Base-promoted reactions of dichlorocarbene adducts of cyclic enamines: A new route to annulated pyrroles

Article abstract of DOI:10.1021/ol7021774

Treatment of the gem-dihalogenocyclopropanes 1-5 with potassium tert-butoxide or LDA results in the formation of the corresponding and annulated pyrroles 13-17, respectively.

Full text of DOI:10.1021/ol7021774

ORGANIC
LETTERS
2
007
Vol. 9, No. 26
421-5424
Base-Promoted Reactions of
Dichlorocarbene Adducts of Cyclic
Enamines: A New Route to Annulated
Pyrroles
5
Alex C. Bissember, Andrew T. Phillis, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of AdVanced Studies, The Australian National
UniVersity, Canberra, ACT 0200, Australia
mgb@rsc.anu.edu.au
Received September 24, 2007
ABSTRACT
Treatment of the gem-dihalogenocyclopropanes 1−5 with potassium tert-butoxide or LDA results in the formation of the corresponding and
annulated pyrroles 13 17, respectively.
−
Recently, we reported that the dichlorocarbene adducts of
various alkyl enol ethers react with strong base to give
furans. This process thus provides a method for the three-
Scheme 1
1
step furannulation of various enolizable ketones, and we have
demonstrated the utility of it in the synthesis of the racemic
modification of the furanosesquiterpenoid natural product
1
pallescensin A. The relevant reaction sequence is shown in
Scheme 1, and the pathway by which the furan-forming step
proceeds is the subject of ongoing studies within these
laboratories.
In an effort to extend this type of chemistry, we were
prompted to examine the base-promoted reactions of the
corresponding dihalogenocarbene adducts of enamines. A
major motivation for doing so was the expectation that these
reactions might lead to pyrroles bearing otherwise difficult
to obtain substitution patterns and so provide a useful
addition to the repertoire of methods available for preparing
2
these particularly important aromatic heterocycles. Although
the dichlorocarbene adducts of enamines are known, we are
not aware of any systematic studies of the base-promoted
reactions of such compounds. Herein, therefore, we detail
our preliminary studies of this matter and report on the
3
successful generation of a range of unusual pyrrolic systems.4
The adducts 1-10 used in the present study were generally
prepared (29-85%) by subjecting the relevant enamine to
reaction with chloroform or bromoform and sodium hydrox-
ide in the presence of the phase-transfer catalyst triethyl-
(1) Foot, J. S.; Phillis, A. T.; Sharp, P. P.; Willis, A. C.; Banwell, M. G.
Tetrahedron Lett. 2006, 47, 6817.
1
0.1021/ol7021774 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/29/2007

