single
regioisomers. Unfortunately, however, alkyl-substituted alkynes
such as 1-octyne and cyclopropylacetylene proved to be much
less reactive, and generated the corresponding heterocyclic
products 7–10 in much lower yields, albeit with the same high
regiocontrol.[9]
The cycloaddition reactions shown in Schemes 4, 6 and 7
highlighted that the incorporation of electron-deficient groups
Scheme 4. Cycloaddition reactions of 4-trifluoroacetylated münchnones. [a] 2
equiv. of alkyne used in these cases.
The lower reactivity of alkyl-substituted alkynes relative to
that of phenylacetylene was confirmed by a series of competi-
tion experiments carried out on münchnones 1a–d. In all cases,
Scheme 6. Cycloaddition reactions of 4-imide-substituted münchnones. Ts =
4-tolylsulfonyl; TCA = trichloroacetyl.
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at the münchnone C4 position offered a convenient opportu- roacetyl groups in 4 and 5 allowed us to access pyrrolecarboxy-
nity to isolate these mesoionic substrates, while imparting ex- lic acids 20 and 21 [Equation (1)], whereas heating of N-acyl-
cellent levels of regiocontrol in the reactions with alkynes. In sulfonamides 11a and 13 resulted in 5H-pyrroles 11b and 22
addition, an unexpected observation was made in the final fate [Equation (2)]. This latter process highlighted the potential of
of the stabilizing group. In contrast to trifluoroacetate, which N-acylsulfonamides as traceless münchnone-stabilizing groups.
proved to be stable to the reaction conditions, the N-acylsulfon- Finally, Equation (3) summarizes our finding that trichloro-
amide underwent partial cleavage of the directing group, while acetimides function as primary amide equivalents in the alkyne
the trichloroacetimide underwent conversion into the corre- cycloaddition process.
sponding amide. These results prompted us to exploit the stabi-
lizing group in order to expand the flexibility of the pyrrole
functionality in the final cycloadducts; our results are summa-
Conclusions
rized in Scheme 8. The base-mediated hydrolysis of the trifluo-
We report the cycloaddition reactions of alkynes and a series of
stabilized münchnones, including an unusual family of amide-
substituted analogues that are prepared by a novel isocyanate-
mediated cyclodehydration functionalization reaction. The
cycloadditions are highly regioselective and provide direct ac-
cess to densely substituted functionalized pyrroles. Moreover,
the stabilizing groups can be further manipulated to furnish
carboxylic acid and amide groups, or removed altogether to
provide the unsubstituted pyrrole. A current limitation is the
low yields associated with alkyl-substituted alkynes, and work
is underway to develop solutions to this drawback.
Experimental Section
Typical Cycloaddition Procedure as Exemplified by the Forma-
tion of 5-Trifluoroacetyl-1,2,4-triphenyl-1H-pyrrole (3): A solu-
tion
of
2,3-diphenyl-4-trifluoroacetyl-1,3-oxazolonium-5-olate
(100 mg, 0.30 mmol) and ethynylbenzene (61 mg, 0.60 mmol) in
xylenes (0.30 mL) in a sealed microwave vessel was heated at 140 °C
for 16 h. After cooling, the crude materials were purified by flash
chromatography on silica gel (eluting with 10 % EtOAc in petroleum
ether) to provide the title compound as a yellow solid (107 mg,
91 %); m.p. 164–165 °C. 1H NMR (400 MHz, CDCl3): δ = 7.48–7.42
(m, 5 H), 7.39–7.36 (m, 3 H), 7.25–7.20 (m, 5 H), 7.17–7.13 (m, 2 H),
6.56 (s, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 174.1 (q, J =
37.0 Hz), 143.3, 138.3, 137.6, 134.8, 130.7, 129.3, 129.0, 128.8, 128.5,
128.3, 128.2, 128.1, 128.0, 127.9, 125.5, 116.0 (q, J = 290.0 Hz),
Scheme 7. Cycloaddition scope of imide-substituted münchnones. Ts = 4-
tolylsulfonyl; TCA = trichloroacetyl. [a] 2 equiv. of alkyne used in these cases.
114.0 ppm. 19F NMR (376 MHz, CDCl3): δ = –71.4 ppm. FTIR: ν =
˜
1661 (s), 1596 (m), 1272 (s), 1239 (s), 1195 (s) cm–1. HRMS: calcd. for
C19H15NOF3 330.1106, found 330.1099.
Acknowledgments
We are grateful to The Higher Committee for Education Devel-
opment in Iraq and the University of Sheffield SURE Scheme for
financial support.
Keywords: Münchnones · Cycloaddition · Pyrroles ·
Regioselectivity · Heterocycles
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Scheme 8. Manipulation of the directing group. Ts = 4-tolylsulfonyl; TCA =
trichloroacetyl.
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Received: April 19, 2016
Published Online: May 20, 2016
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