Anionic indole N-carbamoyl N → C translocation. A directed remote metalation route to 2-aryl- and 2-heteroarylindoles. Synthesis of benz[a]carbazoles and indeno[1,2-b]indoles

Article abstract of DOI:10.1021/ol800307g

(Chemical Equation Presented) A new LDA-induced anionic N-C carbamoyl migration of 2-arylindoles (7) is reported. Treatment of N-carbamoylindoles 10 and 13, readily available by direct and ipso-borodesilylative Suzuki-Miyaura cross-coupling routes from 8 and 12, respectively, provides a general route to functionalized 2-arylindoles 11 and 14, respectively (Tables 1 and 2). The reaction has been applied to the synthesis of benzo[a]carbazoles 16 and indeno[1,2-b]indoles 18, and its intramolecularity has been established by a crossover experiment (Scheme 4).

Full text of DOI:10.1021/ol800307g

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2617-2620
Anionic Indole N-Carbamoyl N f C
Translocation. A Directed remote Metalation
Route to 2-Aryl- and 2-Heteroarylindoles.
Synthesis of Benz[a]carbazoles and
Indeno[1,2-b]indoles
Zhongdong Zhao,† Ashley Jaworski,‡ Isabel Piel,§ and Victor Snieckus*
Department of Chemistry, Queen’s UniVersity, Kingston, ON K7L 3N6, Canada
snieckus@chem.queensu.ca
Received February 11, 2008
ABSTRACT
A new LDA-induced anionic N-C carbamoyl migration of 2-arylindoles (7) is reported. Treatment of N-carbamoylindoles 10 and 13, readily
available by direct and ipso-borodesilylative Suzuki-Miyaura cross-coupling routes from 8 and 12, respectively, provides a general route to
functionalized 2-arylindoles 11 and 14, respectively (Tables 1 and 2). The reaction has been applied to the synthesis of benzo[a]carbazoles 16
and indeno[1,2-b]indoles 18, and its intramolecularity has been established by a crossover experiment (Scheme 4).
Carbanion chemistry1 continues to noticeably impact syn-
Scheme 1a
thetic method development for the construction of aromatics
and heteroaromatics.1c–d In context of contributions from our
laboratories which aim to enhance links to the directed ortho
metalation (DoM) reaction,2 the anionic O- (1)3 and N-ortho
(2) Fries,4 its remote (3)5 and homologous (4)6 counterparts,
and most recently, O- to C-carbamoyl transfer (5)7 have
constituted key steps in establishing unusual substitution
patterns and facilitating efficient total synthesis (Scheme 1).8
† Current address: CGI Pharmaceuticals, Inc., Branford, CT, 06405.
‡ Current address: Department of Chemistry, Stanford University, CA
94305-5080.
aDMG ) directed metalation group.
§ Current address: Institute of Organic Chemistry, University of Mu¨nster,
48149, Mu¨nster, Germany.
(1) (a) Buncel, E.; Dust, J. M. Carbanion Chemistry: Structures and
Mechanisms; American Chemistry Society: Washington, DC, 2003. (b)
Majewski M., Snieckus, V., Eds. Science of Synthesis; Thieme: Stuttgart,
2006; Vol. 8a, pp 1-862. (c) Reed, J. N. In Science of Synthesis; Majewski,
M., Snieckus, V., Eds.; Thieme: Stuttgart, 2006; Vol. 8a, p 329. (d) Gribble,
G. W. In Science of Synthesis; Majewski, M., Snieckus, V., Eds; Thieme:
Stuttgart, 2006; Vol. 8a, p 357.
The recent finding that the indole N-CONEt2 serves, after
2-TMS protection, as an excellent DMG for C-7 deproto-
nation (6)9 and the availability of 2-arylindoles by Suzuki-
Miyaura cross-coupling chemistry10 have provided, in com-
bination, the opportunity for the discovery of a new directed
remote metalation (DreM) concept (7). Herein, we report
preliminary studies on this reaction which piggy-backs the
carbamoyl DMG to the 2-aryl substituent for further DoM.
