Synthesis of fused 4,5-disubstituted indole ring systems by intramolecular friedel-crafts acylation of 4-substituted indoles

Article abstract of DOI:10.1021/jo702591p

(Chemical Equation Presented) 4-Substituted indoles containing a variety of electrophiles and N-substituents undergo Friedel-Crafts acylation to give exclusively the products of cyclization at the 5-position of indole. These indanones and tetralones have been scarcely prepared and are subunits in natural products and analogues of potential biological significance.

Full text of DOI:10.1021/jo702591p

Synthesis of Fused 4,5-Disubstituted Indole Ring
Systems by Intramolecular Friedel-Crafts
Acylation of 4-Substituted Indoles
Eric Fillion* and Aaron M. Dumas
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario N2L 3G1, Canada
efillion@uwaterloo.ca
ReceiVed December 4, 2007
FIGURE 1. Examples of 3,4- and 4,5-substituted indole natural
products.
SCHEME 1. Intramolecular FC Acylation of 4-Substituted
Indoles To Yield 3,4-Bridged and 4,5-Fused Products
4-Substituted indoles containing a variety of electrophiles
and N-substituents undergo Friedel-Crafts acylation to give
exclusively the products of cyclization at the 5-position of
indole. These indanones and tetralones have been scarcely
prepared and are subunits in natural products and analogues
of potential biological significance.
Indole-containing natural products and bioactive molecules
represent a substantial portion of alkaloids, and as such have
been the subject of innumerable synthetic forays. We were
particularly interested in 3,4-bridged and 4,5-fused indole-
containing molecules (indole numbering), which include the
ergot alkaloids1 (such as festuclavine) and hapalindoles/am-
biguines2 and lolitrems and lolicines,3 respectively (Figure 1).
Retrosynthetically, intramolecular Friedel-Crafts (FC) acy-
lation of 4-substituted indoles appears to be a logical discon-
nection to access these ring systems. FC acylation has been
among the most powerful and widely used means of function-
alizing arenes, which makes the lack of examples of this reaction
as it pertains to 4-substituted indoles surprising.4,5 FC acylation
with Vilsmeier-Haack reagents derived from N,N-dimethyla-
mides, reported by Ishikawa,6 and carboxylic acids, reported
by Spadoni,7 cyclize from the 4- to the 3-position of indole
exclusively (Scheme 1a).8 In both of these cases, the indole
nitrogen was unprotected, although in the latter case the
5-position was blocked. Boger disclosed the cyclization of an
acid chloride to the 5-position in a comparatively deactivated
2-carbomethoxyindole (Scheme 1b). Indoles containing this 4,5-
indanone motif are of medicinal relevance as such a substructure,
appended to the CPI unit of CC-1065, greatly increases the
cytotoxicity of the analogues.9
Based on this precedent, the factors affecting the regioselec-
tivity of the acylation are unclear. Considering the potentially
wide range of products available by these routes, we undertook
a study of the regioselectivity of FC acylations of 4-substituted
indoles. These studies focused on the effect of changing the
electrophile, the N-protecting group, and the tether length
(Scheme 2).
The intramolecular FC acylation of Meldrum’s acid deriva-
tives was chosen as the initial probe reaction, as the molecules
are easily prepared and functionalized, but are highly reactive
FC acylating agents.10 These are conveniently synthesized by
Knoevenagel condensation of an aldehyde with Meldrum’s acid
(3).11 In this case, the π-nucleophilicity of indole-4-carboxal-
(1) Rˇeha´cˇek, Z.; Sajdl, P. Ergot Alkaloids: Chemistry, Biological Effects,
Biotechnology; Elsevier: New York, 1990.
(2) Isolation of ambiguine H: Smitka, T. A.; Bonjouklian, R.; Doolin,
L.; Jones, N. D.; Deeter, J. B. J. Org. Chem. 1992, 57, 857-861.
(3) Isolation of lolicine A: Munday-Finch, S. C.; Wilkins, A. L.; Miles,
C. O. J. Agric. Food Chem. 1998, 46, 590-598.
(4) Examples of FC alkylation of 4-substituted indoles: (a) Natsume,
M.; Muratake, H. Tetrahedron Lett. 1989, 30, 1815-1818. (b) Matsumoto,
M.; Watanabe, N.; Kobayashi, H. Heterocycles 1987, 26, 1479-1482.
(5) A related anionic cyclization of a 4-substituted indole to the 3-position
was reported in a total synthesis of lysergic acid: Hendrickson, J. B.; Wang,
J. Org. Lett. 2004, 6, 3-5.
(7) Spadoni, G.; Balsamini, C.; Diamantini, G.; Di, Giacomo, B.; Tarzia,
G.; Mor, M.; Plazzi, P. V.; Rivara, S.; Lucini, V.; Nonno, R.; Pannacci,
M.; Fraschini, F.; Stankov, B. M. J. Med. Chem. 1997, 40, 1990-2002.
(8) For an example of cyclization from the 3- to the 4-position of indole,
see: Komoda, T.; Nakatsuka, S. Heterocycl. Commun. 2003, 9, 119-122.
(9) Boger, D. L. Int. Patent WO2004101767, 2004.
(6) Kurokawa, M.; Watanabe, T.; Ishikawa, T. HelV. Chim. Acta 2007,
90, 574-587.
10.1021/jo702591p CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/06/2008
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J. Org. Chem. 2008, 73, 2920-2923

