Indolynes as electrophilic indole surrogates: Fundamental reactivity and synthetic applications

Article abstract of DOI:10.1021/ol802958a

A mild method to access a variety of substituted indole derivatives has been developed. The strategy relies on the generation of highly reactive indolyne intermediates, which function as electrophilic indole surrogates.

Full text of DOI:10.1021/ol802958a

ORGANIC
LETTERS
2009
Vol. 11, No. 4
1007-1010
Indolynes as Electrophilic Indole
Surrogates: Fundamental Reactivity and
Synthetic Applications
Sarah M. Bronner, Kevin B. Bahnck, and Neil K. Garg*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
California 90095-1569
neilgarg@chem.ucla.edu
Received December 24, 2008
ABSTRACT
A mild method to access a variety of substituted indole derivatives has been developed. The strategy relies on the generation of highly
reactive indolyne intermediates, which function as electrophilic indole surrogates.
The indole heterocycle is found in an astonishing number
of natural products and medicinal agents.1,2 More than 10000
biologically active indole derivatives have been discovered
to date, with over 200 of these currently being marketed as
pharmaceuticals or undergoing clinical trials.3 In the past
century, countless efforts have been devoted to the develop-
ment of methods that enable the synthesis of functionalized
indoles. Although numerous methods for accessing C2- and
C3-substituted products from indole building blocks have
been discovered, access to C4-, C5-, C6-, or C7-substituted
indoles remains a significant challenge.1
Our approach to this problem rests opposite the well-
known paradigm of indole reactivity. Indoles typically
function as excellent nucleophiles that readily participate in
electrophilic aromatic substitution reactions (1 f 2, Figure
1); in contrast, methods for rendering indoles susceptible to
attack by nucleophiles are rare (1 f 3).4 A method for
reversing the inherent reactivity of indoles from nucleophilic
to electrophilic would be conceptually interesting and could
also allow for the preparation of compounds that are difficult
to obtain by conventional means. In this paper, we describe
an efficient and mild method for accessing electrophilic
indole surrogates via the generation of aryne derivatives of
indoles, or “indolynes” (i.e., 4).5,6
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970. (b) Sundberg, R. J. Pyrroles and Their Benzoderivatives:
Synthesis and Applications. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, UK, 1984;
Vol. 4, pp 313-376. (c) Sundberg, R. J. In Indoles (Best Synthetic Methods);
Academic Press: New York, 1996; pp 7-11. (d) Joule, J. A. Indole and its
Derivatives. In Science of Synthesis: Houben-Weyl Methods of Molecular
Transformations; Thomas, E. J., Ed.; George Thieme Verlag: Stuttgart,
Germany, 2000; Category 2, Vol. 10, Chapter 10.13.
(4) For the activation of indoles with stoichiometric chromium, see: (a)
Semmelhack, M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1399–1402. (b)
Semmelhack, M. F.; Knochel, P.; Singleton, T. Tetrahedron Lett. 1993,
34, 5051–5054. For the Pd-catalyzed enolate arylations of indoles, see: (c)
MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421–
3424. (d) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7,
4087–4089.
(2) Horton, D. A.; Bourne, G. T.; Smyth, M. L. Chem. ReV. 2003, 103,
893–930
.
(5) For reviews regarding heteroaromatic arynes, see: (a) Reinecke, M. G.
Tetrahedron 1982, 38, 427–498. (b) Kauffmann, T.; Wirthwein, R. Angew.
Chem., Int. Ed. 1971, 10, 20–33.
(3) MDL Drug Data Report; MDL Information Systems Inc.: San
Leandro, CA.
10.1021/ol802958a CCC: $40.75
Published on Web 01/29/2009
2009 American Chemical Society

construct libraries of substituted indoles, (b) the general use
of indolynes as electrophilic indole surrogates, and (c) the
site preference for nucleophilic attack on indolynes, including
its variation as a function of the nucleophile.
