Pyridines from azabicyclo[3.2.0]hept-2-en-4-ones through a proposed azacyclopentadienone

Article abstract of DOI:10.1021/ol202924s

Pyridines have been formed by heating azabicyclo[3.2.0]hept-2-en-4-ones in toluene. The generation of a 3-azacyclopentadienone intermediate via a [2 + 2]-cycloreversion is proposed as the key step. A Diels-Alder reaction of a styrene, extrusion of carbon monoxide, and loss of hydrogen then gives the pyridine. The process parallels the well-known synthesis of benzenes from cyclopentadienones. The azabicyclo[3.2.0]hept-2-en-4-ones were synthesized from the reaction between readily available cyclopropenones and 1-azetines, in which the cyclopropenones behave as all-carbon 1,3-dipolar equivalents.

Full text of DOI:10.1021/ol202924s

ORGANIC
LETTERS
2012
Vol. 14, No. 1
126–129
Pyridines from Azabicyclo[3.2.0]-
hept-2-en-4-ones through a Proposed
Azacyclopentadienone
Karl Hemming,* Musharraf N. Khan, Vishnu V. R. Kondakal, Arnaud Pitard,
M. Ilyas Qamar, and Craig R. Rice
Institute for Materials, Medicines and Molecular Sciences, Division of Chemistry,
School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield,
West Yorkshire, HD1 3DH, United Kingdom
k.hemming@hud.ac.uk
Received October 29, 2011
ABSTRACT
Pyridines have been formed by heating azabicyclo[3.2.0]hept-2-en-4-ones in toluene. The generation of a 3-azacyclopentadienone intermediate via
a [2 þ 2]-cycloreversion is proposed as the key step. A DielsꢀAlder reaction of a styrene, extrusion of carbon monoxide, and loss of hydrogen
then gives the pyridine. The process parallels the well-known synthesis of benzenes from cyclopentadienones. The azabicyclo[3.2.0]hept-2-en-4-
ones were synthesized from the reaction between readily available cyclopropenones and 1-azetines, in which the cyclopropenones behave as
all-carbon 1,3-dipolar equivalents.
The pyridine ring occupies a position of great impor-
tance to the synthetic chemist due to its relevance in the
pharmaceutical industry, in the agrochemical industry, in
natural product chemistry, and in materials science.1ꢀ3 It is
thus the case that the synthesis of the pyridine ring by the
use of new cycloaddition1 and other2 methodologies con-
tinues to be of current value, and such recent contributions
ensure that this most studied3 of areas remains a rich
source for significant discoveries. Among the more recent1
and established3 cycloaddition methodologies, the use of
azacyclopentadienone in pyridine synthesis remains an
(1) (a) Wang, Y.-F.; Tof, K. K.; Ng, E. P. J; Chiba, S. J. Am. Chem.
Soc. 2011, 133, 6411. (b) D’Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett.
2011, 13, 2936. (c) Coffinier, D.; El Kaim, L.; Grimaud, E.; Orru,
R. V. A. Tetrahedron Lett. 2011, 52, 3023. (d) Kral, K.; Hapke, M.
Angew. Chem., Int. Ed. 2011, 50, 2434. (e) Chughtai, M.; Eagan, J. M.;
Padwa, A. Synlett 2011, 215. (f) Garcia, P.; Evanno, Y.; George, P.;
Sevriv, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon, V. Org. Lett.
2011, 13, 2030. (g) Coffinier, D.; El Kaim, L.; Grimaud, L.; Hadrot, S.
Tetrahedron Lett. 2010, 51, 6186. (h) Chuang, T.-H.; Chen, Y.-C.; Pola, S.
J. Org. Chem. 2010, 75, 6625. (i) Miclo, Y.; Garcia, P.; Evanno, Y.;
George, P.; Sevrin, M.; Malacria, M.; Gandon, V.; Aubert, C. Synlett
2010, 2314. (j) Sakai, T.; Danheiser, R. L. J. Am. Chem. Soc. 2010, 132,
13203. (k) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474. (l) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (m)
Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (n)
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Poupon, E. Tetrahedron Lett. 2011, 52, 3523. (b) Wu, P.; Cia, X. M.;
Wang, Q. F.; Yan, C. G. Synth. Commun. 2011, 41, 841. (c) Liu, J.; Wang,
C.;Wu, L.;Liang, F.; Huang, G. Synthesis 2010, 4228. (d) Shen, L.; Cao, S.;
Wu, J.; Hui, L.; Zhang, J.; Wu, M; Qian, X. Tetrahedron Lett. 2010, 51,
4866. (e)Chen, Z.;Zhu, J.;Xie, H.;Li, S.;Wu, Y.;Gong, Y.Org. Lett. 2010,
12, 4376. (f) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570.
(g) Rizk, T.; Bilodeau, E. J.-F.; Beauchemin, A. M. Angew. Chem., Int. Ed.
2009, 48, 8325. (h) Hu, J.; Zhang, Q.; Yuan, H.; Liu, Q. J. Org. Chem.
2008, 73, 2442. (i) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
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r
10.1021/ol202924s
Published on Web 12/21/2011
2011 American Chemical Society