(2) (a) Snieckus, V.; Macklin, T. In Handbook of C-H Transformations:
Applications in Organic Synthesis; Dyker, G., Ed.;Wiley-VCH: Weinheim,
2005; p 106. (b) Hartung, C. G.; Snieckus, V. in Modern Arene Chemistry;
Astruc, D., Ed; Wiley-VCH Verlag: Weinheim, 2002; p 330. (c) Snieckus,
V. Chem. ReV 1990, 90, 879.
10.1021/ol800307g CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society

It also facilitates formation of derivatives 11 which, due to
steric encumbrance, are obtained less efficiently or may be
unavailable by direct cross-coupling11 and allows the con-
struction of benzocarbazoles and indeno[1,2-b]indoles
(Schemes 2 and 3), compounds of considerable current
interest in the areas of antitumor,12 estrogen deficiency,13
melatoninergic disorder,14 and protein kinase inhibition.15
Table 1. Synthesis of 2-(Carbamoyl)arylindoles 11a-i: The
Direct Suzuki-Miyaura Cross-Coupling Route from 8
Scheme 2
Scheme 3
The results of our preliminary investigations comprise two
series of 2-aryl- and 2-heteroarylindoles and are summarized
in Tables 1 and 2. In the first series with a view toward remote
anionic cyclization chemistry to fused carbazoles,11 N-carbam-
oyl-2-aryl-3-methylindoles 10a-i16 were prepared by generally
efficient Suzuki-Miyaura cross-coupling of the N-carbamoyl-
a Isolated yields. b Pd2(dba)3/SPhos/K3PO4/MeOH/50 h. c -40°C/1 h.
d -40°C/2 equiv of LDA/1 h. e 0 °C/2 equiv/40 min.
2-bromoskatole 817 with a variety of aryl- and heteroarylboronic
acids 9a-i, respectively (Table 1).18 In the prototype reaction
(Table 1, entry 1), treatment of 10a with 2 equiv of LDA19 led
to the formation of the N-carbamoyl migration product 11a in
80% yield. Table 1 illustrates selected cases which deserve brief
(3) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
(4) MacNeil, S. L.; Wilson, B. J.; Snieckus, V. Org. Lett. 2006, 8, 1133.
(5) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
(6) Kalinin, A. V.; Miah, M. A. J.; Chattopadhyay, S.; Tsukazaki, M.;
Wick, M.; Nguen, T.; Coelho, A. L.; Kerr, M.; Snieckus, V. Synlett 1997,
839.
(16) For methods of 2-arylindole synthesis, see: (a) Fischer indole
synthesis: Robinson, B. Chem. ReV 1969, 69, 227; Slätt, J.; Bergman, J.
Tetrahedron 2002, 58, 9187. (b) Transition-metal-catalyzed coupling-cycli-
zation: Hong, K. B.; Lee, C. W.; Yum, E. K. Tetrahedron Lett. 2004, 45,
693; Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (c)
C-H arylation: Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007,
72, 146, and references cited therein. (d) From acyclic phosphoryloxy ene
carbamates: Fuwa, H.; Sasaki, M. Org. Lett. 2007, 9, 3347. For their
bioactivity studies, see: (e) Harper, S.; Pacini, B.; Avolio, S.; Di Filippo,
M.; Migliaccio, G.; Laufer, R.; De Francesco, R.; Rowley, M.; Narjes, F.
J. Med. Chem. 2005, 48, 1314 (Inhibitors of Hepatitis C Virus NS5B
Polymerase). (f) Meng, C. Q.; Ni, L.; Worsencrott, K. J.; Ye, Z.; Weingarten,
M. D.; Simpson, J. E.; Skudlarek, J. W.; Marino, E. M.; Suen, K.; Kunsch,
C.; Howard, R. B.; Sundell, C. L. 229th ACS National Meeting, San Diego,
CA, March 13-17, 2005; American Chemical Society: Washington, DC,
2005; Abstract No. 587 (antiasthmatic). (g) Kaufmann, D.; Pojarova, M.;
Vogel, S.; Liebl, R.; Gastpar, R.; Gross, D.; Nishino, T.; Pfaller, T.; von
Angerer, E. Bioorg. Med. Chem. 2007, 15, 5122 (antimitotic).
(17) Prepared in 92% yield by ipso-bromodesilylation of N,N-diethyl-
3-methyl-2-(trimethylsilyl)-1H-indole-1-carboxamide; see the Supporting
Information.
(7) Reed, M. A.; Chang, M.; Snieckus, V. Org. Lett. 2004, 6, 2297.
(8) (a) For an outstanding review, see: Clayden, J. In Chemistry of
Oganolithium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley &
Sons, Ltd.: Chichester, 2004; p 495. (b) For discussion regarding the
mechanistic and synthetic aspects of the complex-induced proximity effect
(CIPE) on organolithium chemistry, including DreM, see: Whisler, M. C.;
MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
(9) Hartung, C. G.; Fecher, A.; Chapell, B. J.; Snieckus, V. Org. Lett.