SCHEME 2. Planned Study of FC Acylation of
4-Substituted Indoles
SCHEME 4. Intramolecular FC Acylation of Meldrum’s
Acid Derivatives
SCHEME 3. Preparation of N-Ns-indolyl Meldrum’s Acid
Derivatives
a Reaction time 30 min. b Reaction performed with 10 mol % of
Yb(OTf)3, heating for 6 min.
SCHEME 5. Intramolecular FC Acylation of Spiro
Meldrum’s Acid Derivatives
SCHEME 6. Attempted FC Acylation of N-H Indoles
dehyde (1) was attenuated by protection as the 4-nitrophenyl-
sulfonyl (Ns) derivative 2 to prevent intermolecular FC alky-
lation of indole by the alkylidene Meldrum’s acid, a reaction
which occurs readily.12 Condensation of 2 proceeded cleanly,
and reduction of 4 with NaBH3CN and alkylation with various
electrophiles gave substrates 5a-d suitable for Lewis acid-
catalyzed FC acylation (Scheme 3).
Acylation was performed under conditions previously used
for reaction of phenyl-containing Meldrum’s acid derivatives.10
Under BF3‚OEt2 catalysis, all substrates cyclized exclusively
at the 5-position of indole; in no case were the products of
the extent to which regioselectivity is controlled by π-nucleo-
philicity. However, under conditions previously successful for
the FC acylation of reactive-nitrogen containing aromatics with
Meldrum’s acid derivatives,10a no cyclized products could be
isolated from the reactions of 5e and 5f. Rather, a complex
mixture indicative of decomposition was produced (Scheme 6).
The propensity of these acylations to occur at the 5-position
is in one sense counterintuitive, in that the 3-position is typically
the most electron-rich and π-nucleophilic portion of indoles.15
As well, we had previously shown that 6-membered rings form
faster than 5-membered ones in FC acylation using Meldrum’s
acid derivatives.10a However, intermolecular FC reactions of
indoles can occur with unexpected regioselectivity depending
on the electrophile and N-substituent.16
1
3-position cyclization detected in the H NMR of the crude
reaction mixture. Enolizable Meldrum’s acid 5a reacted in much
lower yield; the yield increased under Yb(OTf)3 catalysis and
with equal selectivity (Scheme 4).
The same regioselectivity was observed in spirocyclic Mel-
drum’s acid derivative 7. This was obtained by thermal Diels-
Alder reaction of alkylidene Meldrum’s acid 4 followed by BF3‚
OEt2-promoted FC acylation in 1,2-dichloroethane (Scheme 5).13
At this point, it was clear that substitution of groups not directly
involved in the acylation had no effect on the regioselectivity.
Therefore, deprotection of the Ns group14 to give more
electron-rich N-H indoles was performed in order to determine
Because of a lack of precedent for FC acylations of N-Ns
indoles, it was not clear if this deactivating protecting group
was altering 3-position nucleophilicity in favor of a more
(10) (a) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem.
2005, 70, 1316-1327. (b) Fillion, E.; Fishlock, D. Org. Lett. 2003, 5, 4653-
4656.
(11) Dumas, A. M.; Seed, A.; Zorzitto, A. K.; Fillion, E. Tetrahedron
Lett. 2007, 48, 7072-7074.
(12) (a) Boisbrun, M.; Jeannin, L.; Toupet, L.; Laronze, J.-Y. Eur. J.
Org. Chem. 2000, 3051-3057. (b) Jeannin, L.; Nagy, T.; Vassileva, E.;
Sapi, J.; Laronze, J.-Y. Tetrahedron Lett. 1995, 36, 2057-2058. (c) Oikawa,
Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 20, 1759-1762.
(13) Fillion, E.; Dumas, A. M.; Hogg, S. A. J. Org. Chem. 2006, 71,
9899-9902.
(14) Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawing, A. M. Z. J. Org.
Chem. 2005, 70, 5840-5851.
(15) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.; Boubaker,
T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088-9095.
(16) Sundberg, R. J. Best Synthetic Methods: Indoles; Academic Press:
San Diego, CA, 1996; pp 136-137.
J. Org. Chem, Vol. 73, No. 7, 2008 2921

