Regioselective Diels-Alder cycloadditions and other reactions of 4,5-, 5,6-, and 6,7-indole arynes

Article abstract of DOI:10.1016/j.tetlet.2008.10.086

The regioselectivity of Diels-Alder cycloadditions of indole arynes (indolynes) at all three benzenoid positions was examined. Cycloadditions with the 4,5-and 5,6-indolynes, derived via metal-halogen exchange from the corresponding o-dibromo indoles, show

Full text of DOI:10.1016/j.tetlet.2008.10.086

Tetrahedron Letters 50 (2009) 63–65
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective Diels–Alder cycloadditions and other reactions of 4,5-, 5,6-,
and 6,7-indole arynes
Neil Brown a,b, Diheng Luo a, David Vander Velde b, Shaorong Yang a, Allen Brassfield a, Keith R. Buszek a,b,
*
a Department of Chemistry, University of Missouri-Kansas City, 205 Spencer Chemical Laboratories, 5100 Rockhill Road, Kansas City, MO 64110, USA
b The University of Kansas Center of Excellence in Chemical Methodologies and Library Development, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, KS 66045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselectivity of Diels–Alder cycloadditions of indole arynes (indolynes) at all three benzenoid posi-
tions was examined. Cycloadditions with the 4,5-and 5,6-indolynes, derived via metal–halogen exchange
from the corresponding o-dibromo indoles, showed essentially no selectivity with 2-t-butylfuran. In con-
trast, the 6,7-indolyne displayed virtually complete preference for the more sterically congested cycload-
duct. This same cycloadduct undergoes a facile acid-catalyzed rearrangement to afford the annulated
enone, or alternatively, undergoes hydrolysis and oxidation in the presence of air to give the indolobenzo-
quinone. The 5,6-difluoroindoles show anomalous behavior and give either 5-fluoro-6,7-indolynes with
n-BuLi in ether, or 5,6-indolynes with n-BuLi in toluene. We have also demonstrated that benzenoid
indolynes can be easily and conveniently generated by the fluoride-induced decomposition of o-trimeth-
ylsilyl triflates.
Received 17 September 2008
Accepted 17 October 2008
Available online 1 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Unlike the familiar benzenoid arynes such as benzyne 1,1 the
naphthalynes (2a and 2b),2 and the pyridynes (3a and 3b)
(Fig. 1),3 all of which have been known for at least 40 years, the
tetrad of arynes 4–7 derived from the ubiquitous indole aromatic
nucleus was until recently unknown.4,5
The absence of these arynes from the literature was surprising,
given the potential utility of these reactive intermediates for an
attractive entry into the indole alkaloid class of complex natural
products such as the trikentrins,6 herbindoles,6a,c teleocidins,7
cytoblastin,8 and lyngbyatoxin9 (Fig. 2).
Me
Me
Me
Me
Me
Me
H
H
H
N
N
N
MeN
OH
MeN
OH
Me
MeN
OH
O
O
O
Me
Me
N
H
N
H
N
H
OH
Me
Me
OH
N
H
lyngbyatoxin A
cytoblastin
teleocidin B
We recently reported the existence of and first Diels–Alder
cycloaddition examples with all three indole arynes derived from
the benzenoid part of the indole nucleus.4 We are now pleased
N
H
N
H
N
H
N
H
cis-trikentrin A
cis-trikentrin B
herbindole A
herbindole B
Figure 2. Indole-containing complex natural products.
N
N
1
2a
2b
3a
3b
to follow that communication with this Letter on the regiochemical
behavior of these cycloadditions.10
The 4,5-, 5,6-, and 6,7-indolynes were generated from the corre-
sponding o-dibromoindoles in the manner previously described.4
Treatment of 8 with 2.2 equiv of n-BuLi in either ether or toluene11
at À78 °C in the presence of an excess of 2-t-butylfuran was found
to give an approximate 1:1 mixture of regioisomers 9 and 10
(Scheme 1).12 In a similar fashion, the generation of the 5,6-indo-
lyne from 11 and trapping in the same manner also afforded a
1:1 mixture of regioisomers 12 and 13.
N
H
N
N
H
N
H
H
4,5-indolyne, 4
5,6-indolyne, 5
6,7-indolyne, 6
2,3-indolyne, 7
Figure 1. Benzenoid aryne systems.
* Corresponding author. Tel.: +1 816 235 2292; fax: +1 816 235 5502.
E-mail addresses: buszekk@umkc.edu, krvb@ksu.edu (K. R. Buszek).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.086

64
N. Brown et al. / Tetrahedron Letters 50 (2009) 63–65
t-Bu
N
F
F
Ph
F
Ph
+
F
Ph
n-BuLi (2.2 eq)
Et2O, -78 °C to r.t.