To initiate our studies, indolyne 4 was selected as our
primary target (Figure 1).9 Interestingly, indolyne 4 would
possess both highly nucleophilic10 (at C3) and electrophilic6
(at C4 and C5) sites. As current methods for generating C3-
unsubstituted indolynes were relatively harsh for our intended
studies (i.e., KNH2/NH3 or BuLi),7,8,11 we sought an alterna-
tive method to access the key indolyne species 4. The
approach to arynes by Kobayashi appeared optimal, as it
would permit indolyne formation from an indolyl silyltriflate
precursor using mild fluoride-mediated conditions.12
Although the synthesis of an appropriate indolyl silyltriflate
proved challenging,13 an efficient route was ultimately
developed (Scheme 1). Commercially available 5-benzy-
loxyindole (13) was converted to hydroxyindole 14 following
a known two-step sequence.14,15 Next, hydroxyindole 14 was
allowed to react with isopropyl isocyanate in the presence
of cat. Et3N to afford carbamate 15. The net conversion of
13 to carbamate 15 proceeds in 85% yield and requires only
one final chromatographic purification event. Following the
protocol disclosed by Snieckus and Hoppe,16 carbamate 15
was lithiated and quenched with TMSCl to provide silyl
carbamate 16.17 Of note, the relatively acidic C2 proton of
the N-methylindole is not disturbed in this process, which is
testament to the outstanding ortho-directing ability of car-
bamates.18 Although initial attempts to elaborate silyl car-
bamate 16 to silyltriflate 17 in a stepwise fashion were met
with difficulty,19 an efficient one-pot deprotection/triflation
sequence proved successful. Our optimized route to silyl-
triflate 17 can be carried out on multigram scale, and
proceeds in 63% overall yield. To confirm that silyltriflate
17 would function as a suitable precursor to the targeted 4,5-
indolyne, 17 was reacted with TBAF in the presence of furan
(10) to afford Diels-Alder product 18 in 85% yield.
Figure 1. Indolyne 4 as an electrophilic indole surrogate.
Although heteroaromatic arynes have been a subject of
debate in the past,5a the existence of indolynes has been
substantiated by experimental data. In the 1960s, it was found
that C3-unsubstituted 4,5-indolyne 6 could be generated from
5-bromoindole (5) and KNH2 in ammonia to afford a
complex mixture of products, which upon purification
furnished 4- and 5-aminoindole products 7 and 8 (Figure
2).7 In 2007, the Buszek laboratory demonstrated that C3-
substituted indolynes could be generated from dihaloindoles
in the presence of butyllithium reagents.8a The presumed
indolyne intermediates were trapped with furan to afford
Diels-Alder products (e.g., 9 + 10 f 12). Further studies
have recently been reported8b,c that include indolyne
Diels-Alder reactions of substituted furans and cyclopen-
tadiene.
(9) Attempts to synthesize 2,3-indolynes have been met without success;
see: (a) Muller, H. Dissertation, University of Heidelberg, 1964. (b)
Hoffman, R. W. Dehydrobenzene and Cycloalkynes; Academic Press: New
York, 1967. (c) Conway, S. C.; Gribble, G. W. Heterocycles 1992, 34,
2095–2108. See also ref 5a.
Figure 2. Previous syntheses of indolynes.
(10) For the nucleophilicity of N-methylindole, see: Mayr, H.; Kempf,
B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(11) During preparation of this manuscript, Buszek and co-workers
reported the synthesis of C3-substituted indolyl silyltriflates using a Fischer
indolization strategy; see ref 8b.
Despite these significant advances in the chemistry of
indolynes, many areas have remained unexplored, namely
(a) the potential to utilize indolynes as building blocks to
(12) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12,
1211–1214.
(13) Challenges are primarily associated with the acidity of the C2
hydrogen and the electron-rich nature of the indole ring (e.g., undesired
reactivity at C3 and propensity to undergo protodesilylation at C4).
(14) (a) Stadlwieser, J. F.; Dambaur, M. E. HelV. Chim. Acta 2006, 89,
936–946. (b) Gwaltney, S. L.; et al. Bioorg. Med. Chem. Lett. 2001, 11,
(6) For recent reviews regarding aryne chemistry and synthetic applica-
tions, see: (a) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701–730.