SCHEME 7. Intermolecular FC Acylation of N-Ns Indole
SCHEME 9. FC Acylation of Various N-Protected
3-(4-Indolyl)propanoyl Chlorides
SCHEME 8. Preparation of 3-(4-Indolyl)propanoic Acid
Derivatives
SCHEME 10. FC Acylation of N-Ns 3-(4-Indolyl)propanoic
Acid
in refluxing (CH2Cl)2. Both the N-sulfonamide and N-carbonyl
derivatives reacted to give the substituted indanones 6b/6e-g
as the only detectable cyclized product (Scheme 9). This
corresponds with the results of Boger,6 in that 3-(4-indolyl)-
propanoyl chlorides containing electron-withdrawing substitu-
ents cyclize at the 5-position.
These results, in comparison with the reactions of Meldrum’s
acid derivatives 5a-d, suggest that the nature of the electrophile
plays a less important role in determining the regioselectivity
than do the substituents on the indole. In this regard, it was
concluded that electron-withdrawing N-substituents favor cy-
clization at the 5-position. This was further confirmed by the
direct acylation of the carboxylic acid 14a with PPA, which
again cyclized exclusively at the 5-position (Scheme 10).
The above examples all involved the competitive formation
of either a six-membered 3,4-substituted or five-membered, 4,5-
substituted indole. However, it was unknown whether a longer
chain length (extended by one methylene unit) would affect the
regioselectivity of the FC acylation. A Meldrum’s acid derivative
with the appropriate tether length was synthesized from known
and easily prepared N-tosyl-4-cyanomethylindole 17.19 Acid
hydrolysis of the nitrile, followed by DCC-promoted condensa-
tion of indoleacetic acid 18 with Meldrum’s acid and in-situ
reduction of the resulting alkylidene with NaBH4, gave the
enolizable Meldrum’s acid derivative 19a.20 Methylation under
standard conditions gave the quaternized product 19b (Scheme
11).
reactive 5-position. However, intermolecular FC acylation of
N-Ns indole 9 with disubstituted Meldrum’s acid derivative 10,
promoted by either BF3‚OEt2 or Yb(OTf)3, gave the 3-acylated
product 11 exclusively (Scheme 7).17 This suggests that although
the 3-position in N-Ns indoles 5a-d is more nucleophilic than
the 5-position, the difference in nucleophilicity is insufficient
to overcome the kinetic preference for formation of the 4,5-
fused product.
To explore the effect of different electrophiles and N-
protecting groups, 3-(4-indolyl)propanoic acids were synthesized
(Scheme 8). R-Secondary carboxylic acids were used to be as
similar to the Meldrum’s acid substrate 5a as possible. All were
prepared from indole-4-carboxaldehyde by various routes
outlined in Scheme 8. Substrates containing N-sulfonamide
indoles were synthesized by HWE reaction and hydrogenation
of the crude unsaturated ester in high yield. Subsequent
N-protection, followed by base hydrolysis of 13b gave the
carboxylic acid. Acid hydrolysis of 13a was needed to avoid
cleaving the sensitive N-Ns derivative.18 A shorter route was
developed to prepare N-carbonyl derivatives 14c and 14d, as
both N-Ac and N-CO2Me groups were cleaved by acid or base
hydrolysis. Therefore, the unsaturated benzyl ester 16 was
prepared; N-protection and simultaneous reduction of the alkene
and benzyl ester gave 14c and 14d.
Meldrum’s acid substrates 19a and 19b were cyclized under
Yb(OTf)3-catalysis in MeNO2 at 100 °C. In both cases, the
products were exclusively the result of acylation at the 5-position
to give tetralones 20a and 20b (Scheme 12). This motif is a
privileged substructure of the tremorgenic natural product
family, and as such a convenient and simple route is potentially
of value.21
These results clearly demonstrate that cyclization of 4-sub-
stituted indoles to the 5-position is the preferred mode for indoles
(19) Ponticello, G. S.; Baldwin, J. J. J. Org. Chem. 1979, 44, 4003-
4005.
FC acylation of these substrates was performed by derivati-
zation to the acid chloride, followed by treatment with AlCl3
(20) (a) Hin, B.; Majer, P.; Tsukamoto, T. J. Org. Chem. 2002, 67, 7365-
7368. (b) Smrcina, M.; Majer, P.; Majerova´, E.; Guerassina, T. A.;
Eissenstat, M. A. Tetrahedron 1997, 53, 12867-12874.
(21) The only other reported route to these tetralones was disclosed by
Kerr, who prepared an acyclic 4,5-disubstituted indole and built the tetralone
by a clever domino process involving the non-aromatic portions of the
molecule. See: England, D. B.; Magolan, J.; Kerr, M. A. Org. Lett. 2006,
8, 2209-2212.
(17) The position of acylation was determined unambiguously based on
the disappearance of the signal for the C-3 proton and 1H-1H COSY
correlations.
(18) For example, N-Ns indole 9 is rapidly (3 h) and quantitively
deprotected by aqueous LiOH in DMF or 1,4-dioxane at rt.
2922 J. Org. Chem., Vol. 73, No. 7, 2008