Br
O
O
Ph
+
Br
Ph
Ph
Ph
t-Bu
n-BuLi (2.2 eq)
PhMe, -78 °C to r.t.
N
N
t-Bu
N
O
Me
Me
20
O
Me
O
t-Bu
N
N
t-Bu
(5 eq)
O
Me
Me
Me
t-Bu
(1:1)
9
10
21
22
8
89%
(5 eq)
88%
t-Bu
t-Bu
Ph
+
Ph
Br
Br
n-BuLi (2.2 eq)
PhMe, -78 °C to r.t.
Ph
+
Ph
n-BuLi (2.2 eq)
PhMe, -78 °C to r.t.
O
O
O
O
N
N
N
O
Me
Me
N
N
t-Bu
(5 eq)
Me
12
t-Bu
O
Me
(1:1)
Me
t-Bu
t-Bu
13
11
13
(5 eq)
12
91%
86%
Scheme 3. Regioselectivity of 5,6-difluoroindole-derived indolynes.
Scheme 1. Regioselectivity of 4,5- and 5,6-indolyne cycloadducts.
Ph
Ph
Ph
Ph
n-BuLi (4 eq)
Ph
n-BuLi
80%
n-BuLi (2.2 eq)
PhMe, -78 °C to r.t.
CHCl3
Et2O, -78 °C to r.t.
Br
N
trace HCl
8 h
quant.
N
Bu
N
Br
N
N
Me
Me
Me
Br
Me
O
Me
O
R
Br
23
Scheme 4. Cine substitution in 6,7-indolynes.
24
R
14
14
(5 eq)
89%
15 R = t-Bu (>15:1)
16 R = Me (4:1)
Ph
Ph
PPTS (0.1 eq)
O
17 R = t-Bu
18 R = Me
N
Me
O
THF/MeOH (10:1)
air, 12 h, quant.
6-butyl indole 24 (Scheme 4). This finding, which is reminiscent
of typical substituted benzyne behavior,16 is a potentially useful
method for installing substitution at this position. This operation
is usually difficult to accomplish in indoles with other non-aryne
strategies. So far, the reaction selectivity in this reaction manifold
is only seen with the 6,7-indolynes.
These 6,7-indolyne-derived cycloaddducts can also be opened
in a highly regio-selective and exo-selective manner by exposure
to alkyllithium reagents in ether. We first noticed this behavior
with t-butyllithium and the unsubstituted furan cycloadduct 25
from the 6,7-indolyne 14.4 In this case, acid-promoted elimination
occurs preferentially to give the aromatic annulated product 26
(Scheme 5).
However, in the present substituted example, elimination is
precluded due to steric congestion with the N-methyl substituent
(Scheme 6). Symmetrical furan cycloadducts have been opened un-
der metal-catalyzed conditions with carbon, oxygen, and nitrogen
nucleophiles.17 We have found that catalysis is unnecessary with
our cycloadducts, at least with carbon-based nucleophiles.
Thus, simply recommitting the cycloadduct to ether and treat-
ment with n-Bu-, s-Bu-, or t-BuLi gives exclusively the ring-opened
products 27–29.
N
R
Me
H
O
19
Scheme 2. Regioselectivity of 6,7-indolyne cycloadducts.
By stark contrast, the 6,7-indolyne derived from 14 gave a vir-
tually complete regioselective cycloadduct 15 (Scheme 2). The
structure was unequivocally confirmed via NOESY and COSY anal-
yses. The formation of the more sterically crowded product can be
rationalized in terms of a previously observed polarization phe-
nomenon that has been invoked for substituted benzynes in which
fluorine acts as powerful regiochemical director.13–15 The effect
correlates with electronegativity values and is reduced with meth-
oxy substituents14 and finally reversed with electron-donating
groups such as methyl.15 The powerful polarizing effect of the pyr-
role unit is apparent even with 2-methylfuran, which exhibits a 4:1
preference for the more sterically congested product 16.
The stable initial cycloadducts 15–16 can be made to undergo
rearrangement upon prolonged exposure to a trace amount of acid
in chloroform to give the annulated enones 17–18. Aromatization
is precluded in this case which would otherwise force the bulky
t-butyl group and even smaller methyl group into an unavoidable
steric conflict with the planar N-methyl substituent on the pyrrole.
Interestingly, hydrolysis of the cycloadduct 15 in the presence of
air resulted in loss of the t-butyl group and concomitant oxidation
to give the indoloquinone 19. This rearrangement was only
observed with the t-butyl-substituted arynes.
