Indole-derived arynes and their diels - Alder reactivity with furans

Article abstract of DOI:10.1021/ol701595n

Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (CI, Br, F) were synthesized and reacted under metal-halogen exchange conditions to give Diels-Alder cycloadducts in high yield with furan. The use of an excess of fert-butyllithium resulted in the rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with furan.

Full text of DOI:10.1021/ol701595n

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4135-4137
Indole-Derived Arynes and Their
Diels Alder Reactivity with Furans
−
Keith R. Buszek,*,†,‡ Diheng Luo,‡ Mikhail Kondrashov,‡ Neil Brown,‡ and
David VanderVelde§
Department of Chemistry, Kansas State UniVersity, 111 Willard Hall,
Manhattan, Kansas 66506, Department of Chemistry, UniVersity of Missouri-
Kansas City, 205 Spencer Chemical Laboratories, 5100 Rockhill Road, Kansas City,
Missouri 64110, and Center for Chemical Methodologies and Library DeVelopment,
UniVersity of Kansas, 1501 Wakarusa DriVe Lawrence, Kansas 66047
buszekk@umkc.edu
Received July 7, 2007
ABSTRACT
Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation
and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (Cl, Br, F) were synthesized and reacted under metal-halogen
exchange conditions to give Diels−Alder cycloadducts in high yield with furan. The use of an excess of tert-butyllithium resulted in the
rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with
furan.
The existence of benzyne 1 was first reported by Roberts in
1953 (Figure 1).1 Since that landmark discovery, accounts
derived from the ubiquitous indole nucleus (e.g., 6,7-indolyne
6) have never been reported. Inter- and intramolecular indole
aryne cycloaddditions would provide an attractive entry into
complex natural products that feature, inter alia, substitution
at the C6 and C7 positions. Examples of such targets include
the teleocidins,3 trikentrins,4 and herbindoles.4a,c As part of
a program to utilize aryne cycloaddition strategies for the
(1) (a) Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan,
C. W. J. Am. Chem. Soc. 1953, 75, 3290-3291. (b) Roberts, J. D.;
Semenow, D. A.; Simmons, H. E., Jr.; Carlsmith, L. A. J. Am. Chem. Soc.
1956, 78, 601-611. For the first cycloadditions with benzyne, see: (c)
Wittig, G.; Pohmer, L. Angew. Chem. 1955, 67, 348.
Figure 1. Examples of common benzenoid arynes.
(2) For a review of arynes, see: (a) Hoffmann, R. W. Dehydrobenzene
and Cycloalkynes; Academic: New York, 1967. (b) Pellissier, H.; Santelli,
M. Tetrahedron 2003, 59, 701-730. (c) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502-528. (d) Reinecke, M. G.
Tetrahedron 1982, 38, 427-498. Pyridynes: (e) Kauffmann, T.; Boettcher,
F. P. Angew. Chem. 1961, 73, 65-66. (f) Martens, R. J.; den Hertog, H. J.
Tetrahedron Lett. 1962, 643-645. Naphthalynes: (g) Bunnett, J. F.;
Brotherton, T. K. J. Org. Chem. 1958, 23, 904-906. (h) Huisgen, R.;
Zirngibl, L. Chem. Ber. 1958, 91, 1438-1452.
(3) (a) Nakatsuka, S.; Matsuda, T.; Goto, T. Tetrahedron Lett. 1987,
38, 3671-3674. (b) Nakatsuka, S.; Masuda, T.; Goto, T. Tetrahedron Lett.
1986, 27, 6245-6248. (c) Nakatsuka, S.; Masuda, T.; Asano, O.; Terame,
T.; Goto, T. Tetrahedron Lett. 1986, 27, 4327-4330.
of other metastable benzenoid arynes appeared over the next
several years.2 For example, the two isomers of pyridyne (2
and 3),2e,f and naphthalyne (4 and 5)2g,h have been detected
and their reactivity thoroughly studied. Surprisingly, arynes
* Current address: University of Missouri - Kansas City.
† Kansas State University.
‡ University of Missouri-Kansas City.
§ University of Kansas.
10.1021/ol701595n CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/19/2007

