Construction of carbocyclic ring of indoles using ruthenium-catalyzed ring-closing olefin metathesis

Article abstract of DOI:10.1021/ol201510u

The selective synthesis of substituted indoles was achieved by the ring-closing olefin metathesis (RCM)/elimination sequence or the RCM/tautomerization sequence of functionalized pyrrole precursors. The RCM/elimination sequence was also applied to double

Full text of DOI:10.1021/ol201510u

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4762–4765
Construction of Carbocyclic Ring of
Indoles Using Ruthenium-Catalyzed
Ring-Closing Olefin Metathesis
Kazuhiro Yoshida,* Kazushi Hayashi, and Akira Yanagisawa*
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho,
Inage-ku, Chiba 263-8522, Japan
kyoshida@faculty.chiba-u.jp; ayanagi@faculty.chiba-u.jp
Received June 6, 2011
ABSTRACT
The selective synthesis of substituted indoles was achieved by the ring-closing olefin metathesis (RCM)/elimination sequence or the RCM/
tautomerization sequence of functionalized pyrrole precursors. The RCM/elimination sequence was also applied to double ring closure to yield a
substituted carbazole.
Indoles are important synthetic targets because of their
diverse biological activities.1 A large number of methods
for the construction of the indole skeleton have been
reported,2 and those methods can be classified into two
broad categories (Scheme 1). One is the construction of
a pyrrole ring onto a functionalized benzene precursor,
and the other is the construction of a benzene ring onto
a functionalized pyrrole precursor. Compared with the
former, however, the latter is considerably rare.3 Taking
into account differences in product variation between the
two approaches, more attention should be given to the
latter approach.
Scheme 1. Two Synthetic Approaches to Indole Skeleton
(1) For selected reviews, see: (a) Sundberg, R. J. Indoles; Academic
Press: London, 1996. (b) Somei, M.; Yamada, F. Nat. Prod. Rep 2004, 21,
278–311. (c) Somei, M.; Yamada, F. Nat. Prod. Rep 2005, 22, 73–103. (d)
Brancale, A.; Silvestri, R. Med. Res. Rev. 2007, 27, 209–238. (e) Higuchi,
K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843–868. (f) Sharma, V.;
Kumar, P.; Pathak, D. J. Heterocycl. Chem. 2010, 47, 491–502.
(2) For selected reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045–1075. (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893–930. (c) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2005, 105, 2873–2920. (d) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875–2911.
The construction of aromatic rings using ruthenium-
catalyzed ring-closing olefin metathesis (RCM)4,5 has
(3) For examples, see: (a) Katritzky, A. R.; Ledoux, S.; Nair, S. K. J.
Org. Chem. 2003, 68, 5728–5730 and references cited therein. (b) Barluenga,
(5) For reports on the pharmaceutical application of RCM in multi-
kilogram scale (>400 kg of cyclized product), see: (a) Nicola, T.;
Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9,
513–515. (b) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos,
R. P.; Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.;
Fuchs, V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.;
Vitous, J.; Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.;
Nicola, T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org.
Chem. 2006, 71, 7133–7145. (c) Tsantrizos, Y. S.; Ferland, J.-M.;
McClory, A.; Poirier, M.; Farina, V.; Yee, N. K.; Wang, X.-J.;
Haddad, N.; Wei, X.; Xu, J.; Zhang, L. J. Organomet. Chem. 2006, 691
5163–5171.
ꢀ
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J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Adv. Synth. Catal.
2005, 347, 526–530. For examples of the synthesis of indolines, see:
(c) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426–2430.
ꢀ
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(d) Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M. Chem. Commun.
2000, 1965–1966.
(4) For a comprehensive review, see: (a) Handbook of Metathesis;
Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003. For recent reviews, see: (b)
Gaich, T.; Mulzer, J. Curr Top. Med. Chem. 2005, 5, 1473–1494. (c) Hoveyda,
A. H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (d) Samojlowicz, C.;
Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708–3742. (e) Diesendruck,
C. E.; Tzur, E.; Lemcoff, N. G. Eur. J. Inorg. Chem. 2009, 4185–4203.
(f) Takao, K.-i.; Tadano, K.-i. Heterocycles 2010, 81, 1603–1629. (g) Tori,
M.; Mizutani, R. Molecules 2010, 15, 4242–4260.
(6) For reviews, see: (a) Donohoe, T. J.; Orr, A. J.; Bingham, M.
Angew. Chem., Int. Ed. 2006, 45, 2664–2670. (b) van Otterlo, W. A. L.; de
Koning, C. B. Chem. Rev. 2009, 109, 3743–3782.
r
10.1021/ol201510u
Published on Web 08/25/2011
2011 American Chemical Society

