Microwave-promoted tin-free iminyl radical cyclization with TEMPO trapping: A practical synthesis of 2-acylpyrroles

Article abstract of DOI:10.1021/ol5035047

Microwave-promoted iminyl radical cyclizations can be terminated by trapping with TEMPO, affording functionalized adducts. The use of alkynes as radical acceptors delivers a range of 2-acylpyrroles in good yields. Toxic and hazardous reagents, which are frequently employed in radical reactions, are not required. The O-phenyl oxime ether substrates are constructed in a single step from readily available ketones.

Full text of DOI:10.1021/ol5035047

Letter
pubs.acs.org/OrgLett
Microwave-Promoted Tin-Free Iminyl Radical Cyclization with
TEMPO Trapping: A Practical Synthesis of 2‑Acylpyrroles
Yu Cai, Ankur Jalan, Aaron R. Kubosumi, and Steven L. Castle*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
S
* Supporting Information
ABSTRACT: Microwave-promoted iminyl radical cyclizations can be termi-
nated by trapping with TEMPO, affording functionalized adducts. The use of
alkynes as radical acceptors delivers a range of 2-acylpyrroles in good yields.
Toxic and hazardous reagents, which are frequently employed in radical
reactions, are not required. The O-phenyl oxime ether substrates are constructed
in a single step from readily available ketones.
adical processes are valued for their mild reaction
conditions, excellent functional group tolerance, and
purpose.6,7 To avoid competitive hydrogen atom trapping, a
R
solvent other than toluene was required. We posited that
trifluorotoluene might serve as a suitable substitute. Our first
experiment involved microwave irradiation of O-phenyl oxime
ether 13 (Table 1), TEMPO, and the ionic liquid 1-ethyl-3-
ability to engage in one-pot multistep cascade transformations.1
A current area of emphasis involves the development of radical
reactions that do not require toxic or hazardous reagents (e.g.,
organotins, azo compounds, or peroxides).2 In this regard, we
became interested in the microwave-promoted iminyl radical
cyclizations of Walton and co-workers, which furnish
dihydropyrroles from alkene acceptors and pyrroles from
alkyne acceptors (Scheme 1).3−5 No radical initiators or tin
Table 1. TEMPO Trapping of Iminyl Radical Cyclization
Scheme 1. Microwave-Promoted Iminyl Radical Cyclization
entry
emimPF6 (equiv)
TEMPO (equiv)
time (min)
yield (%)
1
2
3
1.0
0
1.5
1.5
1.1
15
15
30
93
90
92
0
methyl-1H-imidazol-3-ium hexafluorophosphate (emimPF6,
employed by Walton and co-workers to facilitate efficient
microwave heating of the reaction mixture) in this solvent at
160 °C (the temperature employed in Walton’s study3). A
complex mixture resulted, and further investigation revealed
that TEMPO decomposes under microwave irradiation in
PhCF3 at this temperature. Fortunately, the thermolysis of 1
followed by cyclization and TEMPO trapping took place at
temperatures just below 100 °C, delivering dihydropyrrole 2
rapidly and in excellent yield (Table 1, entry 1). Since PhCF3 is
more polar than toluene, we reasoned that the ionic liquid
additive might not be necessary. Indeed, microwave heating was
efficient in its absence, and the yield of 2 was essentially
unchanged (Table 1, entry 2). Moreover, the amount of
TEMPO could be reduced to 1.1 equiv, albeit with an increase
in the reaction time from 15 to 30 min (Table 1, entry 3).
Walton and co-workers found that 5-exo iminyl radical
cyclizations onto alkyne acceptors furnished pyrroles due to
reagents are required, as the weak N−O bond in the substrate is
cleaved directly via thermolysis and the toluene solvent
functions as a hydrogen atom donor. Attracted by the simple
and environmentally friendly nature of this process, we
wondered if more complex products could be generated by
trapping the cyclic radical intermediate with species other than
hydrogen atoms. Herein, we present our initial findings on this
topic, which have led to a concise and efficient synthesis of 2-
acylpyrroles.
We began by investigating TEMPO as a radical trapping
agent due to the many examples of its successful use for this
Received: December 4, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol5035047
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
isomerization and aromatization of the initially formed adducts
(Scheme 1).3 We wondered if TEMPO-terminated cyclizations
onto alkyne acceptors conducted at lower temperatures would
also be accompanied by isomerization. If aromatization could
be prevented, the resulting dihydropyrrole enol ethers would be
valuable synthetic intermediates possessing numerous possibil-
ities for further functionalization. Interestingly, when alkyne-
containing O-phenyl oxime ether 3a8 was subjected to the
conditions developed with substrate 1, 2-acylpyrrole 4a was
obtained in moderate yield, and the presumed dihydropyrrole
enol ether intermediate was not observed (Table 2, entry 1).
Optimization studies revealed that 3.0 equiv of TEMPO were
required to deliver 4a in good yield (Table 2, entry 3).
Scheme 2. Scope of TEMPO-Terminated Iminyl Radical
Cyclization
Table 2. TEMPO-Terminated Iminyl Radical Cyclization of
Alkyne 3a
entry
TEMPO (equiv)
time (min)
