Rapid synthesis of diversely functionalized 3,4,7-trisubstituted indoles

Article abstract of DOI:10.1016/j.tetlet.2011.04.086

Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two strategies were employed, highlighted by a Bartoli indole synthesis or a sequential and regioselective use of chlorosulfonyl isocyanate to install both the 3-cyano and 7-carboxamido groups. These routes are scalable and afford diversely functionalized indoles for further elaboration.

Full text of DOI:10.1016/j.tetlet.2011.04.086

Tetrahedron Letters 52 (2011) 3376–3378
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid synthesis of diversely functionalized 3,4,7-trisubstituted indoles
⇑
Seth W. Grant , Timothy F. Gallagher, Mark A. Bobko, Celine Duquenne, Jeffrey M. Axten
Cancer Research, GlaxoSmithKline, 1250 South Collegeville Rd., Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-
cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two strate-
gieswereemployed,highlightedbyaBartoliindolesynthesisorasequentialandregioselectiveuseofchloro-
sulfonylisocyanatetoinstallboththe3-cyanoand7-carboxamidogroups.Theseroutesarescalableandafford
diversely functionalized indoles for further elaboration.
Received 25 March 2011
Revised 20 April 2011
Accepted 21 April 2011
Available online 28 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Indoles are commonly found in natural products and medici-
nally active compounds, and the synthesis and functionalization
of the indole core is of great interest to the synthetic chemistry
community. During the course of a medicinal chemistry effort we
prepared indoles of general structure 1 (Fig. 1), in which R1 was
hydrogen or cyano, and R2 was a point of broad diversity. This com-
munication describes the chemistry that we developed for the syn-
thesis of these compounds. Noteworthy is the rapid and selective
functionalization of 4-alkoxyindoles using chlorosulfonyl
isocyanate.
olate reactions involved toxic reagents and harsh conditions, and
the work-up of the cyanation reaction was very tedious even on
modest scales. Consequently, we sought an improved synthesis
of a key intermediate similar to 4 that could be used to explore
substitution of the indole ring at the 3-, 4-, and 7-positions.
A second generation synthesis was developed to circumvent
some of these shortcomings (Scheme 2). Exchanging the methyl
ether in 2 for a benzyl ether prior to indole formation averted
the later use of sodium ethanethiolate. The Bartoli reaction was re-
tained to generate indole 8, but the cyanation step was replaced
with a carbonylation reaction.3 This four-step sequence (22% yield)
was more scalable than the first generation route, providing >10 g
of ester 9, a useful intermediate for further elaboration of the 3-, 4-,
and 7-positions.
During the course of our work, we also required access to the
3-cyanoindole scaffold (1, R1 = CN). While many methods for the
synthesis of 3-cyanoindoles rely on prior aldehyde formation by
Vilsmeier formylation, direct cyanation protocols also exist.4 We
found that the desired 3-cyano group could be conveniently
installed in one step from indole 9 using chlorosulfonyl isocyanate5
Our initial route to compound 1 (R1 = H) is shown in Scheme 1.
The indole ring was formed by reaction of nitrobenzene 2 with
vinylmagnesium bromide according to the Bartoli method.1 Cyana-
tion of 3 using copper(I) cyanide followed by demethylation with
sodium ethanethiolate afforded the 4-hydroxyindole 4. The R2
group was then installed either by a Mitsunobu reaction or by
base-promoted alkylation. Hydration of nitrile 5 under Katritzky
conditions2 cleanly afforded indole-7-carboxamide 6.
Although this synthesis was relatively short, it was not very effi-
cient (3 steps, 18% yield to the key intermediate 4) and several of
the steps were problematic. The Bartoli reaction was low yielding
and difficult to purify, the copper(I) cyanide and sodium ethanethi-
O
O
OH
CN
a
b,c
R2O
R1
N
H
N
H
NO2
Br
Br
2
3
4
N
H
R2O
R2O
H2N
O
f
d or e
1
N
N
H
H
CN
5
H2N
O
Figure 1. General structure of indole-7-carboxamides of interest.
