Synthesis of polycyclic indolone and pyrroloindolone heterocycles via the annulation of indole- and pyrrole-2-carboxylate esters with arynes

Article abstract of DOI:10.1055/s-0029-1217535

A mild and general method for the synthesis of a variety of polycyclic indolone and pyrroloindolone heterocycles via the reaction of indole- and pyrrole-2-carboxylate esters with arynes has been developed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217535

2010
LETTER
Synthesis of Polycyclic Indolone and Pyrroloindolone Heterocycles via the
Annulation of Indole- and Pyrrole-2-Carboxylate Esters with Arynes
S
ynthesis of Poly
o
cyclic
I
ndolo
b
ne ert D. Giacometti, Yeeman K. Ramtohul*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd., P.O. Box 1005,
16711 Trans Canada Highway, Kirkland, Quebec, H9H 3L1, Canada
Fax +1(514)4284900; E-mail: yeeman_ramtohul@merck.com
Received 8 April 2009
R3
R3
Abstract: A mild and general method for the synthesis of a variety
of polycyclic indolone and pyrroloindolone heterocycles via the re-
action of indole- and pyrrole-2-carboxylate esters with arynes has
been developed.
R2
R1
R2
R1
O
TfO
O
F
R5
+
OR4
N
N
TMS
H
Keywords: arynes, indolones, pyrroloindolones, pyrroloindoles,
indoles, annulation reactions
1
2
6
R5
– OR4
R3
F
R3
R2
R1
R2
R1
O
O
Polycyclic heterocycles containing indoles or pyrroles are
interesting structural motifs present in a number of natural
and unnatural products displaying a wide variety of bio-
logical and pharmacological properties.1 Construction of
these polycyclic heterocycles, in particular those contain-
ing an aryl-N-indole or N-pyrrole bond, usually requires
lengthy multiple-step syntheses involving transition-met-
al-catalyzed reactions.2 Hence, the development of new,
mild, and versatile synthetic methods to access and func-
tionalize these polycyclic frameworks continues to attract
considerable attention.
R5
+
OR4
OR4
N
N
3
4
5
R5
Scheme 1
equiv) in acetonitrile at room temperature. Disappointing-
ly, only a trace amount of the desired pyrroloindolone 6a
was isolated alongside unreacted starting material 1a and
the unexpected side product acridone 7, isolated in a poor
yield of 4% (Scheme 2). We hypothesize that the product
pyrroloindolone 6a was reacting faster with benzyne than
the starting material 1a to generate acridone 7. This was
substantiated by reacting 6a (prepared from a literature
procedure)8 with aryne precursor 2b to furnish the unsym-
metrical acridone 8, through a reaction pathway which
presumably involves multiple equivalents of aryne.
Arynes are highly reactive intermediates that have seen a
growing synthetic utility for the functionalization of aro-
matics.3,4 Due to their high electrophilicity, arynes readily
react with a variety of nucleophiles to generate substituted
arenes.5 Recently, Larock et al.6 reported the synthesis of
xanthones, thioxanthones, and acridones via coupling of
arynes with substituted ortho-heteroatom benzoates. With
our ongoing interest in using aryne chemistry7 to generate
heterocycles, we wanted to explore the synthesis of poly-
cyclic indolone and pyrroloindolone heterocycles via the
reaction of indole- and pyrrole-2-carboxylate esters with
arynes. The proposed reaction pathway is depicted in
Scheme 1. The initial step involves deprotonation of the
indole or pyrrole nitrogen 1 with the mildly basic fluoride
anion to generate anion 3. This anion could then add to
benzyne 4, generated via fluoride-induced elimination of
ortho-silyl aryltriflate 2. A subsequent intramolecular nu-
cleophilic displacement of anion intermediate 5 onto the
ester moiety would afford the desired annulated polycy-
clic ring system 6.