2003, 5, 1899.
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(11) Cai, X.; Snieckus, V. Org. Lett. 2004, 6, 2293.
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Knolker, H. J. Top. Curr. Chem. 2005, 244, 115.
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(18) With the exception of 9i, which was prepared by hydroboration
(see: Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed. 2003,
42, 3399), all other arylboronic acids were obtained from commercial
sources.
(19) For a typical experimental procedure, see the Supporting
Information.
(15) (a) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1990; Vol. 39, p 239. (b) Sanchez-Martinez, C.; Shih,
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3835.
2618
Org. Lett., Vol. 10, No. 13, 2008

common starting N-carbamoyl-2-TMS indole 12,9 ipso-borode-
silylation followed by in situ Suzuki-Miyaura cross coupling
of the presumed dichloroborane24,25 with selected aryl bro-
mides led to a variety of 2-aryl (Table 2, entries 1-5) and
heteroaryl (entries 6-8) indole derivatives. For the cross
coupling, expected halogen chemoselectivity26 (entries 3 and
4) was observed (see the Supporting Information). In this series,
the remote metalation-N-carbamoyl migration reaction also
proceeded smoothly and, in some cases (entries 1 and 6,
Table 2), in higher yields than the corresponding skatole deriva-
tives (entries 1 and 8, Table 1). In the heteroaryl series, the
thienyl product 13f, obtained by an inverted partner route,
is unexceptional in terms of greater C-2 over C-3 acidity,20
the pyridyl case 13g follows previous observations on depro-
tonation site selectivity,27 and the isoquinoline derivative 13h
shows presumably the result of great heteroring C-H acidity
and/or CIPE alignment over the alternate peri-position.
Table 2. Synthesis of 2-(Carbamoyl)arylindoles 14a-g: The
ipso-Borodesilyation-Suzuki-Miyaura Cross-Coupling Route
from 12
To further advance synthetic utility, the application of the
directed remote metalation (DreM) concept5,8b was tested
on several carbamoyl-translocated skatole products 11a and
11b (Scheme 2). After a not unexpected failure at an attempt
to affect a one-pot procedure by subjection of a solution of
the initially formed anion corresponding to the migration
product 11a to treatment with additional LDA,28 this reaction
solution was treated with Boc anhydride, and product 15a
was subjected to reaction with LiTMP to give the benzo[a]
carbazole 16a in 88% yield (based on recovered 11a).29,30
The corresponding m-tolyl series, 11b f 15b f 16b, gave,
not surprisingly, a less synthetically useful result.
a Isolated yields. b For preparation, see ref 10. c Boropinacolates were
In a further enhancement of synthetic utility (Scheme 3),
the 2-arylindoles 14a and 14g were protected as the corre-
sponding Boc derivatives 17a and 17b, and the isolated
products were subjected to LDA conditions as above to
used. d 0 °C for 40 min.
comment. In simple cases, 2 equiv of LDA was sufficient for
smooth rearrangement while in substituted derivatives, e.g.,
10c,d, up to 4 equiv of LDA was necessary for optimum yields.
Weak (entry 2) and strong (entry 5) electron-donating groups
provide excellent yields of products and a synergistic DMG
effect, analogous to that observed in m-di-DMG-substituted ben-
zenes, is demonstrated by the regioselective migration result (entry
4) albeit in lower yield. A fluoro substituent is tolerated (entry
6), carbamoyl transfer to furan and thiophene rings is observed
to the expected, more acidic site20 (entries 7 and 8) and a styryl
case (entry 9)21 demonstrating an interesting migration to a vinyl
anion analogous to that observed generally for O-carbamate
series,7 may be noted. The present methodology for the
synthesis of N-substituted skatole derivatives 10 circumvents
the direct Suzuki-Miyaura coupling route,11 whose inefficiency
is presumably due to a tri-ortho-substitution hindrance effect.22
As an alternative route to 2-arylindoles, with the aim of
making 3-unsubstituted systems in order to leave the option
for further well-established electrophilic substitution chemistry,23
the recently disclosed method10 was adapted. Thus, using the
(22) For developments in overcoming steric effects in the Suzuki-Miyaura
reaction, see: Barder, T. E.; Walker, S. D.; Martinelli, S. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685
.