6
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, <5 °C, 41%;
(b) CuCN, DMF, 160 °C, 57%; (c) NaSEt, DMF, 120 °C, 76%; (d) R2OH, polymer-PPh3,
DIAD, THF; (e) R2X, Na2CO3, DMF; (f) H2O2, K2CO3, DMSO.
⇑
Corresponding author.
E-mail address: seth.w.grant@gsk.com (S.W. Grant).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.086

S. W. Grant et al. / Tetrahedron Letters 52 (2011) 3376–3378
3377
the desired indole-7-carboxamide. Consequently, we resubjected
3-cyano-4-benzyloxyindole (12) to CSI, allowing the reaction to
warm to room temperature, which resulted in a second addition
of CSI. This time the intermediate N-chlorosulfonylcarboxamide
(14) was hydrolyzed with dilute acid, which led directly to the
indole-7-carboxamide 15.14 Thus, CSI was used to sequentially
and regioselectively install first a 3-cyano group followed by a
7-carboxamido group, as shown in Scheme 4. Interestingly, while
many examples exist of the addition of strong carbon electrophiles
to C-7 of an indole (e.g., Vilsmeier reactions,15 Friedel–Crafts reac-
tions,15c,16 and addition of oxalyl chloride15a,15c,17), this is the first
reported example of the use of chlorosulfonyl isocyanate to func-
tionalize C-7 of an indole.
Deprotection of the benzyl group of 15 provided intermediate
16 in only three steps from commercially available starting mate-
rials18 with an overall yield of 66%. By comparison, the synthesis of
compound 16 by the route described in Schemes 2 and 3 would
have required eight steps. Importantly, this short and efficient syn-
thesis was scalable, and was used for the synthesis of >50 g of 16, a
versatile intermediate for the preparation of diverse indoles.
In conclusion, we have developed synthetic routes for the prep-
aration of 4-alkoxyindole-7-carboxamides bearing either a hydro-
gen or cyano group at C-3. Of particular note, we developed an
operationally simple, three-step synthesis of 3-cyano-4-hydrox-
yindole-7-carboxamide (16) highlighted by the use of chlorosulfo-
nyl isocyanate to sequentially and regioselectively install both the
cyano and carboxamide groups. Compounds such as 4, 9, 13, and
16 posses multiple orthogonal functionalities amenable to exten-
sive elaboration and diversification.
O
Ph
O
a,b
c
NO2
Ph
NO2
O
Br
Br
7
2
Ph
O
d
N
H
N
H
Br
EtO
O
8
9
Scheme 2. Reagents and conditions: (a) BBr3, DCM, À78 °C to rt, 83%; (b) BnBr,
K2CO3, acetone, 91%; (c) vinylmagnesium bromide, THF, <5 °C, 37%;
(d) Cl2Pd(dppf)ÁCH2Cl2, dppf, Et3N, EtOH, 35 bar CO, 130 °C, 78%.
Ph
O
Ph
O
CN
O
CH3CN, 0 °C
then Et3N
0 °C to rt
Cl S NCO
O
N
H
N
H
EtO
O
EtO
O
9
10
Scheme 3. Direct cyanation of indole 9 with CSI.
(CSI) at 0 °C, according to the method developed by Vorbrüggen6
(Scheme 3), in 80% yield.7
While tri-substituted indole 10 was generated through the
routes shown in Schemes 2 and 3 (5 steps, 17% yield), we surmised
that targeting 3-substituted indoles would provide synthetic
opportunities to circumvent the Bartoli indole synthesis and/or
decrease the step count. We hypothesized that a mono-substituted
4-alkoxyindole could be functionalized sequentially at the 3- and
7-positions. Accordingly, direct cyanation of commercially avail-
able 4-benzyloxyindole with CSI led to 3-cyano-4-benzyloxyindole
in good yield (12, Scheme 4) when the intermediate N-chlorosulfo-
nylcarboxamide was quenched with DMF according to the Lohaus
method.8 In analogy to our 2nd generation synthesis, iodination of
the 7-position,9 followed by carbonylation10 with Mo(CO)6 affor-
ded ester 10. This sequence provided much more efficient access
to key intermediate 10 (3 steps, 39% yield).