The reactivity of pyrroloindolone 6a towards benzyne
prompted us to explore a more hindered substrate, such as
indole-2-carboxylate ester. To this end, indole-2-carboxy-
late ester 9a was reacted with ortho-silyl aryltriflate 2a in
the presence of cesium fluoride in acetonitrile at room
temperature. We were pleased to see that the desired prod-
uct 10a was obtained in a modest yield of 48% (Table 1,
entry 1) along with two side products 11 and 12 in a com-
bined yield of 22% (1:1 ratio), which can be separated by
column chromatography over silica gel. Compound 11
could be envisioned arising via protonation of the aryl an-
ionic intermediate 5 (Scheme 1), and compound 12 could
form through a sequential pathway involving arylation at
C-3 of indole 9a followed by nucleophilic displacement
onto the ester moiety and an ultimate arylation of the in-
dole nitrogen with another equivalent of benzyne. The
possibility of 12 arising via arylation of compound 11 at
C-3 followed by nucleophilic displacement onto the ester
group can be ruled out since treatment of 11 under the
same reaction conditions did not produce 12. Further op-
We first attempted the reaction of pyrrole-2-carboxylate
ester 1a with ortho-silyl aryltriflate 2 (1.1 equiv) under a
heterogeneous condition using cesium fluoride (2.5
SYNLETT 2009, No. 12, pp 2010–2016
x
x
.x
x
.2
0
0
9
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1217535; Art ID: S03809ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Polycyclic Indolone
2011
O
O
TfO
CsF (2.5 equiv)
+
+
CO2Et
N
MeCN, r.t.,
24 h
N
H
N
H
TMS
1a
2a
(1.1 equiv)
6a
trace
7
4%
O
O
TfO
O
O
O
O
CsF (2.5 equiv)
+
N
MeCN, r.t.,
7 h
TMS
N
H
8
6a
2b
(1.1 equiv)
27%
Scheme 2
timization of this reaction is shown in Table 1. Increasing The use of an alternative fluoride source such as KF/18-
the temperature from room temperature to 80 °C afforded crown-69 had a deleterious effect on the yield (entry 6)
a modest improvement in the yield of 10a, from 48–58% with a significant amount of unreacted starting material
(entries 1–4) with a slight decrease in the yield of side recovered. Switching to a homogenous source of fluoride
products 11 and 12 (22–18%). Using the conditions re- such as TBAF10 also reduced the yield, presumably due to
ported by Larock et al.6 (4 equiv CsF in THF at 65 °C) for the presence of residual amount of water. The stronger
a related transformation in the synthesis of acridones, and anhydrous tetrabutylammonium difluorotriphenylsil-
however, did not improve the yield of 10a (entry 5).
icate (TBAT)5d afforded an increased yield of 10a (55%,
entry 8), but required a higher reaction temperature
Table 1 Optimization Results for the Reaction of Indole-2-carboxylate Ester 9a with ortho-Silyl Aryltriflate 2aa
O
TfO
F
conditions
CO Et
+
+
+
CO2Et
2
N
N
N
TMS
H
N
O
Ph
11
Ph
9a
2a
10a
12
Entry
1
Solvent
MeCN
MeCN
MeCN
MeCN
THF
F– Source
CsF
Temp (°C)
Time (h)
Yield 10a (%)b Yield 11 + 12 (%, ratio)b,c
r.t.
40
60
80
65
r.t.
r.t.
65
r.t.
65
0
8
6
48
56
56
58
39
10
44
55
75
68
74
74e
22 (1:1)
20 (1:2)
20 (1:2)
18 (1:1)
23 (1:4)
–
2
CsF
3
CsF
4
4
CsF
2
5
CsFd
4
6
THF
KF/18-c-6
TBAF
TBAT
TMAF
TMAF
TMAF
TMAF
18
1
7
THF
3 (1:2)
–
8
THF
5
9
THF
1
15 (1:15)
15 (1:14)
15 (1:35)
17 (1:24)
10
11
12
THF
1
THF
1
THF
r.t.