(b) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003,
42, 502–528. (c) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 217–291.
(7) (a) Julia, M.; Huang, Y.; Igolen, J. C. R. Acad. Sci., Ser. C 1967,
265, 110–112. (b) Igolen, J.; Kolb, A. C. R. Acad. Sci., Ser. C 1969, 269,
54–56. For related studies, see: (c) Julia, M.; Goffic, F. L.; Igolen, J.;
Baillarge, M. C. R. Acad. Sci., Ser. C 1967, 264, 118–120. (d) Julia, M.;
Igolen, J.; Kolb, M. C. R. Acad. Sci., Ser. C 1971, 273, 1776–1777.
(8) (a) Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.; Vander-
Velde, D. Org. Lett. 2007, 9, 4135–4137. (b) Brown, N.; Luo, D.;
VanderVelde, D.; Yang, S.; Brassfield, A.; Buszek, K. R. Tetrahedron Lett.
2009, 50, 63–65. (c) Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009,
11, 201–204.
871–874
.
(15) 5-Hydroxyindoles can also be readily prepared by the classic
Nenitzescu indole synthesis; for a review, see: Allen, G. R. Org. React.
1973, 20, 337–454
.
(16) (a) Kauch, M.; Snieckus, V.; Hoppe, D. J. Org. Chem. 2005, 70,
7149–7158. (b) Kauch, M.; Hoppe, D. Synthesis 2006, 1578–1589.
(17) For the selective C4 lithiation of a related N-silylated substrate,
see: Griffen, E. J.; Roe, D. G.; Snieckus, V. J. Org. Chem. 1995, 60, 1484–
1485.
(18) Snieckus, V. Chem. ReV. 1990, 90, 879–933.
(19) Cleavage of the carbamate of 16 was routinely accompanied by
loss of the C4 silyl substituent under a variety of reaction conditions.
1008
Org. Lett., Vol. 11, No. 4, 2009

Scheme 1
.
Synthesis of Silyltriflate 17 and Diels-Alder Product
Table 1. Synthetic Applications of Indolynes
18
As shown in Table 1, a number of heteroatom- and carbon-
based nucleophiles undergo smooth reaction with indolyne
4, which indeed functions as an electrophilic indole surrogate.
Treatment of silyltriflate 17 with either p-cresol or aniline,
in the presence of CsF, led to the formation of products 19a,b
and 20a,b (entries 1 and 2, respectively).20 In addition,
indolyne formation in the presence of p-methylthiophenol
afforded sulfur-containing products 21a,b (entry 3). With
respect to carbon-based nucleophiles, a cyclic ꢀ-enaminoke-
tone could be used to prepare monosubstituted indole
products 22a,b (entry 4),21 whereas employment of potas-
sium cyanide afforded cyanoindoles 23a,b (entry 5). The
latter result is notable because cyanide has rarely been used
in nucleophilic addition reactions to arynes.22
Indolyne precursor 17 could also be used in a variety of
formal cycloaddition processes to access several unique 4,5-
disubstituted indole derivatives. For instance, reaction of
benzylazide and silyltriflate 17, in the presence of TBAF,
provided access to indolyltriazoles 24a,b in 86% yield, using
a formal aryne [3 + 2] cycloaddition (Table 1, entry 6).23
Moreover, a formal [2 + 2] cycloaddition provided indolyl-
cyclobutanones 25a,b (entry 7), whereas a variant involving
cycloaddition followed by fragmentation provided ketoesters
26a,b (entry 8).24
Several salient features of the reactions shown in Table 1
should be noted: (a) the diverse collection of compounds
synthesized demonstrates the potential to utilize silyltriflate
17 as a common precursor to a library of substituted indole
derivatives; (b) many of the products obtained would not be
readily accessible by conventional means; (c) the C3 position
in all products remains unfunctionalized, and thus could be
easily substituted if so desired; (d) high-yielding access to
these compounds is only made possible by the mild reaction
a Conditions: 17, CsF, CH3CN, 50 °C. b Conditions: 17, CsF, CH3CN,
40 °C. c Conditions: 17, TBAF, CH3CN, 23 °C. d Conditions: 17, CsF,
CH3CN, 23 °C. e Conditions: 17, CsF, CH3CN, 80 °C.
conditions employed; most of the trapping agents and
products shown in Table 1 would not be stable to more basic
butyllithium or amide base conditions for indolyne genera-
tion; and (e) each of the examples shown reflect an interesting
general preference for initial nucleophilic attack at C5 of
the presumed indolyne intermediate 4 with selectivity as high
as 12.5:1 (entry 2).