yield (%)
1
2
3
1.5
2.5
30
30
60
41
43
83
a
3.0
a
1.5 equiv of TEMPO was added at the beginning of the reaction, and
a second portion was added after 30 min.
a
TEMPO added in two 1.5 equiv portions, 60 min reaction time.
11% of the dihydropyrrole enol ether 5 was also obtained.
b
Given the importance of pyrroles and the high level of
interest in developing new methods for their synthesis,9,10 we
examined TEMPO-terminated microwave-promoted radical
cyclizations of various alkyne-containing O-phenyl oxime ethers
311 (Scheme 2). The reaction exhibited a broad substrate scope,
delivering a variety of different 2-acylpyrroles. Acyl groups
larger than acetyl could be easily installed (4b), and both aryl
and alkyl groups were tolerated at the C-5 position (cf. 4b vs
4c). Acyl groups bearing alcohols protected with either acid-
labile (4d, 4e) or base-labile (4f) protecting groups were
compatible with the mild procedure. Interestingly, a small
amount of TEMPO-containing dihydropyrrole enol ether 5 was
obtained alongside pyrrole 4d. In addition to the acyl group
present at C-2 and the alkyl or aryl group located at C-5 of the
pyrrole, substituents at either C-3 or C-4 were also tolerated
(4g−i). Cyclic substrates were viable, furnishing bicyclic
pyrroles possessing fused five- (4j), six- (4k), and seven-
membered rings (4l). While most of the iminyl radical
cyclizations were conducted by adding the entire 3.0 equiv of
TEMPO in a single portion, the sequential addition of two 1.5
equiv portions afforded slightly better results in a few cases (4a,
4d, 4j).
In addition to conducting the microwave-promoted reac-
tions, we briefly investigated TEMPO-terminated iminyl radical
cyclizations under conventional conditions. Heating a solution
of oxime ether 1 and TEMPO in PhCF3 at 98 °C in an oil bath
for 3 h afforded dihydropyrrole 2 in 84% yield. The cyclization
of 3a under identical conditions required more time (12 h) and
delivered 2-acylpyrrole 4a in modest (52%) yield. These
experiments demonstrate that microwave irradiation is
beneficial but not required for these iminyl radical cyclizations
to take place. It is unlikely that microwave-specific acceleration
is operative, since this effect has only been documented in cases
where microwave-absorbing polar or ionic solutes are
selectively heated in nonpolar solvents that are essentially
transparent to microwaves.12 Our reactions employ a micro-
wave-absorbing polar solvent, so it is likely that the entire
solution is heated in relatively uniform fashion upon microwave
irradiation.
To probe the mechanism of 2-acylpyrrole formation, we
conducted the iminyl radical cyclization of alkyne 6, which is
unable to afford an aromatic product (Scheme 3). This reaction
Scheme 3. Microwave-Promoted Cyclization of Alkyne 6
furnished a complex mixture from which we were unable to
1
isolate the products. H NMR and mass spectrometry analysis
of the crude reaction mixture indicated the presence of enol
ether 7 and its isomer 8. Ketone 9, which would have formed
via fragmentation of 8, was not detected. While it is premature
to draw conclusions from this result, it does suggest that
formation of an aromatic pyrrole ring system is necessary for
the TEMPO group to fragment and generate a ketone.
We then subjected dihydropyrrole enol ether 5 to microwave
heating in the absence of TEMPO (Scheme 4). Isomerization
to generate the pyrrole was facile, as 10 was the major product
1
visible in the H NMR spectrum of the reaction mixture.
However, 2-acylpyrrole 4d was not detected, indicating that the
B
DOI: 10.1021/ol5035047
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Letter
In summary, we have found that microwave-promoted iminyl
radical cyclizations can be terminated by trapping with
TEMPO. The use of alkynes as radical acceptors furnishes 2-
acylpyrroles by a process involving isomerization and
fragmentation. The O-phenyl oxime ether cyclization substrates
are easily prepared in a single step from ketones, which are
themselves readily available. 2-Acylpyrroles have traditionally
been synthesized by Friedel−Crafts acylations17 or Vilsmeier
reactions.18 When compared to these methods and others that
are used to construct substituted pyrroles,9,10 this protocol is
attractive for its mild conditions that tolerate the presence of
both acid- and base-sensitive functional groups. Its scope,
simplicity, and good yields are also noteworthy. Moreover, toxic
or hazardous reagents such as organotins, azo compounds, and
peroxides are not required. Further applications of microwave-
promoted iminyl radical cyclizations are currently under
investigation in our laboratory.
Scheme 4. Heating of 5 in the Absence of TEMPO
presence of radicals facilitates fragmentation of 10 and related
adducts.
A plausible mechanism for the formation of 2-acylpyrroles 4
is shown in Scheme 5. Microwave irradiation of O-phenyl
Scheme 5. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: scastle@chem.byu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Brigham Young University (MEG Award to S.L.C.,
Undergraduate Research Award to A.R.K.) for support.
■
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