recently emerged as an interesting and efficient strategy for
the preparation of aromatic compounds.6À9 Inthe pastfew
years, we have focused our efforts10 on this field and have
reported that substituted benzenes 2 can be synthesized by
RCM/dehydration of 1,5,7-octatrien-4-ols 1 (eq 1).10e One
of the advantages of this strategy is that it enables the
flexible and selective introduction of various substituents
to the benzene rings.
Based on this background, we report herein a new
synthetic strategy that employs the RCM/dehydration
sequence to yield substituted indoles 4 from functionalized
pyrrole precursors 3 (eq 2).
Scheme 2. Retrosynthetic Analysis of Substrates 3
Table 1. Synthesis of Substituted Indoles 4 by RCM/Dehydration Sequencea
a Ring-closing olefin metathesis was carried out with 3 and ruthenium catalyst (8, 7.5 mol %) in toluene. The reaction mixture was treated with
p-toluenesulfonic acid (10 mol %) at room temperature for 1 h. b Isolated yield by silica gel chromatography. c A mixture of 3b and a regioisomer (1:0.18)
was used (see the Supporting Information). d 3eÀf were found to be somewhat unstable. e The dehydration was carried out at 80 °C for 1.5 h. f The
reaction was carried out with 15 mol % of 8.
Org. Lett., Vol. 13, No. 18, 2011
4763

Precursors 3 were synthesized from three basic segments
5À7 (Scheme 2). A combination of the cross-coupling
reaction of 511 with vinylmetal reagents 6, and the allyla-
tion of the resulting coupling products with allylic metal
reagents 7 led to 3.12
Scheme 3. Synthetic Sequence to Substituted Carbazole 10
With the desired precursors in hand, we looked into the
synthesis of indoles 4 using Grubbs second-generation
catalyst13 8. Examples of the synthesis of indoles having
a benzyl group and a benzenesulfonyl group attached
to nitrogen are listed in entries 1À4 and entries 5À12 in
Table 1, respectively. The reaction of 3a that has a benzyl
group at the R1 position and a methyl ester group at the
R5 position proceeded, but the yield of desired indole 4a
was only 12% (entry 1). Because we suspected that a
vinyl group at the R3 position and a methyl ester group
at the R2 position of 3a or 4a inactivated the catalyst by
forming a HoveydaÀGrubbs-type complex,14 the reac-
tion of 3b, the structure of which is the same as that of 3a
except that an aryl group is found at the R3 position
instead of a vinyl group, was next examined. However,
the result was almost the same as that of 3a and product
4b was obtained in only 13% yield (entry 2). Then, the
reaction of 3c, which is analogous to 3a but has a methyl
ester group at a different position (R6), was performed.
Much improvement was noted in this case and indole 4c
was formed in 53% yield (entry 3). Removing the methyl
ester group from the R6 position of 3c further improved
the reactivity. The RCM of 3d proceeded even at
Scheme 4. Synthetic Sequence to 7-Hydroxyindole 12
(7) (a) Arisawa, M.; Nishida, A.; Nakagawa, M. J. Organomet.
Chem. 2006, 691, 5109–5121. (b) Donohoe, T. J.; Fishlock, L. P.;
Procopiou, P. A. Chem.;Eur. J. 2008, 14, 5716–5726.
(8) For recent examples, see: (a) Donohoe, T. J.; Bower, J. F.;
Basutto, J. A.; Fishlock, L. P.; Procopiou, P. A.; Callens, C. K. A.
Tetrahedron 2009, 65, 8969–8980. (b) Donohoe, T. J.; Bower, J. F. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 3373–3376. (c) Ziffle, V. E.; Cheng, P.;
Clive, D. L. J. J. Org. Chem. 2010, 75, 8024–8038.
(9) For examples of the construction of benzene rings fused to
aromatic heterocycles, see: (a) Selvakumar, N.; Khera, M. K.; Reddy,
B. Y.; Srinivas, D.; Azhagan, A. M.; Iqbal, J. Tetrahedron Lett. 2003, 44,
7071–7074. (b) Bennasar, M. L.; Zulaica, E.; Tummers, S. Tetrahedron
Lett. 2004, 45, 6283–6285. (c) Pelly, S. C.; Parkinson, C. J.; Van Otterlo,
W. A. L.; De Koning, C. B. J. Org. Chem. 2005, 70, 10474–10481. (d)
Mamane, V.; Fort, Y. J. Org. Chem. 2005, 70, 8220–8223.
(10) (a) Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127,
10470–10471. (b) Yoshida, K.; Kawagoe, F.; Iwadate, N.; Takahashi,
H.; Imamoto, T. Chem. Asian J. 2006, 1, 611–613. (c) Yoshida, K.;
Horiuchi, S.; Iwadate, N.; Kawagoe, F.; Imamoto, T. Synlett 2007,
1561–1564. (d) Yoshida, K.; Toyoshima, T.; Imamoto, T. Chem. Com-
mun. 2007, 3774–3776. (e) Yoshida, K.; Takahashi, H.; Imamoto, T.
Chem.;Eur. J. 2008, 14, 8246–8261. (f) Yoshida, K.; Shishikura, Y.;
Takahashi, H.; Imamoto, T. Org. Lett. 2008, 10, 2777–2780. (g) Yoshida,
K.; Narui, R.; Imamoto, T. Chem.;Eur. J. 2008, 14, 9706–9713. (h)
Yoshida, K.; Toyoshima, T.; Imamoto, T. Bull. Chem. Soc. Jpn. 2008,
81, 1512–1517. (i) Yoshida, K.; Kawagoe, F.; Hayashi, K.; Horiuchi, S.
Imamoto, T.; Yanagisawa, A. Org. Lett. 2009, 11, 515–518. (j) Takahashi,
H.; Yoshida, K.; Yanagisawa, A. J. Org. Chem. 2009, 74, 3632–3640. (k)
Yoshida, K.; Shida, H.; Takahashi, H.; Yanagisawa, A. Chem.;Eur. J.
2011, 17, 344–349.
(11) (a) Fukuda, T.; Hayashida, Y.; Iwao, M. Heterocycles 2009, 77,
1105–1122. (b) Fukuda, T.; Ohta, T.; Sudo, E.-i.; Iwao, M. Org. Lett.
2010, 12, 2734–2737.
(12) See the Supporting Information for details of the synthesis of 3.
(13) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.;
Wilhelm, T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs,
R. H. J. Am. Chem. Soc. 2003, 125, 2546–2558. (c) Vougioukalakis,
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room temperature and 4d was obtained in good yield
(entry 4).
On the other hand, the reaction of simpler 3e that has a
benzenesulfonyl group at the R1 position gave desired
indole 4e quantitatively (entry 5). In the reactions of
substrates that have the basic structure of 3e, good yields
wereobserved(entries 6À10). The introduction ofa methyl
ester group at the R5 or R6 position was no longer a serious
problem and the reaction of 3f,g gave indoles 4f,g in good
yields (entries 6 and 7 vs 1À3). Substrates having substi-
tuents at the R4 or R7 position were also converted into
corresponding products 4hÀj in excellent yields without
any problems (entries 8À10).15 Although the reaction of
(14) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168–8179.
(15) The ThorpeÀIngold effect may be responsible for the high yield
of 4i. See: Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735–1766.
4764
Org. Lett., Vol. 13, No. 18, 2011