References and notes
1. (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129–2132; (b) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163–178.
2. Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 949–950.
3. For an example of carbonylation of a similar indole see: Smith, A. B., III; Kürti,
L.; Davulcu, A. H. Org. Lett. 2006, 8, 2167–2170.
4. For example: (a) Tamura, Y.; Kawasaki, T.; Adachi, M.; Tanio, M.; Kita, Y.
Tetrahedron Lett. 1977, 18, 4417–4420; (b) Reddy, B. V. S.; Begum, Z.; Reddy, Y.
J.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 3334–3336; (c) Ushijima, S.; Togo, H.
Synlett 2010, 1067–1070; (d) Smaliy, R. V.; Chaikovskaya, A. A.; Pinchuk, A. M.;
Tolmachev, A. A. Synthesis 2002, 2416–2420; (e) Dohi, T.; Morimoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org.
Chem. 2007, 72, 109–116.
5. Miller, M. J.; Ghosh, M.; Guzzo, P. R.; Vogt, P. F.; Hu, J.; Filzen, G. F.; Geyer, A. G.
Chlorosulfonyl Isocyanate. In Encyclopedia of Reagents for Organic Synthesis
(Online); Crich, D., Charette, A. B., Fuchs, P. L., Molander, G., Paquette, L. A., Eds.;
Wiley & Sons: New York, 2010.
6. (a) Vorbrüggen, H. Tetrahedron Lett. 1968, 9, 1631–1634; (b) Vorbrüggen, H.;
Krolikiewicz, K. Tetrahedron 1994, 50, 6549–6558.
In addition, we sought a facile route to the indole-7-carboxam-
ide, and considered a direct aminocarbonylation11 at C-7 of 12. We
recognized that CSI may be used for such a functionalization,5,12
and we hypothesized13 that we could employ it to directly access
7. The yield of 10 is based on the NMR purity of a crude weight.
Ph
O
Ph
O
I
CN
Ph
O
Ph
O
CN
CN
a
b
c
N
N
N
H
N
H
H
H
O
EtO
11
12
13
10
d
Ph
O
CN
OH
Ph
O
CN
CN
f
e
N
O
S
N
N
H
H
H
Cl
N
O
H2N
O
H2N
O
O
H
14
15
16
Scheme 4. Reagents and conditions: (a) CSI, CH3CN, À45 °C, then DMF, À45 °C to rt, 72%; (b) ICl, AcOH, 83%; (c) Mo(CO)6, 10% Pd/C, DMAP, DIPEA, EtOH, dioxane, 120 °C, 66%;
(d) CSI, CH3CN, 0 °C to rt; (e) 1 M HCl, 96%; (f) H2, 10% Pd/C, DMF, 96%.

3378
S. W. Grant et al. / Tetrahedron Letters 52 (2011) 3376–3378
8. Lohaus, G. Chem. Ber. 1967, 100, 2719–2729.
9. Al-Said, N. H.; Shawakfeh, K. Q.; Abdullah, W. N. Molecules 2005, 10, 1446–
1457.
washed with water, satd NaHCO3, and brine, then dried (MgSO4), filtered,
and evaporated. The crude material was purified by dissolving in chloroform
and passing through silica gel (10 cm diam. Â 10 cm thick), eluting with 0–3%
ethyl acetate in chloroform to give 4-benzyloxy-3-cyano-1H-indole (12, 8.03 g,
32.3 mmol, 72%) as an off-white solid. LC–MS (ES) m/z = 271 [M+Na]+. 1H NMR
(400 MHz, CDCl3) d 5.31 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H),
7.22 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.58–7.67
(m, 3H), 8.93 (br s, 1H). Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28.