SCHEME 11. Preparation of Extended Tether FC
Acylation Substrates
MeNO2. The flask was sealed tightly and placed in a temperature
controlled oil bath at 100 °C. After 15 or 30 min, the flask was
removed from the bath and cooled to rt. The contents were rinsed
into a round-bottom flask with CH2Cl2 and concentrated. Purifica-
tion by flash column chromatography yielded the cyclized products.
General Procedure B: FC Acylation of Carboxylic Acids
14a-d. Carboxylic acid (0.1 mmol, 1.0 equiv) was dissolved in
benzene (1.0 mL) in a flask equipped with an oven-dried, water-
cooled condenser. To this was added distilled (COCl)2 (35 µL, 0.4
mmol, 4.0 equiv) at rt, and the solution heated to reflux for 1 h.
The flask was removed from heat, cooled to rt, and concentrated
by rotary evaporation. The residue was dissolved in benzene
(2 mL) and concentrated, followed by the same procedure with
(CH2Cl)2 (2 × 2 mL). The resulting crude acid chloride was
dissolved in (CH2Cl)2 (2 mL) at rt, and AlCl3 (40 mg, 0.3 mmol,
3.0 equiv) was added. The suspension was heated to reflux for 30
min, cooled to rt, and quenched with saturated NaHCO3 (10 mL).
The reaction was poured into a separatory funnel and the layers
separated; the aqueous phase was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over MgSO4, filtered,
and concentrated. Purification by flash column chromatography or
recrystallization yielded the indanones.
SCHEME 12. Synthesis of 4,5-Disubstituted Indolyl
Tetralones
Cyclized product 6b was obtained as an off-white powder in
92% yield (68 mg) from 5b by procedure A and in 73% yield (27
mg) from 14a by procedure B: mp 189-191 °C; 1H NMR (CDCl3,
300 MHz) 8.28 (dd, J ) 7.0, 1.9 Hz, 2H), 8.06 (dd, J ) 7.0, 1.9
Hz, 2H), 7.99 (d, J ) 8.6 Hz, 1H), 7.71 (d, J ) 8.6 Hz, 1H), 7.67
(d, J ) 3.7 Hz, 1H) 6.95 (d, J ) 3.6 Hz, 1H), 3.49 (dd, J ) 17.4,
7.6 Hz, 1H), 2.83-2.73 (m, 2H), 1.31 (d, J ) 7.3 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) 208.2 (C), 150.9 (C), 148.7 (C), 143.1
(C), 137.9 (C), 132.6 (C), 128.2 (overlapping C and 2 × CH), 127.1
(CH), 124.7 (2 × CH), 120.7 (CH), 113.0 (CH), 108.4 (CH), 41.9
(CH), 33.4 (CH2), 16.5 (CH3); HRMS(EI) m/z calcd for C18H14N2O5S
(M+) 370.0623, found 370.0631.
a Reaction time 1.75 h. b Reaction time 30 min.
protected with electron-withdrawing N-substituents. This se-
lectivity is general across a range of electrophiles, Lewis acids,
N-protecting groups, and tether lengths. The regioselectivity
observed for these substrates is noteworthy, as in no case was
there evidence of the 3,4-disubstituted product. Therefore, the
intramolecular FC acylation of 4-substituted indoles is a
convenient means of preparing N-protected, 4,5-fused indole
ring systems. As some of these motifs have potential medical
applications, and considering that the scarcity of reported
procedures for their preparation has limited biological evaluation
of these structures, this methodology may be of further use.
Acknowledgment. This work was supported by the Merck
Frosst Centre for Therapeutic Research, AstraZeneca Canada
Inc., NSERC, CFI, OIT, and the University of Waterloo. A.M.D.
thanks the Governments of Canada and Ontario and the
University of Waterloo for graduate scholarships.
Experimental Section
Supporting Information Available: Procedures for preparation
of all new starting materials and products and characterization and
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
General Procedure A: FC Acylation of Meldrum’s Acid
Derivatives 5a-d. An oven-dried Schlenk flask cooled under
nitrogen was charged with Meldrum’s acid derivative (0.2 mmol,
1.0 equiv) and dissolved in 0.8 mL of MeNO2. BF3‚OEt2 (5.0 µL,
0.04 mmol, 0.2 equiv) was washed into the flask with 0.5 mL of
JO702591P
J. Org. Chem, Vol. 73, No. 7, 2008 2923