Lewis base directed cycloaddition reactions of 2-pyrones and alkynylaluminum reagents

Article abstract of DOI:10.1021/ol401952k

In situ generated alkynylaluminum reagents have been utilized in a [4 + 2] cycloaddition with 2-pyrones bearing a Lewis basic donor. The reactions proceed at or below room temperature and with complete regiocontrol. This one-pot method affords diversely s

Full text of DOI:10.1021/ol401952k

ORGANIC
LETTERS
2013
Vol. 15, No. 16
4222–4225
Lewis Base Directed Cycloaddition
Reactions of 2‑Pyrones and
Alkynylaluminum Reagents
ꢀ
Damien F. Crepin and Joseph P. A. Harrity*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, U.K.
j.harrity@sheffield.ac.uk
Received July 10, 2013
ABSTRACT
In situ generated alkynylaluminum reagents have been utilized in a [4 þ 2] cycloaddition with 2-pyrones bearing a Lewis basic donor. The
reactions proceed at or below room temperature and with complete regiocontrol. This one-pot method affords diversely substituted aromatic
compounds under very mild conditions.
The selective formation of aromatic compounds has
attracted considerable interest in synthetic chemistry due
to their importance in diverse areas of the chemical in-
dustry. Various methods have been developed for their
synthesis, mainly including electrophilic or nucleophilic
substitution reactions, transition-metal-catalyzed cross-
coupling, or CꢀH bond functionalization of preformed
aromatic compounds.1 Another strategy relies on regiose-
lective benzannulation reactions that obviate the need for
specific directing groups when incorporating substituents,
and a range of such methods have been reported that
employ metal promoted or pericyclic reactions.2 As out-
lined in Figure 1, we have become interested in the
potential of the substrate directing group concept3 for
promoting such cycloadditions and have reported the
implementation of in situ generated alkynyldifluorobo-
ranes toward this end.4 This mild method allows for the
formation of diversely substituted aromatic compounds
which can easily undergo further functionalization. We
envisaged that this method could allow access to other
arene-based organometallics by the cycloaddition of al-
kynes bearing other Lewis acids. In this context, we report
herein the use of alkynylaluminum derivatives as new
2π components in a directed [4 þ 2] cycloaddition with
2-pyrones.
Figure 1. Lewis base directed cycloaddition of 2-pyrones and
alkynes.
Preliminary investigations into the cycloaddition of
2-pyrones and alkynyldichloroboranes5 proved to be dis-
appointing. Thesealkynesappearedtobe unreactive atlow
tempertaure (ꢀ78 °C) and served to decompose the py-
rones at more elevated temperatures. In contrast however,
in situ generated diethyl(phenylethynyl)aluminum 2a re-
acted with 2-pyrone 3a at ambient temperature to provide
(1) (a) Miura, M.; Momura, M. Top. Curr. Chem. 2002, 219, 212. (b)
Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(2) (a) Saito, S.; Yao, Y. Chem. Rev. 2000, 100, 2901. (b) D’Souza,
€
D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095.
(3) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307.
(4) (a) Vivat, J. F.; Adams, H.; Harrity, J. P. A. Org. Lett. 2010, 12,
160. (b) Kirkham, J. D.; Butlin, R. J.; Harrity, J. P. A. Angew. Chem., Int.
Ed. 2012, 51, 6402. For cycloadditions of 2-pyrones and alkynylboronic
esters, see: (c) Kirkham, J. D.; Leach, A. G.; Row, E. C.; Harrity, J. P. A.
Synthesis 2012, 44, 1964. (d) Delaney, P. M.; Browne, D. L.; Adams, H.;
Plant, A.; Harrity, J. P. A. Tetrahedron 2008, 64, 866.
(5) For examples of synthesis and use of alkynyldichloroboranes, see:
(a) Leung, S.-W.; Singleton, D. A. J. Org. Chem. 1997, 62, 1955. (b)
Kabalka, G. W.; Yao, M.-L.; Borella, S. Org. Lett. 2006, 8, 879.
r
10.1021/ol401952k
Published on Web 08/05/2013
2013 American Chemical Society