1
a Reaction conditions: indole 9a (0.40 mmol), ortho-silyl aryltriflate 2a (0.44 mmol), and fluoride source (1 mmol) in 0.1 M solvent in a sealed
vial.
b Isolated yield.
c Ratio of 11 and 12 was determined by HPLC-MS.
d The amount of 4 equiv of CsF was used.
e Slow addition of 2a.
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

2012
R. D. Giacometti, Y. K. Ramtohul
LETTER
(65 °C) for completion. Although side products 11 and 12 to 0 °C, and finally slow addition of ortho-silyl aryltriflate
were not observed in this reaction, an unidentified side 2a to the reaction mixture did not further improve the
product, which incorporates a molecule of THF solvent, yield of 10a nor minimize the formation of side products
was isolated. Interestingly, rapid generation of benzyne 11 and 12 (entries 10–12). We also examined the effect of
with anhydrous tetramethylammonium fluoride (TMAF) different solvents such as acetonitrile, acetone, dichlo-
in THF at room temperature for 1 hour (entry 9) appeared romethane, and toluene in combination with TMAF, how-
to be the most ideal condition for this transformation, af- ever, none of these solvents show superiority over THF.
fording product 10a in 75% yield along with side products
11 and 12 in a combined low yield of 15% (1:15 ratio). In-
creasing the reaction temperature to 65 °C or decreasing it
Table 2 Reaction of Substituted Indole-2-carboxylate Ester 9 with ortho-Silyl Aryltriflate 2aa,12
R2
O
R2
4
3
TfO
5
TMAF, THF
2
CO2R3
R1
N
+
r.t., 1–2 h
R1
6
1
N
TMS
H
7
10
9
2a
Entry
1
Indole 9
Indole 10
Yield (%)b
O
R1, R2 = H,
R3 = Et
9a
75
N
10a
O
R1 = 6-Br, R2 = H,
2
R3 = Et
73
N
9b
Br
10b
O
R1 = 5-Br, R2 = H,
3
4
5
6
R3 = Et
9c
75
62
71
53
N
Br
10c
O
R1 = 5-F, R2 = H,
R3 = Et
N
F
9d
10d
O
R1 = 5-EtO2C, R2 = H,
R3 = Et
N
EtO2C
9e
10e
O
R1 = 5-MeO, R2 = H,
R3 = Et
N
MeO
9f
10f
Cl
O
R1 = H, R2 = Cl,
7
R3 = Et
9g
90
N
10g
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

LETTER
Synthesis of Polycyclic Indolone
2013
Table 2 Reaction of Substituted Indole-2-carboxylate Ester 9 with ortho-Silyl Aryltriflate 2aa,12 (continued)
R2
O
R2
4
3
TfO
5
TMAF, THF
2
CO2R3
R1
N
+
r.t., 1–2 h
R1
6
1
N
TMS
H
7
10
9
2a
Entry
8
Indole 9
Indole 10
Yield (%)b
Cl
O
R1 = 4,6-di-Me,
R2 = Cl, R3 = Et
9h
84
N
10h
Br
O
O
O
O
R1 = H, R2 = Br,
9
10
11
12
13
14
R3 = Et
9i
89
94
42
94
88
58
N
N
N
N
10i
MeO2C
R1 = H, R2 = MeO2C,
R3 = Me
9j
10j
OHC
R1 = H, R2 = CHO,
R3 = Et
9k
10k
Ph
R1 = H, R2 = Ph,
R3 = Et
9l
10l
BnO
O
R1 = 5-F, R2 = OBn,
R3 = Me
N
F
9m
10m
MeO
O
R1 = H, R2 = OMe,
R3 = Et
N
9n
10n
a Reaction conditions: indole 9 (0.40 mmol), ortho-silyl aryltriflate 2a (0.44 mmol), and TMAF (1 mmol) in 0.1 M THF in a sealed vial at r.t.
b Isolated yield.