synthesis of complex natural products,5 we had a need to
investigate the feasibility of incorporating indole arynes into
such schemes. The literature reveals very few inquiries into
this area.2d,6 We are now pleased to report that various ortho
dihalo indoles readily give their corresponding arynes under
metal-halogen exchange conditions and are subsequently
trapped with furans to give stable, isolable cycloadducts or
rearranged products in excellent yields.
Scheme 2. Generation and Trapping of Indole Aryne with
Furan
Among the many different precursors available for aryne
generation,7 we settled on the use of ortho dihalides in the
indole system for their ease of preparation and for the
extensive body of data regarding their facile conversion to
the aryne. It was also critical that we be able to access all
three positional isomers of dihalo indoles at the benzenoid
core, namely, the 4,5-, 5,6-, and 6,7-dihaloindoles. Our initial
efforts began with the synthesis of the 6,7-dichloroindole
(Scheme 1). Commercially available 2,3-dichloroaniline was
group, and another heteroatom, although the structure could
not be unambiguously determined. Further analysis by 2D
NMR methods (COSY, NOESY, HMBC, and HSQC)
allowed the unequivocal structure to be assigned as 13. The
most reasonable explanation for the formation of this product
involves the expected metal-halogen exchange and elimina-
tion to give the reactive indole aryne intermediate 11, in the
same manner as reported for other benzyne systems, followed
by trapping with furan to afford the initial cycloadduct 12.
This compound, however, could not be isolated. Rather, a
highly regioselective SN2′ nucleophilic attack by the remain-
ing tert-butyllithium at the olefin induced cleavage of the
oxygen bridge resulting in the observed product as a single
regioisomer in 78% yield. This process has ample precedent
with many different nucleophiles, including hindered alkyl-
lithiums.9 Aromatization was induced by stirring in chloro-
form for several hours to afford quantitatively the fused
tricyclic derivative 14.
The formation of a single regioisomer is a curious
observation. A related experiment was carried out with the
hindered 2,5-dimethylfuran (Scheme 3), which gave a similar
result, but now with an approximately equal mixture of
regioisomers 16 and 17 being formed in a combined 84%
yield. The difference in regiochemical outcome of these two
reactions can perhaps be rationalized on the basis of ground-
state destabilization. The opening of the furan cycloadduct
12 from the opposite side of the olefin would experience
greater torsional strain thereby leading only to the observed
product. This strain is significantly less pronounced from
either direction with 15, owing to the presence of the larger
methyl groups, and a statistical distribution of products is
found instead. The issue of regiocontrol in these systems
remains the subject of further investigation.
Scheme 1. Fischer-Indole Synthesis of 10
diazotized and reduced with stannous chloride in one pot to
give the corresponding hydrazine in 85% yield.8 Condensa-
tion of 8 with phenylacetaldehyde under Fischer conditions
with polyphosphoric acid afforded the expected 6,7-dichloro-
indole 9. Methylation of the NH group gave the N-methyl
indole 10 in 83% yield. With the desired aryne precursor in
hand, many protocols for generating benzynes from ortho
dihalo arenes were examined.
We elected initially to treat 10 with an excess (4 equiv)
of t-BuLi in ether at -78 °C in the presence of an excess of
furan and then slowly warm the reaction to room temperature
over 4 h (Scheme 2). The color of the initially light-yellow
solution changed briefly to deep red upon addition of the
lithium reagent, then returned to and remained a pale yellow.
Examination of the products by TLC analysis revealed just
one major component. Proton NMR analysis of this com-
pound indicated a single product containing a tert-butyl
(4) (a) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405-1411.
(b) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8, 3403-3406. (c) Jackson,
S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7, 1215-1218. (d)
MacLeod, J. K.; Monahan, L. C. Tetrahedron Lett. 1988, 29, 391-392.
(5) (a) Buszek, K. R. Tetrahedron Lett. 1995, 36, 9125-9128. (b) Buszek,
K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129-9132.
(6) Approaches to the generation of 2,3-indolyne have appeared: (a)
Conway, S. C.; Gribble, G. W. Hetereocycles 1992, 34, 2095-2108. (b)
Gribble, G. W.; Conway, S. C. Synth. Commun. 1992, 22, 2129-2141.
(7) Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001, 66,
2932-2936.
Even more significantly, we were gratified to discover that
arynes can be easily generated and trapped as their Diels-
Alder cycloadducts with furan from all three isomeric ortho
dibromo indoles (Scheme 4). In this case the use of 1.2 equiv
(9) For an excellent recent review, see: (a) Lautens, M.; Fagnou, K.;
Hiebert, S. Acc. Chem. Res. 2003, 36, 48-58. For other recent applications,
see: (b) Chen, C.; Martin, S. F. J. Org. Chem. 2006, 71, 4810-4817 and
references cited therein.
(8) Blair, J. B.; Kurrasch-Orbaugh, D.; Marona-Lewicka, D.; Cumbay,
M. G.; Watts, V. J.; Barker, E. L.; Nichols, D. E. J. Med. Chem. 2000, 43,
4701-4710.
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Org. Lett., Vol. 9, No. 21, 2007