With the goal of accessing additional 4,5-disubstituted
indole products, the propensity of indolyne 4 to participate
in Diels-Alder reactions was investigated (Table 2). We
were delighted to find that N-Boc-pyrrole and cyclopenta-
(20) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198–3209.
(21) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029–1032.
(22) Scardiglia, F.; Roberts, J. D. Tetrahedron 1958, 3, 197–208.
(23) (a) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008,
10, 2409–2412. (b) Campbell-Verduyn, L.; Elsinga, P. H.; Mirfeizi, L.;
Dierckx, R. A.; Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3461–3463.
(24) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340–
5341.
Org. Lett., Vol. 11, No. 4, 2009
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diene could also be used to trap indolyne 4, thus affording
adducts 27 and 28 (entries 1 and 2). In addition, reaction in
the presence of R-pyrone produced benzoindole 29 (entry
3), presumably via a Diels-Alder/retro-Diels-Alder process
with concomitant loss of CO2. Finally, trapping of indolyne
4 with anthracene furnished indolyltriptycene 30 in good
yield (entry 4).
of 20a and 20c, reflecting a curious preference for attack of
aniline at C5 of indolyne 34. That a preference is observed
in this case suggests that the origin of selectivity in the attack
of indolynes is likely not controlled strictly by steric factors.
The subtle factors that govern the observed selectivity are
currently under active investigation in our laboratory.
Scheme 2. Preparation of 5,6-Indolyne 34 and Related Studies
Table 2. Diels-Alder Reactions of Indolyne 4
In summary, we have developed an efficient new method
for accessing a variety of substituted indole derivatives. Our
strategy relies on the generation of highly reactive indolyne
intermediates, which function as electrophilic indole sur-
rogates. These studies have shown, for the first time, that
nucleophilic addition to 4,5- and 5,6- indolynes occurs with
a general preference for attack at C5. Studies geared toward
the synthesis of complex molecules using indolynes as
surrogates for electrophilic indoles are currently underway
in our laboratory, as are efforts to obtain a fundamental
understanding of selectivity in nucleophilic addition reactions
to indolynes.
a Conditions: 17, TBAF, CH3CN, 23 °C. b Conditions: 17, CsF, CH3CN,
100 °C. c Conditions: 17, CsF, CH3CN, 80 °C.
Acknowledgment. The authors are grateful to the Uni-
versity of California, Los Angeles and Boehringer Ingelheim
for financial support. Professors Jung and Houk (UCLA) are
acknowledged for chemicals and pertinent discussions. The
Garcia-Garibay laboratory (UCLA) is thanked for the gener-
ous use of instrumentation. Dr. John Greaves (UC Irvine) is
acknowledged for obtaining mass spectral data. Dr. Xia Tian
(UCLA) is thanked for experimental assistance.
The potential to synthesize 5,6-indolyne 34 was also
explored as a means to further study the generation and
reactivity of indolynes (Scheme 2). Fortunately, it was
possible to access indolyne precursor 32 from silyl carbamate
31 in a straightforward manner.25 With silyltriflate 32
available, we investigated formation of indolyne 34. Upon
treatment of 32 with TBAF in the presence of furan (10),
Diels-Alder reaction took place to provide cycloadduct 33
in 92% yield. Additionally, reaction of silyltriflate 32 with
CsF and aniline resulted in the formation of a 3:1 mixture
Supporting Information Available: Detailed experimen-
tal details and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(25) See the Supporting Informationfor details.
OL802958A
1010
Org. Lett., Vol. 11, No. 4, 2009