The 5,6-difluoro indole 20 displays anomalous behavior
(Scheme 3). Treatment of this compound with 4 equiv of t-butyl-
lithium (but not n-BuLi) resulted in exclusive deprotonation at
the C7 position, followed by dehydrohalogenation to give the 5-flu-
oro-6,7-aryne which was trapped as a nearly equimolar mixture of
regioisomers 21 and 22. In this case, the fluorine presumably com-
petes effectively with the polarizing properties of the pyrrole unit
and therefore displays no selectivity. As observed by Coe et al.,11 by
changing solvents from ether to toluene, the acid–base reaction
manifold is almost completely suppressed in favor of metal–halo-
gen exchange, and the 5,6-indolyne is generated instead which
as noted above affords a 1:1 mixture of the same cycloadducts
12 and 13.
These results with the 6,7-indolyne cycloadducts have clear
implications for the production of libraries based on these hereto-
Ph
Ph
Ph
t-BuLi
Et2O, -78 °C to r.t.
CHCl3
trace HCl, r.t.
N
N
N
Me
O
Me
Me
OH
14
t-Bu
t-Bu
25
26
Scheme 5. Exo- and regioselective ring-opening and aromatization in 6,7-indolyne
furan cycloadducts.
Ph
Ph
RLi (2.1eq)
Et2O, -78 °C to r.t.
65-91%
27 R = n-Bu, 65%
N
N
O
28 R = s-Bu, 87%
29 R = t-Bu, 91%
Me
Me
R = n-Bu, t-Bu, s-Bu
t-Bu
OH
t-Bu
R
15
In the absence of any diene, the putative 6,7-indolyne 23 under-
goes cine substitution with excess n-butyllithium to give the
Scheme 6. Regio- and exo-selective ring-opening of 6,7-indolyne furan
cycloadducts.

N. Brown et al. / Tetrahedron Letters 50 (2009) 63–65
65
OTf
TMS
OH
OTf
i) SnCl2, EtOH
reflux
TMS
TfO
Ph
TMS
TMS
TBAT (2.5 eq), THF, r.t., 6 h
Tf2O, pyridine
9 + 10 (1:1)
88%
or
ii) HCl, Et2O
99%
CH2Cl2
95%
N
CsF (3.0 eq), MeCN, r.t., 6 h
Me
NH3+Cl-
38
NO2
NO2
O
t-Bu
(5 eq)
33
32
30
TMS
OTf
TfO
Ph
Ph
TfO
Ph
Ph
TMS
PhCH2CHO
EtOH, reflux
49%
i) NaNO2, 6 M HCl, 0 °C
ii) SnCl2, HCl, Et2O
52%
TBAT (2.5 eq), THF, r.t., 6 h
12 + 13 (1:1)
89%
or
N
H
TMS
N
+
CsF (3.0 eq), MeCN, r.t., 6 h
Me
39
NHNH3+Cl-
35
36
O
t-Bu
TfO
34
(5 eq)
TMS
N
H
TBAT (2.5 eq), THF, r.t., 6 h
15 (>15:1)
88%
or
5,6 : 4,5 (>5 : 1)
TMS
N
CsF (3.0 eq), MeCN, r.t., 6 h
Me
OTf
40
O
Scheme 7. Fischer indole synthesis of 4,5- and 5,6-o-trimethylsilyl triflate indolyne
t-Bu
precursors.
(5 eq)
Scheme 8. 4,5-, 5,6-, and 6,7-indolynes derived from o-silyltriflates.
fore unknown chemotypes. The 6,7-furan cycloadducts thus repre-
sent a potentially versatile platform for the synthesis of novel 6,7-
annulated indole libraries of either type, 17–18 or 27–29. Addition-
ally, the olefin handle in either type of structure provides a further
point of diversification and the opportunity to generate stereo-
chemically dense annulated indole arynes.
Acknowledgments
We acknowledge the support of this work by the National Insti-
tutes of Health, Grant R01 GM069711. Additional support of this
work was provided by the NIH (Grant P50 GM069663 via the Uni-
versity of Kansas Chemical Methodologies and Library Develop-
ment Center of Excellence (KU-CMLD).