biaryl 4 in high yield. We presume that 4 results from the
hydrolysis of intermediate A (vide infra).6 Similarly, di-
methyl(phenylethynyl)aluminum 2a0 can also be prepared
in situ and employed in the cycloaddition with pyrone 3a,
affording compound 4 in 82% yield.7 The importance of
the Al-moiety in this reaction was confirmed by reacting
3a with phenylacetylene; we were unable to detect any
cycloadduct after heating the substrates at 60 °C over an
extended time period.
Table 1. Optimization of the [4 þ 2] Cycloaddition
n equiv
isolated
entry
of 2aa
solvent
temp
rt
time
yield of 4
Scheme 1. Initial Conditions of Cycloaddition
1
2
3
4
5
6
7
3
DCE
THF
DCE
DCE
DCE
DCE
DCE
1 h
78%
ꢀ
3
rt
1 h
3
ꢀ78 °C
0 °C
rt
1 h
ꢀ
3
2 h
59%
73%
72%
69%
1.5
1.5
1.1
1 h
0 °C
rt
1.5 h
2.5 h
a Alkyne 2a was prepared in situ following the conditions shown in
Scheme 1.
found that pyrones 3b and 3c, respectively substituted by a
thioamide and an ester group, did not undergo the cy-
cloaddition; instead the starting material was recovered in
each case (entries 2 and 3). In contrast, pyrones that
incorporated various amide groups 3dꢀf afforded the
corresponding cycloadducts 7ꢀ9 in good yields (entries
4ꢀ6), including substrate 3f that bears a free NꢀH group.
Wenextlooked at a range of N-heteroaromaticsinorder to
establish their potential as directing groups for the cy-
cloaddition of 2a. While pyridine-substituted pyrone 3g
gave product 10 in 78% yield (entry 7), we were surprised
to recover oxazole and thiazole subtituted pyrones 3h
and 3i unreacted (entries 8 and 9). Interestingly, when
the pyrone is branched at the C2 position of the thiazole
instead of positon C4 (3j versus 3i), cycloadduct 13 was
produced in 70% yield (entry 10). Moreover, imidazole-
substituted pyrone 3k was also reactive, affording 14 in
69% yield (entry 11). Finally, we discovered that different
The optimization of the initial conditions (Table 1,
entry 1) was carried out using diethyl(phenylethynyl)alu-
minum 2a due to the less pyrophoric nature of diethylalu-
minum chloride relative to the dimethyl- analog. We
observed no reactivity upon changing the reaction solvent
for THF, or reducing the reaction temperature to ꢀ78 °C
(entries 2 and 3). However, conducting the reaction in
DCE at 0 °C resulted in full conversion after 2 h and 4 was
isolated in 59% yield. Moreover, we found that the
stoichiometry of diethyl(phenylethynyl)aluminum reagent
2a could be reduced to 1.5 equiv, affording biphenyl 4 in
73% yield when the reaction was conducted at rt (entry 5).
Decreasing the temperature to 0 °C gave 4 in a similar yield
(entry 6). Finally, we found that pyrone 3a also undergoes
the cycloaddition when treated with only 1.1 equiv of
alkynylaluminum 2a (entry 7). Under these conditions, 4
was isolated in 69% yield.
Scheme 2. Functionalization of Aryl(dimethyl)aluminum
Intermediatesa
We next investigated the scope of the reaction, using
3 equiv of alkynyldiethylaluminum compounds 2aꢀd
throughout to ensure complete conversion (Table 2). We
(6) For examples of the use of dialkyl(aryl)aluminum intermediates
in synthesis, see: (a) Hawner, C.; Li, K.; Cirriez, V.; Alexakis, A. Angew.
Chem., Int. Ed. 2008, 47, 8211. (b) Gao, H.; Knochel, P. Synlett 2009,
1321.
(7) For examples of synthesis and use of alkynyl(dialkyl)aluminum
species in cycloaddition reactions, see: (a) Tirado, R.; Torres, G.;
Torres, W.; Prieto, J. A. Tetrahedron Lett. 2005, 46, 797. (b) von
Zezschwitz, P. Synthesis 2008, 1809. (c) Jackowski, O.; Lecourt, T.;
Micouin, L. Org. Lett. 2011, 13, 5664. (d) Zhou, Y.; Lecourt, T.;
Micouin, L. Angew. Chem., Int. Ed. 2010, 49, 2607.
a The aryl(dimethyl)aluminum intermediates were prepared accord-
ing to the optimized conditions, using Me2AlCl.
Org. Lett., Vol. 15, No. 16, 2013
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Table 2. Scope of the Cycloadditiona
a Alkyne (1aꢀd) (3 equiv), BuLi (3 equiv), Et2AlCl (3 equiv); pyrone (3aꢀk) (1 equiv), rt, 1 h. b Pyrone substrate was recovered. c Reaction conducted
for 3 h. d Reaction conducted for 12 h.
terminal alkynes can be employed. Hence, trimethylsilyl-
acetylene 1b and 1-hexyne 1c reacted with pyrones 3a, 3g,
and 3k, affording aromatic compounds 15ꢀ19 (entries
12ꢀ16). Finally, 1-ethynylcyclohexene 1d was also em-
ployed, giving 20 in moderate yield (entry 17).
The role played by the Al-group in promoting the
reaction together with the consistent meta-substitution
pattern observed in products generated by this process
provided circumstantial evidence for the operation of a
directed cycloaddition process (along the lines depicted
in Figure 1). In order to gather further evidence however,
we attempted to identify and characterize an intermedi-
ate arylaluminum cycloadduct. Although we found these
intermediates to be hydrolytically unstable, careful con-
centration of the reaction mixture derived from the
dimethylaluminum promoted cycloaddition of 1c and 3k
1
allowed us to record a H NMR spectrum of the crude
material (Figure 2a). We were able to identify a signal at
0.09 ppm that was consistent with the Me-Al group.8
Furthermore, quenching this reaction mixture with D2O
resulted in the formation of compound d-19 after work-
1
up (Figure 2b). The H NMR spectrum shows approxi-
mately 90% incorporation of the deuterium label occurred
in this case (Figure 2c).8
(8) Although we have been unable to gather clear evidence for the
formation of a Lewis acidꢀbase complex in these products (e.g. B in
Figure 2) Blum and co-workers have reported similar intramolecularly
stabilized dialkyl(aryl)aluminum complexes; see: Blum, J.; Gelman, D.;
Baidossi, W.; Sharkh, E.; Rosenfeld, A.; Aizenshtat, Z. J. Org. Chem.
1997, 62, 8681.
4224
Org. Lett., Vol. 15, No. 16, 2013