(23) (a) Sundberg, R. J. Indoles; 2nd ed.; Academic Press: London, San
Diego, 1996. (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry; 4th ed.;
Blackwell Science: Oxford, 2000; p 325. (c) Joule, J. A. Science of Synthesis;
Thomas, E. J., Ed.; Thieme: Stuttgart, 2000; Vol. 10, p 361
(24) Known but sensitive compounds, see: (a) Haubold, W.; Herdtle,
.
J.; Gollinger, W.; Einholz, W. J. Organomet. Chem. 1986, 315, 1. (b)
Kaufmann, D. Chem. Ber. 1987, 120, 853
.
(25) In some cases (entries 6 and 7), the corresponding boropinacolates
were isolated and gave, upon cross coupling, better yields of products. This
may be due to the more robust nature and easier handling of the boropinacolates;
see: Abaraca, B.; Ballesteros, R.; Blanco, F.; Bouillon, A.; Collot, V.;
Dominguez, J.-R.; Lancelot, J.-C.; Rault, S. Tetrahedron 2004, 60, 4887
.
(26) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: New York, 2004; Chapter 2. (b) Grushin,
V. V.; Alper, H. Chem. ReV. 1994, 94, 1047.
(27) (a) Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059. (b)
Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Heterocycl.
Chem. 1991, 52, 187
.
(28) The resulting N-anion is expected to deacidify the already weakly
acidic 3-methyl hydrogens. The indole C-3 methyl hydrogen acidity is
expected to be lower than the corresponding C-2 acidity on the basis of
previous results (Naruse, Y.; Ito, Y.; Inagaki, S. J. Org. Chem. 1991, 56,
2256), and our observation that deprotonation of 1,2,3-trimethylindole
followed by methyl iodide quench affords 1,3-dimethyl-2-ethylindole (95%
yield: Zhao, Y.; Snieckus, V. Unpublished results).
(20) (a) Reutov, O. A.; Beletskaya, I. P.; Butin, K. P. CH-Acids;
Pergamon Press: Oxford, 1978; pp 67–119. (b) Katritzky, A. R.; Ress, C. W.
ComprehensiVe Heterocyclic Chemistry; Pergamon Press: Oxford, 1984;
pp 238, 650–771.
(29) For recent syntheses of carbazoles, see: (a) Tsuchimoto, T.;
Matsubayashi, H.; Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew.
Chem., Int. Ed. 2005, 44, 1336. (b) Liu, C.-Y.; Knochel, P. Org. Lett. 2005,
7, 2543. (c) Mart´ınez-Espero´n, M. F.; Rodr´ıguez, D.; Castedo, L.; Saa´, C.
Org. Lett. 2005, 7, 2213. (d) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 581.
(21) The structure of 11i was confirmed by 2D NMR, see the Supporting
Information.
Org. Lett., Vol. 10, No. 13, 2008
2619

Scheme 4
rate differences in the migration of 13b and 19 were qualita-
tively observed, this result nevertheless supports an intramo-
lecular pathway for the N-carbamoyl translocation reaction.
In conclusion, a new and general anionic N-carbamoyl migra-
tion, 10, 13 f 11, 14 has been added to the tool box of synthetic
carbanionic aromatic chemistry (Scheme 1).37 This reaction
offers an alternative to direct cross-coupling approaches to
2-arylindoles16whichmaybeunderminedbysterichindranceeffects16
and provides products 11 and 14, useful for further DoM and
DreM reactions as well as additional anionic technology for
the synthesis of benzocarbazoles (16a,b)38 and an anionic route
to indeno[1,2-b]indole (18a) and azaindeno[1,2-b]indole (18b).
Figure 1. ORTEP view of compound 10e with atomic numbering
scheme.
afford the indeno[1,2-b]indoles 18a and the corresponding
aza derivative 18b in 78% and 35% yields, respectively.
Interestingly, since, to the best of our knowledge, direct
Friedel-Crafts reaction of the carboxylic acids corresponding
to 17a,b-type compounds has not been reported, the above
DreM route may serve as a useful method for the preparation
of these somewhat unexplored ring systems.13,14
Based on considerable precedent,8b a carbamoyl-LDA
coordination (CIPE) is suggested to play a role in the
deprotonation-migration reaction.31 Examination of models
and the X-ray crystal structure of 10e (Figure 1), although
with the normal caveat of inadequate argument based on
solid-state analysis and lack of knowledge of the structure
of the derived lithiated species,32 one may expect a reason-
able Burgi-Dunitz angle33 trajectory approach of an incipient
2-aryl anion toward the carbamoyl carbonyl.1
Acknowledgment. We thank NSERC Canada for continu-
ing support via the Discovery Grant program and Merck Frosst
Canada for an unrestricted grant. Z.Z.D. is grateful to Queen’s
University for fellowships. A.J. was an NSERC Undergraduate
Research Summer Assistant (USRA) awardee (2005), and I.P.
was a visiting student from Universitat Mu¨nster (summer 2006).