benzylammonium chloride (TEBAC) under conditions first
defined by M a¸ kosza.5 Despite the propensity of gem-
dihalogenocyclopropanes carrying electron-donating substit-
6
uents to undergo facile electrocyclic ring cleavage, these
adducts proved to be rather stable and generally crystalline
materials. Indeed, the structures of compounds 4 and 6 were
7
confirmed by single-crystal X-ray analysis. In contrast,
however, no success was had in efforts to isolate the
dichlorocarbene adducts of the morpholino-based enamines
derived from indan-1-one and cyclopentanone or the same
types of adducts from the pyrrolidine-derived enamines of
R-tetralone or cyclohexanone. In each instance only complex
mixtures of materials were obtained. Interestingly, attempts
to add dichlorocarbene to the double bond of the readily
prepared amino-substituted cinnamate 11 delivered, as the
only isolable material, what is tentatively identified as the
dichlorocarbene insertion product 12 (11%).
Table 1. Products Derived from Base-Promoted Reactions of
Compounds 1-10a
temp time
yield
(%)
entry substrate
base
LDA
LDA
LDA
LDA
t-BuOK
LDA
t-BuOK
t-BuOK
LDA
(°C)
(h)
product
b,c,d
c,e
1
2
3
4
5
6
7
8
9
0
1
2
1
2
3
4
4
5
5
6
7
8
9
0
0
0
3
3
3
13
14
15
82
66
54
f
g
d
0
5
16
43
0
0
0.5
3
16
17
28
45
18
18
0
16
22
8
17
30-35
79
d,h
d
18
NRi
19
1
1
1
LDA
LDA
LDA
0
3
81
0
0
8
8
NR
NR
10
a
All reactions were carried out using THF as solvent, except for entry
b
c
5
where 1:1 v/v THF/DMSO was used. Reference 3a. Reference 3e.
d
Reference 3f. e Reference 3b. Reference 8. g Reference 9. h Reference 3c.
f
i
NR ) no reaction.
studies also revealed that lithium diisopropylamide (LDA)
was a superior base to t-BuOK. The structures of the products
were established by standard spectroscopic methods and
confirmed through the single-crystal X-ray analyses of
7
compound 16 and a derivative of congener 17 (vide infra).
The selective and efficient formation of the pyrrolo[2,1-a]-
isoquinoline-type system 17 over its pyrrolo[1,2-b]isoquino-
line-based isomer is noteworthy.
(3) (a) Ohno, M. Tetrahedron Lett. 1963, 1753. (b) Wolinsky, J.; Chan,
The reaction of substrates 1-5 with base at 0-18 °C for
.5-5.0 h produced the expected outcomes in that the
corresponding pyrroles, 13-17 respectively, were obtained
in yields ranging from 28-82% (Table 1, entries 1-7). Such
D.; Novak, R. Chem. Ind. (London, UK) 1965, 720. (c) Pandit, U. K.; de
Graaf, S. A. G.; Braams, C. T.; Raaphorst, J. S. T. Recl. TraV. Chim. Pays-
Bas 1972, 91, 799. (d) de Graaf, S. A. G.; Pandit, U. K. Tetrahedron 1973,
29, 2141. (e) M a¸ kosza, M.; Kacprowicz, A. Bull. Acad. Pol. Sci., Chim.
0
1
974, 22, 467. (f) Graefe, J.; Adler, M.; Muehlstaedt, M. Z. Chem. 1975,
15, 14.
(
4) This work was undertaken as part of a program within our group to
(
2) For useful points of entry into the literature detailing new methods
exploit gem-dihalogenocyclopropanes as building blocks for chemical
synthesis. For representative publications, see: (a) Banwell, M. G.; Gable,
R. W.; Peters, S. C.; Phyland, J. R. J. Chem. Soc., Chem. Commun. 1995,
1395. (b) Banwell, M.; Edwards, A.; Harvey, J.; Hockless, D.; Willis, A.
J. Chem. Soc., Perkin Trans. 1 2000, 2175. (c) Banwell, M. G.; Harvey, J.
E.; Hockless, D. C. R.; Wu, A. W. J. Org. Chem. 2000, 65, 4241. (d)
Banwell, M. G.; Ebenbeck, W.; Edwards, A. J. J. Chem. Soc., Perkin Trans.
1 2001, 114. (e) Banwell, M. G.; Harvey, J. E.; Jolliffe, K. A. J. Chem.
Soc., Perkin Trans. 1 2001, 2002. (f) Banwell, M. G.; Edwards, A. J.;
Jolliffe, K. A.; Smith, J. A.; Hamel, E.; Verdier-Pinard, P. Org. Biomol.
Chem. 2003, 1, 296. (g) Taylor, R. M. Aust. J. Chem. 2003, 56, 631. (h)
Banwell, M. G.; Sydnes, M. O. Aust. J. Chem. 2004, 57, 537. (i) See
reference 2b. (j) See reference 1. (k) Banwell, M. G.; Vogt, F.; Wu, A. W.
Aust. J. Chem. 2006, 59, 415. (l) Banwell, M. G.; Phillis, A. T.; Willis, A.
C. Org. Lett. 2006, 8, 5341. For a review of certain aspects of our work in
this area, see reference 2c.
for the synthesis of pyrroles, their biogenesis, and their chemical manipula-
tion, see: (a) Reisser, M.; Maas, G. J. Org. Chem. 2004, 69, 4913. (b)
Agarwal, S.; Kn o¨ lker, H.-J. Org. Biomol. Chem. 2004, 2, 3060. (c) Banwell,
M. G.; Beck, D. A. S.; Stanislawski, P. C.; Sydnes, M. O.; Taylor, R. M.
Curr. Org. Chem. 2005, 9, 1589. (d) Blaszykowski, C.; Aktoudianakis, E.;
Bressy, C.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043. (e) Hiroya,
K.; Matsumoto, S.; Ashikawa, M.; Ogiwara, K.; Sakamoto, T. Org. Lett.
006, 8, 5349. (f) Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann, J.
F.; Nogle, L.; Dooley, R.; Mahaney, P. E. Org. Lett. 2006, 8, 5837. (g)
Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep.
2
2
006, 23, 517. (h) Banwell, M. G.; Goodwin, T. E.; Ng, S.; Smith, J. A.;
Wong, D. J. Eur. J. Org. Chem. 2006, 3043. (i) T o´ th, J.; Nedves, A.; Dancs o´ ,
A.; Blask o´ , G.; T _o ke, L.; Nyerges, M. Synthesis 2007, 1003. (j) Pan, Y.;
Lu, H.; Fang, Y.; Fang, X.; Chen, L.; Qian, J.; Wang, J.; Li, C. Synthesis
2
007, 1242.
5422
Org. Lett., Vol. 9, No. 26, 2007