Finally, in an effort to find an alternate route to the indole ary-
nes that does not rely exclusively on metal–halogen exchange pro-
tocols, we developed a Fischer indole synthesis to the 4,5-, 5,6-,
and 6,7-o-trimethylsilyl triflates (Scheme 7). Treatment of 2-tri-
methylsilylphenol18 with Cu(NO3)2 (0.55 equiv) in acetic acid at
0 °C for 3 h afforded an equimolar mixture of 4-nitro-2-(trimethyl-
silyl)phenol 30 and 2-nitro-6-(trimethylsilyl)phenol 31.19 The
nitrophenol 30 was triflated (95%) and converted to its hydrazine
hydrochloride salt 34 in 51% overall yield. Reaction of 34 under
Fischer conditions (EtOH, reflux, 4 h) with phenylacetaldehyde
was remarkably regioselective albeit moderately yielding, giving
a greater than 5:1 ratio of the 5,6- and 4,5-indole products 36
and 35, respectively. This result stands in contrast to the corre-
sponding dibromides or dichlorides4 which under the same condi-
tions resulted in a nearly 1:1 mixture of isomers. By carrying 2-
nitro-6-(trimethylsilyl)phenol 31 through the same scheme, the
corresponding 6-(trimethylsilyl)-1H-indol-7-yl triflate 37 is also
available by this method in 32% overall yield.
References and notes
1. (a) Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughn, 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 a review of arynes in
general, see: (c) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic:
New York, 1967.
2. (a) Bunnett, J. F.; Brotherton, T. K. J. Org. Chem. 1958, 23, 904–906; (b) Huisgen,
R.; Zirngibl, L. Chem. Ber. 1958, 91, 1438–1452.
3. (a) Kauffmann, T.; Boettcher, F. P. Angew. Chem. 1961, 73, 65–66; (b) Martens, R.
J.; den Hertog, H. J. Tetrahedron Lett. 1962, 643–645.
4. Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.; VanderVelde, D. Org. Lett.
2007, 9, 4135–4137.
5. For attempts to generate the elusive 2,3-indolyne, see: (a) Conway, S. C.;
Gribble, G. W. Heterocycles 1992, 34, 2095–2108; (b) Gribble, G. W.; Conway, S.
C. Synth. Commun. 1992, 22, 2129–2141.
6. (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.
The compounds 35, 36, and 37 each give, after N-methylation,
their respective 5,6-, 4,5-, and 6,7-indolyne cycloadducts by treat-
ment with TBAT20 (2.5 equiv) in THF, or alternatively, CsF
(3.0 equiv) in MeCN, for several hours at room temperature in
the presence of 2-t-butylfuran (Scheme 8). The same ratios of iso-
meric cycloadducts as shown previously were obtained.
7. (a) Nakatsuka, S.; Matsuda, T.; Goto, T. Tetrahedron Lett. 1987, 38, 3671–3674;
(b) Nakatsuka, S.; Matsuda, 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.
8. Moreno, O. A.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 8180–8181.
9. Muratake, H.; Natsume, M. Tetrahedron Lett. 1987, 28, 2265–2268.
10. Presented at the 236th American Chemical Society National Meeting,
Philadelphia, PA, August 17–21, 2008 (ORGN 679).
In conclusion, we have shown that while 4,5- and 5,6-indolynes
show virtually no regioselectivity in Diels–Alder cycloadditions,
the 6,7-indolyne by contrast is highly regioselective, presumably
due to the polarization influence of the pyrrole ring. Adducts de-
rived from this flexible system can undergo acid-catalyzed rear-
rangement to give stable annulated enones, hydrolysis in air to
give benzoquinones, or react with alkyllithiums to afford exo-
and regioselective ring-opened products. We are presently adapt-
ing this versatile methodology for use in library development as
well as in the total synthesis of indole alkaloid natural products.
The results of these efforts will be reported as developments
warrant.
11. Coe, J. W.; Wirtz, M. C.; Bashore, C. G.; Candler, J. Org. Lett. 2004, 6, 1589–1592.
12. All new compounds reported herein exhibited satisfactory 1H NMR, 13C NMR,
COSY and NOESY NMR, mass spectral, and elemental analysis data consistent
with their structures.
13. Gribble, G. W.; Keavy, D. J.; Branz, S. E.; Kelly, W. J.; Pals, M. A. Tetrahedron Lett.
1988, 29, 6227–6230.
14. Giles, R. G. F.; Sargent, M. V.; Sianipar, H. J. Chem. Soc., PT1 1991, 1571–1579.
15. Newman, M. S.; Kannan, R. J. Org. Chem. 1976, 41, 3356–3359.
16. Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273–412.
17. Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48–58.
18. (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214; (b)
Wilbur, D. S.; Stone, W. E.; Anderson, K. W. J. Org. Chem. 1983, 48, 1542–1544.
19. Anuradha, V.; Srinivas, P. V.; Aparna, P.; Rao, J. M. Tetrahedron Lett. 2006, 47,
4933–4935.
20. Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901–6905.