unexploited avenue, an absence that is all the more curious
given the well-known4 process by which the corresponding
all-carbon diene, cyclopentadienone, is used to access the
benzene ring. The absence of azacyclopentadienone based
pyridine syntheses is undoubtedly related to the difficulties
encountered in accessing this elusive system either in stable
form or from readily available suitable precursors. The
2-azacyclopentadienone ring 1 (see Figure 1) is rare, but its
formation and use are known.5 Of particular relevance to
our work, species 1 has been generated from a polymeric
5-sulfonateof 2-oxopyrrolidine and shown toact asa diene
toward a polymer supported alkyne, allowing access toone
example of a pyridine ring.6 Work by the same group7
gave access to a single example of the even more elusive
3-azacyclopentadienone 2, generated in similar fashion
as an unstable intermediate from a polymeric 1-acyl
3-oxopyrrolidine. A stable 3-thione analogue of azacyclo-
pentadienone 2 has also been reported.8 In view of this
scarcity and lack of applicability, there is a requirement
for new methods which allow the generation of 3-
azacyclopentadienones. We wish to report one such meth-
od in this paper and show that such systems can be used to
generate pyridines.
synthesized as an unstable, but isolable, mixture of diaster-
eoisomers from the reaction of 2-methylthio-4-(4-tolyl)-
1-azetine 5a with diphenylcyclopropenone 6a, a reaction in
which the cyclopropenone acts asan all-carbon 1,3-dipolar
equivalent. The chemistry and applications of cyclo-
propenones9 and their acetals/ketals10 have gained mo-
mentum in recent years, and there are also other reports of
imines reacting with cyclopropenones.11 The topic of
3-carbon 1,3-dipole equivalents is an area of importance
in its own right due to the potential for such processes to
provide access to 5-membered rings in [3 þ 2]-cycloaddition
reactions.12
Table 1. Reaction of Cyclopropenones with 1-Azetines
yield
(%)
[diast.
entry
1
product
Ar
4-Tol
R
R1
Ph
R2
Ph
ratio]
4a
Me
63
[3:2]
63
2
3
4
5
6
7
4b
4c
4d
4e
4f
Ph
Et
Ph
H
Ph
[5:3]
52
Ph
Me
Me
Et
Ph
[6:5]
62
Figure 1. Azacyclopentadienones and bicyclic pyrrolinones.
Ph
Ph
Ph
Ph
n-Bu
Ph
[5:4]
66
4-Tol
2-Naphth
Ph
Ph
Our work started with the synthesis of a range of
azabicyclo systems 3 which incorporate the 3-oxopyrrolidine
moiety. We investigated the azabicyclo[3.2.0]hept-2-
en-4-one system 4 on the basis that this system might
readily yield the desired azacyclopentadienone. Our first
example of this system, compound 4a (Table 1), was
[3:2]
51
Me
Et
Ph
[3:2]
58
4g
n-Bu
[3:2]
(9) (a) Manova, R.; van Beek, T. A.; Zuilhof, H. Angew. Chem., Int.
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2008, 49, 4060. (f) O’Gorman, P. A.; Chen, T.; Cross, H. E.; Naeem, S.;
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2009, 74, 4242.
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Org. Lett., Vol. 14, No. 1, 2012
127