Scheme 2
There are a number of instances in which pyrrole formation
of compound 17 into the brominated derivative 21 and then
11
is not observed. For example, subjection of compound 6,
the regioisomer of cyclopropane 4, to treatment with t-BuOK
failed to give the hoped for pyrrole. Rather, the â-oxygenated
Suzuki-Miyaura cross-coupling of the latter material with
3,4-methylenedioxyphenylboronic acid to give compound 22
(40% from compound 5), the structure of which was secured
7
7
cycloheptenone 18 was obtained in 79% yield (Table 1,
by single-crystal X-ray analysis. Pyrrole 22 bears some
entry 8). The origin of the divergent behavior of compounds
structural resemblance to the pentacyclic ring system as-
sociated with certain members of the lamellarin class of
4
and 6 remains unclear at present. The lack of reaction of
1
2
the dichlorocarbene adducts 7, 9, and 10 when subjected to
the sorts of conditions just mentioned (see entries 9, 11, and
marine alkaloids, e.g., 23 (lamellarin K), so the method
described here offers considerable potential for the rapid
preparation of a range of analogues of these biologically
intriguing natural products. Work directed toward such ends
is now underway in these laboratories and results will be
reported in due course.
12) was also surprising and prompted an examination of the
behavior of the gem-dibromo analogue 8, of compound 7,
under the same conditions. Treatment of compound 8 with
LDA (entry 10) provided the diquinane 19 in 81% yield.
Presumably this compound arises through LDA-promoted
lithium-for-bromine exchange at the apical cyclopropyl
carbon, and this is followed by loss of the elements of lithium
bromide to give the corresponding cyclopropylidene. This
last species then undergoes insertion into the remote and syn-
10
orientated benzylic C-H bond to give the observed product.
On the basis that treatment of the carbene insertion product
2 with base might deliver a pyrrole, this was treated with
1
potassium tert-butoxide. However, the product so formed was
the oxazolidinone 20 (62%), the structure of which follows
from a single-crystal X-ray analysis.7
At least two distinct reaction pathways can be envisaged
for the base-promoted conversion of compounds 1-5 into
the corresponding pyrroles. Both of these (paths a and b,
Scheme 2) would involve dehydrochlorination of the sub-
strate, e.g., 4, to give the corresponding ring-fused cyclo-
1
3
propene 24 that then engages in ring opening to the
(
8) Kolind-Andersen, H.; Lawesson, S.-O. Bull. Soc. Chim. Belg. 1977,
6, 543.
9) Volodina, M. A.; Mishina, V. G.; Terent’ev, A. P.; Kiryushkina, G.
V. Zh. Obshch. Khim. 1962, 32, 1922.
10) For an example of a related conversion, see: Marquis, E. T.;
Gardner, P. D. Tetrahedron Lett. 1966, 2793.
11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(12) For useful reviews on the biological properties and synthesis of the
lamellarins, see: (a) Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents
2004, 4, 363. (b) Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005,
37, 411. Also see: (c) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213.
(13) These types of ring-fused cyclopropenes are readily trapped in
Diels-Alder cycloaddition reactions. For example, see: Banwell, M. G.;
Corbett, M.; Gulbis, J.; Mackay, M. F.; Reum, M. E. J. Chem. Soc., Perkin
Trans. 1 1993, 945.
8
(
The utility of the pyrrole-forming reaction described above
is highlighted by the conversion, using N-bromosuccinimde,
(
(
(
5) (a) M a¸ kosza, M.; Wawrzyniewicz, M. Tetrahedron Lett. 1969, 4659.
For a discussion of the methods available for the generation of dihalogeno-
carbenes, see: (b) Banwell, M. G.; Reum, M. E. In AdVances in Strain in
Organic Chemistry; Halton, B., Ed.; JAI Press: London, 1991; Vol. 1, p
1
9.
(
(
6) Fedorynski, M. Chem. ReV. 2003, 103, 1099.
7) Details of the single-crystal X-ray analyses carried out as part of
this study are provided in Supporting Information.
Org. Lett., Vol. 9, No. 26, 2007
5423

corresponding vinylcarbene 25a/zwitterion 25b.14 This last
species could undergo C-H insertion (path a) to give the
chlorinated dihydropyrrole 26 that loses a second equivalent
of HCl to deliver the observed and fully aromatic product,
e.g., 16. An alternate pathway (path b, Scheme 2) would
involve intramolecular proton transfer within intermediate
Our recent and soon-to-be published mechanistic studies on
the equivalent furan-forming reaction lead us to believe that
path a is more likely to be followed.
15
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for generous
financial support.
2
5 to give the ylide 27. Such a species might then be
2a,16
expected to undergo electrocyclic ring closure
to give
dihydropyrrole 26, the final intermediate in the reaction
sequence and one that is common to both paths a and b.
Supporting Information Available: Full experimental
procedures; crystallographic data and atomic displacement
ellipsoid plots and CIFs for compounds 4, 6, 16, 18, 20, and
(
14) For a review on thermally-induced cyclopropene to carbene rear-
rangements, see: Baird, M. S. Chem. ReV. 2003, 103, 1271.
15) For a related pathway that has been proposed to account for the
1
7 1
13
(
22; H and/or C NMR spectra of compounds 1-5, 13-
0, and 22. This material is available free of charge via the
formation of an annulated furan, see: Mueller, P.; Pautex, N. HelV. Chim.
Acta 1988, 71, 1630.
2
(
16) These types of ring-closures are well documented. For a review,
see: Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
17) CCDC numbers 652972-652977.
Internet at http://pubs.acs.org.
(
OL7021774
5424
Org. Lett., Vol. 9, No. 26, 2007