We are grateful to Dr. Francoise Sauriol39 for assistance with
NMR spectra determination and Dr. Ruiyao Wang39 for X-ray
crystal structure analysis of compound 10e. We warmly thank
Frontier Scientific, Inc., for providing a number of boronic acids,
which greatly assisted this methodological study.
The carbamoyl translocation reaction of 13a was conveniently
followed by React IR and showed smooth disappearance of
the N-CONEt2 band at ν 1684 cm-1 over 1 h and the
concomitant appearance of the CONEt2 band at ν 1601 cm-1.
This suggests that the migration proceeds via the tetrahedral
intermediate 20, whose conversion to product rather than 6-oxo-
6H-isoindolo[2,1-a]indole 21 (ν 1720 cm-1)34 is driven by strain
and indole N-anion leaving group propensity.35,36 As a test of
intramolecularity of the migration, a crossover experiment
was executed (Scheme 4). Thus, treatment of a 1:1 mixture
of 13b and 19 under the standard LDA conditions afforded
14band 22 in quantitative conversions. Although the expected
Note Added in Proof. For a more direct approach to
N-carbamoyl-2,3-diphenylindoles, see: Leogane, O.; Lebel,
H. Angew. Chem., Int. Ed. 2008, 47, 350.
Supporting Information Available: Experimental proce-
dures and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800307G
(34) (a) Itahara, T. Synthesis 1979, 2, 151. (b) For an intramolecular
aerobic oxidative coupling synthesis, see: Dwight, T. A.; Rue, N. R.; Charyk,
D.; Josselyn, R.; DeBof, B. Org. Lett. 2007, 9, 3137.
(35) For React IR evidence of DreM paths to fluorenones, see: Alessi,
M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus,
V. J. Org. Chem. 2007, 75, 1588.
(30) Since compounds 16a,b were found to be unstable, they were
transformed into their triflate 16c and acetate 16d derivatives, respectively,
for characterization; see the Supporting Information.
(36) Interestingly, in a recent report, LDA treatment of N-pivaloyl
2-phenylindole has been shown not lead to the analogous migration but
loss of the pivaloyl group. Although a rationale was not given, this result
may be due to its less favorable equilibrium to the alkoxide tetrahedral
intermediate and poorer coordinating and hence metalating properties of
the pivaloyl compared to carbamoyl and perhaps Boc groups; see: Avendanˇo,
C.; Sa´nchez; J, D.; Mene´ndez, J. C Synlett 2005, 1, 107.
(31) For a metal-halogen exchange driven DreM reaction, see: Ruiz,
J.; Ardeo, A.; Ignacio, R.; Sotomayor, N.; Lete, E. Tetrahedron 2005, 61,
3311.
(32) For enlightening work on DMG-based ortho-lithiated aromatics,
see: (a) Singh, K. J.; Collum, D. B. J. Am. Chem. Soc. 2006, 128, 13753.
(b) Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2007, 129, 14818. (c) Clayden,
J.; Davies, R. P.; Hendy, M. A.; Snaith, R.; Wheatley, A. E. H. Angew.
Chem., Int. Ed. 2001, 40, 1238. For synthetic chemists, an essential tutorial
and review on LDA-mediated reactions has appeared: (d) Collum, D. B.;
McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007, 46, 2007.
(33) (a) Burgi, H. B.; Dunitz, J. D.; Lehn, J.-M.; Wipff, G. Tetrahedron
1974, 30, 1563. (b) Burgi, H. B.; Dunitz, J. D. J. Am. Chem. Soc. 1987,
109, 2924.
(37) AttemptstoeffecttheanalogousmigrationusingtheindoleN-phospho-
diamidate (N-P(O)(NR2)2) derivative corresponding to 13a under the same
LDA conditions failed: Zhao, Z.; Snieckus, V. Unpublished results.
(38) Although yields of products from the present and previous route11
are comparable, different phenolic benzocarbazole isomers (C-4 vs C-3)
are obtained.
(39) Department of Chemistry, Queen’s University, Kingston, ON, Canada.
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Org. Lett., Vol. 10, No. 13, 2008