Figure 2. (a) 1H NMR in C6D6 of crude intermediate B. (b) 1H NMR in C3D6O after quench of intermediate B with D2O followed by
standard workup. (c) Comparison of the aromatic region of d-19 and 19.
Finally, we wanted to investigate the synthetic poten-
tial of the aryl(dimethyl)aluminum intermediates, and
some illustrative examples are shown in Scheme 2. First,
we found that the intermediate arylaluminum compounds
reacted smoothly with iodine, affording iodobenzene de-
rivative 21 and 22 in high yield. Moreover, when the inter-
mediate was treated with boron trichloride, dimethylboryl
product 23 was obtained in 74% yield.9 The latter could
be tranformed into methylketone 24 upon exposure to
methyllithium; a similar transformation could be accom-
plished directly from the intermediate aluminum spe-
cies to afford methylketone 25 in 84% yield. Overall,
thistechnique complementsourrecent cycloadditionchem-
istry of alkynyldifluoroboranes,4b as it offers a one-pot
benzannulation of terminal alkynes, with the option of
generating arylhalides or boranes depending on the work-
up employed.
In conclusion, we have demonstrated that in situ gener-
ated alkynylaluminum reagents undergo rapid cycloaddi-
tion reactions with 2-pyrones bearing proximal Lewis
bases. This method provides an effective route to function-
alized benzene derivatives with predictable substitution
patterns and complete regiocontrol.
Acknowledgment. We are grateful to the EPSRC and
the University of Sheffield for financial support.
Supporting Information Available. Full experimental
details for the syntheses reported are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) The structure of this compound, including evidence for coordina-
tion of the amide oxygen atom, was obtained by X-ray crystallography.
The similarity of 11B NMR data in 23 and 24 suggests that 24 has a
similar Lewis acidꢀbase interaction. See Supporting Information for
details.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 16, 2013
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