Scheme 3. Trapping with 2,5-Dimethylfuran Leads to Two
Scheme 5. Generation of Aryne from 22 Proceeds through
Proton-Lithium Exchange
Regioisomers
indole 22 with n-BuLi, however, gave exclusively the
cycloadduct 23 in 80% yield. Initial deprotonation of the
thermodynamically more acidic C7 hydrogen as a result of
the inductive electron withdrawing effect of the adjacent
nitrogen leads to aryne formation. This assumption is also
consistent with well-documented observation that the rate
of transmetallation of fluorine is slow compared with
deprotonation at the ortho position.11 Trapping and cycload-
dition with furan thus gave the observed cycloaddduct, and
19F NMR revealed one remaining fluorine at the C5 position.
In conclusion we have provided the first evidence for the
existence of all three isomeric indole arynes in the benzenoid
core using a practical and general method. The facile
generation of aryne indoles from dibromoindoles in particular
is noteworthy for its synthetic simplicity and good yields.
This discovery adds indoles to the suite of aromatic systems
from which arynes can be easily and readily generated.
Further investigations into the reactivity and behavior of other
mixed dihaloindoles as well as applications of inter- and
intramolecular indole aryne cycloadditions to natural products
total synthesis are underway and will be reported in due
course. Further work into substituent effects (e.g., 3-phenyl)
on the ease of aryne formation is also in progress.
of n-butyllithium gave only the furan cycloaddducts without
rearrangement as stable intermediates in excellent yields.
Trapping of the aryne derived from 18b with 2,5-dimethyl-
furan cleanly gave 21 in 86% yield. Preparation of the these
aryne precursors from the three isomeric ortho dibromo
anilines followed the same protocol outlined earlier in
Scheme 1.10
Scheme 4. Generation and Trapping of All Three Isomeric
Arynes from Dibromoindoles 18a-c
Acknowledgment. We acknowledge support of this work
by the National Institutes of Health, Grant R01 GM69711.
Additional support of this work was provided by the NIH
(Grant P50 GM069663) via the University of Kansas
Chemical Methodologies and Library Development Center
of Excellence (KU-CMLD). We thank Chris Sakai for
technical assistance with this project. The authors wish to
thank the reviewers for their helpful comments and sugges-
tions. This paper is warmly dedicated to Professor Michael
E. Jung on the occasion of his 60th birthday.
Finally, we observed that ortho difluoroindoles exhibit
anomalous behavior upon treatment with alkyllithiums
(Scheme 5). It is known that the more electropositive
halogens undergo the most rapid metal-halogen exchange,
and this was indeed found to be the case with the bromo
indole series. In the fluorine system, the isomeric 4,5- and
6,7-difluoroindoles gave only recovered starting material
under these same conditions. The reaction of 5,6-difluoro-
Supporting Information Available: 1H NMR data for
all compounds reported and experimental details for their
preparation. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL701595N
(11) (a) Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E.
Tetrahedron Lett. 1992, 33, 7495-7498. (b) Coe, P. L.; Waring, A. J.;
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L.; Martins, A. Tetrahedron Lett. 2003, 44, 5987-5990. (d) Masson, E.;
Schlosser, M. Eur. J. Org. Chem. 2005, 4401-4405.
(10) Hanzlik, R. P.; Weller, P. E.; Desai, J.; Zheng, J.; Hall, L. R.;
Slaughter, D. E. J. Org. Chem. 1990, 55, 2736-2742.
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