With the optimal conditions set (Table 1, entry 9), we be- stituent at 5-position of the indole ring resulted in a lower
gan investigating the substrate scope using a variety of yield (53%, entry 6), presumably due to a decrease basic-
substituted indole-2-carboxylate esters (Table 2). Indole ity of the N–H proton of 9f, which might lower its reactiv-
substrates bearing electron-withdrawing groups afforded ity towards benzyne. Indoles bearing electron-
good yields of the desired indolones (entries 2–5). How- withdrawing and -donating groups at 3-position work
ever, the presence of an electron-donating methoxy sub- even better, generating the corresponding indolones in ex-
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

2014
R. D. Giacometti, Y. K. Ramtohul
LETTER
cellent yields (84–94%), except for entries 11 and 14. The itating nucleophilic displacement. In addition, side prod-
high yields may be attributed to steric effects between the ucts of type 12 were not formed in these cases since 3-
substituent at 3-position and the ester moiety, which could position is blocked.
position the ester group closer to the carbanion, thus facil-
Table 3 Reaction of Indole-2-carboxylate Ester 9j with Substituted ortho-Silyl Aryltriflate 2a
MeO2C
O
CO2Me
6
TMAF, THF
r.t., 1 h
TfO
1
2
5
+
CO2Me
R
N
4
N
TMS
3
H
R
9j
2
13
Entry
ortho-Silyl arytriflate 2
Indolene 13
Yield (%)b
MeO2C
O
R = 4,5-OCH2O
2b
N
1
96
94
89
78
O
O
13b
MeO2C
O
R = 4,5-di-MeO
2c
N
2
3
4
OMe
OMe
13c
MeO2C
O
R = 4,5-(CH2)3-
2d
N
13d
MeO2C
O
R = 4,5-(CH2)4-
2e
N
13e
MeO2C
O
R = 4,5-di-F
2f
N
5
6
79
75
F
F
13f
MeO2C
O
Me
R = 3,6-di-Me
2g
N
Me
13g
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

LETTER
Synthesis of Polycyclic Indolone
2015
Table 3 Reaction of Indole-2-carboxylate Ester 9j with Substituted ortho-Silyl Aryltriflate 2a (continued)
MeO2C
O
CO2Me
6
TMAF, THF
r.t., 1 h
TfO
1
2
5
+
CO2Me
R
N
4
N
TMS
3
H
R
9j
2
13
Entry
7
ortho-Silyl arytriflate 2
Indolene 13
Yield (%)b
MeO2C
O
O
OMe
R = 3-MeO
2h
93
N
13h
MeO2C
R = 4-MeO
2i
8
90 (1:1)c
N
OMe
13i
a Reaction conditions: indole 9j (0.40 mmol), ortho-silyl aryltriflate 2 (0.44 mmol). and TMAF (1 mmol) in 0.1 M THF in a sealed vial at r.t.
b Isolated yield.
c Isolated as a 1:1 mixture of regioisomers.
We next examined the annulation of indole-2,3-dicarbox- conditions were unsuccessful. As shown in Table 4 (en-
ylate ester 9j with a variety of substituted arynes. As tries 2–4), methyl substituents on the pyrrole ring are tol-
shown in Table 3 (entries 1–4), the reaction of indole 9j erated, affording modest yields of the corresponding
and arynes bearing electron-donating or aliphatic groups pyrroloindolones. Furthermore, imidazole-2-carboxylate
afforded excellent yields of the corresponding indolones. esters are also viable substrates for the annulation reac-
In addition, an aryne-containing electron-withdrawing tion, affording the desired imidazoloindolone in modest
fluoro substituent furnished indolone 13e in good yield yields (entries 5 and 6).
(entry 5). Even sterically crowded aryne precursor 2g, re-
sulted similarly in a good yield of indolone 13g (entry 6).