3k, in which the formation of a tetrasubstituted double
bond is necessary at the RCM step, was very slow as
predicted (entry 11), increasing the catalyst loading im-
proved the product yield (entry 12).
To extend this methodology, the RCM/dehydration
protocol was applied to the synthesis of carbazole.16,17
The construction of two benzene rings from symmetrically
substituted pyrrole 9, which was prepared by a similar
synthetic strategy to 3, led to the formation of substituted
carbazole 10 in 81% yield (Scheme 3).18
Finally, we attempted to apply the RCM/tautomeriza-
tion sequence to 1119 that was readily prepared by the
DessÀMartin oxidation of 3f. As a result, the desired
7-hydroxyindole 12 was obtained in 95% yield (Scheme 4).
In conclusion, we have presented a new selective syn-
thetic approach to indoles from functionalized pyrroles by
utilizing the RCM/dehydration or the RCM/tautomeriza-
tion sequence. As the method employs a rare approach
(construction of a benzene ring onto a functionalized
pyrrole precursor), unique indoles can be produced with
this method.
(16) For reports on the synthesis of carbazole from a functiona-
lized indole precursor using the RCM/dehydration sequence, see
ref 9a,9b.
(17) For examples of the synthesis of carbazoles, see: (a) Witulski, B.;
Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281–3284. (b) Alayrac, C.;
Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464–1466. For an
example of the synthesis of carbolines, see: (c) Nissen, F.; Richard, V.;
Alayrac, C.; Witulski, B. Chem. Commun. 2011, 47, 6656–6658 and
references cited therein.
Acknowledgment. We appreciate the financial support
from a Grant-in-Aid for Scientific Research (KIBAN
C-22550029) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(18) In the absence of p-toluenesulfonic acid, spontaneous dehydra-
tion occurred in this case.
(19) Although it occurred very slowly, 11 was found to decompose at
room temperature. Therefore, 11 was used immediately in the RCM/
tautomerization sequence after preparation.
Org. Lett., Vol. 13, No. 18, 2011
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