We next found that the treatment of 4a in boiling toluene
for <24 h resulted in the complete consumption of the
starting material and the formation of the pyridine 7a
(Scheme 1) in good yield. A mechanism for this process is
proposed in Scheme 1. An overall [2 þ 2]-cycloreversion
reaction gives the desired 3-azacyclopentadienone 9a plus
styrene 8a. This initial process may be stepwise, polar or
free-radical, and we are unable at the moment to discern
between these possibilities. Recombination of species 9a and
8a in a regioselective [4 þ 2]-cycloaddition would then give
the cycloadduct 10a. Extrusion of carbon monoxide and
aromatization then give the pyridine 7a. The regiochemistry
of the process was established by 2-D NMR studies and by
X-ray crystallographic studies on the final pyridine.13 Based
upon this result, we synthesized other azabicyclo[3.2.0]hept-
2-en-4-ones 4 to act as pyridine precursors. As shown in
Table 1, a series of 1-azetines 5 reacted smoothly with the
cyclopropenones 6 to give the azabicyclo[3.2.0]hept-2-en-4-
ones 4bꢀg. Again, these were found to be unstable but
isolable mixtures of diastereoisomers, which were used with-
in 24 h. Phenylcyclopropenone gave only the 3-phenyl-1-
azabicyclo[3.2.0]hept-2-en-4-one regioisomer 4c, presumably
due to the 1-azetine attacking the least hindered cycloprope-
none carbon. We have found that other monosubstituted
cyclopropenones react in the same manner with 5-, 6-, and
7-membered cyclic imines.11f Diphenylcyclopropenone was
commercially available, phenylcyclopropenone was synthe-
sized by the cyclization of 1-bromo-3-chloro-3-phenyl
acetone acetal,14 and dibutylcyclopropenone was synthe-
sized from the reactionofdichlorocarbene withdecyne and
subsequent hydrolysis.15 It is noteworthy that a large range
of other di- and monosubstituted cyclopropenones is
available by these and other16 routes. The 1-azetines were
readily available by alkylation of the corresponding thio-
β-lactam, which was in turn available from the treatment
of the β-lactam with Lawesson’s reagent.17
Scheme 1. Proposed Mechanism for the Formation of Pyridine
7a
Table 2. Conversion of Azabicyclo[3.2.0]hept-2-en-4-ones 4 into
Pyridines 7
yield
entry
product
Ar
4-Tol
R
R1
Ph
R2
Ph
(%)
1
2
3
4
5
6
7
7a
7b
7c
7d
7e
7f
Me
Et
79
75
62
71
72
69
73
Ph
Ph
H
Ph
Ph
Me
Me
Et
Ph
Ph
Ph
Ph
Ph
n-Bu
Ph
4-Tol
2-Naphth
Ph
Ph
Each of the azabicyclo[3.2.0]hept-2-en-4-ones 4bꢀg
gave the desired pyridine 7bꢀg in good to reasonable
yields when heated in boiling toluene (Table 2). It is of
note that the presence ofthe C2-thioalkyl substituent in the
pyridines 7aꢀg offers the potential of Pd-catalyzed func-
tionalization of the type reported by Liebeskind.18 The
handling of the unstable azabicyclo[3.2.0]hept-2-en-4-ones
4 may be improved by telescoping the cyclopropenone
addition and heating steps, and we are currently exploring
the potential of this process.
Me
Et
Ph
7g
n-Bu
Scheme 2. Evidence for the Proposed Mechanism
To obtain evidence for this mechanism, we have been
able to show that the proposed intermediate 3-azacy-
clopentadienone 9b can be trapped by heating 4b in the
(13) Crystallographic data have been deposited at the Cambridge
Crystallographic data Centre as a CIF deposit with file number 847593.
Copies of these data can be obtained free of charge on application to
CCDC, email deposit@ccdc.cam.ac.uk. The CIF is also included in the
supplementary data; see Supporting Information.
(14) Ando, R.; Sakaki, T.; Jikihara, T. J. Org. Chem. 2001, 66, 3617.
(15) Netland, K. A.; Gundersen, L.-L.; Rise, F. Synth. Commun.
2000, 30, 1767.
(16) Isaka, S.; Ejiri, S.; Nakamura, E. Tetrahedron 1992, 48, 2045.
(17) See Supporting Information.
(18) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349.
128
Org. Lett., Vol. 14, No. 1, 2012