Furthermore, the reaction with unsymmetrical 3-methoxy
benzyne precursor 2h proceeded with high regioselectivi-
In summary, we have developed a mild and general meth-
od for the synthesis of a variety of polycyclic indolone and
pyrroloindolone heterocycles via the reaction of indole
and pyrrole-2-carboxylate esters with arynes in the pres-
ty, affording the corresponding indolone 13h as the sole
ence of TMAF as the fluoride source. This methodology
product. This observed regioselectivity, which is presum-
provides a facile and rapid access to a variety of biologi-
ably due to steric and electronic effects of the methoxy
cally relevant compounds. Further evaluation of these
group, has been observed previously.11 In contrast, the re-
compounds for biological activity using high throughput
screening is under way.
action with 4-methoxy benzyne precursor 2i, furnished a
1:1 mixture of regioisomers in high yield, likely due to the
absence of steric effects between the 4-methoxy group
Acknowledgment
and the indole ring as seen with the 3-methoxy benzyne
precursor 2h.11
The authors gratefully acknowledge Chun Sing Li, Nicolas La-
chance, Jean-Philippe Leclerc, Bruce Mackay, and Erich Grimm
(Merck Frosst) for their helpful discussions. We also thank Merck
Frosst and Brock University (Co-op internship for RDG).
Given the efficiency of TMAF as the fluoride source for
the annulation of indole-2-carboxylate esters with arynes
in THF, we were curious to see how the more difficult
substrate, pyrrole-2-carboxylate ester 1a, would behave
under this condition. Interestingly, when this reaction was References and Notes
performed pyrroloindolone 6a was isolated in 54% yield
(1) (a) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442.
(Table 4, entry 1). This improvement in yield is presum-
ably due to a rapid generation of benzyne and a fast con-
version to product 6a, which minimizes any side reaction
of benzyne with the product. In fact, trace to no acridone
7 was observed in this reaction and the fast reaction times
(1–3 h) as compared to the original CsF conditions
(Scheme 2) also supports this hypothesis. Attempts to fur-
ther optimize this reaction with TMAF under different
(b) Pindur, U.; Lemster, T. Curr. Med. Chem. 2001, 8, 1681.
(c) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev.
2008, 108, 264. (d) Gupton, J. T. Topics in Heterocyclic
Chemistry, Vol. 2; Lee, M., Ed.; Springer: Berlin /
Heidelberg, 2006, 53–92. (e) Galm, U.; Hager, M. H.; Van
Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem. Rev.
2005, 105, 739. (f) Lisowski, V.; Léonce, S.; Kraus-
Berthier, L.; Santos, J. S.-d. . O.; Pierré, A.; Atassi, G.;
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

2016
R. D. Giacometti, Y. K. Ramtohul
LETTER
Caignard, D.-H.; Renard, P.; Rault, S. J. Med. Chem. 2004,
47, 1448.
Table 4 Reaction of Substituted Pyrrole- and Imidazole-2-carboxy-
late Esters 1 with ortho-Silyl Aryltriflate 2aa
(2) (a) Abbiati, G.; Casoni, A.; Canevari, V.; Nava, D.; Rossi, E.
Org. Lett. 2006, 8, 4839. (b) Hwang, S. J.; Cho, S. H.;
Chang, S. J. Am. Chem. Soc. 2008, 130, 16158. (c) Campo,
M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
(d) Ren, h.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45,
3462.
O
R1
R1
TMAF, THF
r.t., 1–3 h
Y3
TfO
4X
2
CO2R2
+
N
5
NH1
TMS
2a
6
1
(3) For reviews on the use of arynes in organic synthesis, see:
(a) Peña, D.; Pérez, D.; Guitián, E. Angew. Chem. Int. Ed.
2006, 45, 3579. (b) Kessar, S. V. Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: New York, 1991, 483–515.
Entry
Compound 1
Product 6
Yield (%)b
O
R1 = H, R2 = Et,
X, Y = C
1a
1
54
(4) (a) For the application of arynes in total synthesis, see:
Allan, K. A.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
17270. (b) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am.
Chem. Soc. 2006, 128, 11752. (c) Sato, Y.; Tamura, T.;
Mori, M. Angew. Chem. Int. Ed. 2004, 43, 2436.
(5) For selected examples of aryne reactions with nucleophiles,
see: (a) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2006, 71,
3198; and references therein. (b) Yoshida, H.; Watanabe,
M.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3292.
(c) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005,
127, 5340. (d) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 1558. (e) Bronner, S. M.;
Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007.
(6) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583.
(7) (a) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029.
(b) Blackburn, T.; Ramtohul, Y. K. Synlett 2008, 1159.
(8) Bailey, A. S.; Scott, P. W.; Vandrevala, M. H. J. Chem. Soc.,
Perkin Trans. 1 1980, 97.
N
6a
6b
6c
6d
O
R1 = 4-Me, R2 = Et,
X, Y = C
1b
2
3
4
5
6
28
37
40
59
44
N
O
O
O
R1 = 5-Me, R2 = Et,
X, Y = C
1c
N
N
N
R1 = 3, 5 di-Me,
R2 = Et, X & Y = C
1d
(9) Yoshihara, T.; Druzhinin, S. I.; Zachariasse, K. A. J. Am.
Chem. Soc. 2004, 126, 8535.
(10) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett.
1983, 1211.
(11) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T.
Angew. Chem. Int. Ed. 2002, 41, 3247. (b) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc.
2006, 128, 11040.
N
R1 = H, R2 = Et,
X = C, Y = N
1e
(12) Representative Experimental Procedure – 5H-
Indolo[1,2-a]indol-5-one (10a)
6e
MeO2C
To a solution of ethyl 1H-indole-2-carboxylate 9a (76 mg,
0.40 mmol) and TMAF (94 mg, 1.0 mmol) in THF (4 mL)
was added 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate (2a, 107 mL, 0.44 mmol) in an oven-dried 8 mL
glass vial. The reaction mixture was stirred at r.t. for 1 h,
monitored by TLC. The solvent was evaporated, the residue
was diluted with H2O (2 mL) and extracted with CH2Cl2
(3 × 2 mL; the organic phase was separated using an organic
phase separator cartridge). The solvent was evaporated and
the product was purified by Combi-flash (ISCO) on silica gel
column (10 g) using a gradient elution of 0–2% EtOAc–
hexanes over 3 min, followed by 2–4% EtOAc–hexanes over
25 min) to afford the title product (66 mg, 75% yield) as a
solid. 1H NMR (500 MHz, acetone-d6): d = 7.80 (d, 1 H,
J = 8.4 Hz), 7.74 (d, 1 H, J = 8.1 Hz), 7.70 (d, 1 H, J = 7.9
Hz), 7.66–7.60 (m, 2 H), 7.50–7.44 (m, 1 H), 7.21 (s, 1 H),
7.19 (d, 1 H, J = 7.3 Hz), 7.18–7.13 (m, 1 H). 13C NMR (126
MHz, acetone-d6): d = 181.5, 146.3, 136.7, 136.5, 135.0,
133.6, 130.0, 128.9, 125.7, 125.4, 124.9, 122.9, 112.8,
112.5, 108.0. HRMS (ESI, MH+): m/z calcd for C15H10NO:
220.0757; found: 220.0755.
O
R1 = 3-MeO2C,
R2 = Me,
X = N, Y = C
1f
N
N
6f
a Reaction conditions: compound 1 (0.40 mmol), ortho-silyl aryltri-
flate 2a (0.44 mmol), and TMAF (1 mmol) in 0.1 M THF in a sealed
vial at r.t.
b Isolated yield.
Synlett 2009, No. 12, 2010–2016 © Thieme Stuttgart · New York

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