process that is consistent with the formation of inter-
mediate 9b, which then undergoes loss of ethene fol-
lowed by dimerization with loss of sulfur. Furthermore
(Scheme 4), when 2-ethylthio-4-phenyl-1-azetine was re-
acted with the nitrile oxide derived from 2-azidobenzohy-
droximoyl chloride,19 the resultant cycloadduct 13 also
underwent a process consistent with the proposed [2 þ 2]-
cycloreversion to give the expectedly stable 1,2,4-oxadia-
zole 14 as the product,20 indicating that such cyclorever-
sions may be a general facet of the chemistry of fused
bicyclic azetidines of general type 15, an aspect that we are
now exploring morefully. Weare currently exploringother
reactions that can trap and utilize the proposed intermedi-
ate 3-azacyclopentadienones 9, as enophiles, ynophiles, or
dienophiles.
Scheme 3. Formation of Bipyrrolinone 12 from Azabicyclo-
[3.2.0]hept-2-en-4-one 11
In conclusion, a new protocol for the synthesis of pyr-
idines has been developed using the reaction of cycloprope-
nones with 1-azetines, where the cyclopropenone functions
as an all-carbon 1,3-dipole. When heated in toluene, the
resulting azabicyclo[3.2.0]hept-2-en-4-ones behave in a
manner that is consistent with the generation of an inter-
mediate 3-azacyclopentadienone generated through a [2 þ 2]-
cycloreversion. This intermediate undergoes a Dielsꢀ
Alder reaction with the styrene product of the cyclorever-
sion, followed by extrusion of carbon monoxide and
aromatization to generate pyridines. This process parallels
the synthesis of benzenes from cyclopentadienones.
Scheme 4. Formation of 1,2,4-Oxadiazole 14 from
Oxadiazabicyclo[3.2.0]heptene 13
Acknowledgment. This work was supported by Univer-
sity of Huddersfield Studentships (to M.N.K., V.R.V.K.,
A.P., and M.I.Q.). We thank Dr Neil McLay, University
of Huddersfield, for NMR and mass spectroscopy sup-
port, and the EPSRC national mass spectroscopy service,
University of Wales, Swansea for HRMS.
presence of a second styrene to give an easily separated
mixture of two pyridines, 7b and 7e (Scheme 2). It is also
of note that we have previously shown11c that the
tetramethyl adduct 11 (Scheme 3) forms the pyrrolyli-
dene-pyrrolone 12 upon heating in dichlorobenzene, a
Supporting Information Available. Experimental pro-
cedures and characterization data for 4aꢀg, 5, 6, 7aꢀg,
1
13, and 14; copies of H and 13C spectra of these com-
pounds; X-ray data for 7a. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) For the synthesis of this compound, see:Hemming, K.; Loukou,
C.; Elkatip, S.; Smalley, R. K. Synlett 2004, 101.
(20) We had anticipated that the azide group may trap the styrene,
but saw no evidence of such a process.
Org. Lett., Vol. 14, No. 1, 2012
129