Found: C, 76.98; H, 4.80; N, 11.16. A solution of CSI (1.5 mL, 17.3 mmol) in
acetonitrile (20 mL) was added dropwise via addition funnel to a mechanically
stirred solution of 12 (3.79 g, 15.3 mmol) in acetonitrile (100 mL) at 0 °C under
nitrogen, and the mixture was allowed to stir and warm to room temperature
over 7 h, after which a precipitate had formed. The mixture was then quenched
with 1 M HCl (60 mL, initial dissolution of reaction mixture followed by rapid
precipitation) and stirred at room temperature overnight. Water (ca. 100 mL)
was then added and the solid was collected by vacuum filtration, washed with
ether, and dried to give 4-benzyloxy-3-cyano-1H-indole-7-carboxamide (15,
4.27 g, 14.7 mmol, 96%) as a white solid. LC–MS (ES) m/z = 292 [M+H]+. 1H NMR
(400 MHz, DMSO-d6) d 5.39 (s, 2H), 6.90 (d, J = 8.3 Hz, 1H), 7.29–7.45 (m, 4H),
7.60 (d, J = 7.1 Hz, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.98–8.11 (br s, 1H), 8.04 (d,
J = 3.0 Hz, 1H), 12.02 (s, 1H). Anal. Calcd for C17H13N3O2Á0.15H2O: C, 69.45; H,
4.56; N, 14.29. Found: C, 69.40; H, 4.40; N, 14.31. A suspension of 15 (4.27 g,
14.7 mmol) and 10 wt % Pd/C (428 mg) in DMF (100 mL) was stirred under an
atmosphere of hydrogen (balloon) for 7 h, then degassed and filtered through a
pad of Celite. The filtrate was concentrated in vacuo then triturated with ether.
The solid was collected by vacuum filtration to give 3-cyano-4-hydroxy-1H-
indole-7-carboxamide (16, 3.00 g, 6 wt % DMF present by 1H NMR, 14.0 mmol,
96%) as an off-white solid. LC–MS (ES) m/z = 202 [M+H]+. 1H NMR (400 MHz,
DMSO-d6) d 6.57 (d, J = 8.3 Hz, 1H), 7.25 (br s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.91
(br s, 1H), 7.95 (d, J = 3.0 Hz, 1H), 10.65 (s, 1H), 11.88 (br s, 1H). Anal. Calcd for
10. Georgsson, J.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2003, 5, 350–352.
11. We found only one example in which a carboxamide was directly introduced at
C-7 of an indole, accomplished by directed ortho metallation. See: Hartung, C.
G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899–1902.
12. (a) Graf, R. Carboxylic amides. German Patent DE 1010958, June 27, 1957.;
(b) Mehta, G. Synthesis 1978, 374–376.
13. In some of our previous cyanations with CSI we had noticed two minor
byproducts, one corresponding to the indole-3-carboxamide, and another
which appeared to result from a second addition of CSI to the indole.
14. The identity of 15 was confirmed by NMR.
15. For example: (a) Brown, V. H.; Skinner, W. A.; DeGraw, J. I. J. Heterocycl. Chem.
1969, 6, 539–543; (b) Black, D. S. C.; Kumar, N.; Wong, L. C. H. Synthesis 1986,
474–476; (c) Jones, A. W.; Wahyuningsih, T. D.; Pchalek, K.; Kumar, N.; Black,
D. S. C. Tetrahedron 2005, 61, 10490–10500.
16. For example: (a) Nakatsuka, S.; Masuda, T.; Asano, O.; Teramae, T.; Goto, T.
Tetrahedron Lett. 1986, 27, 4327–4330; (b) Laufer, S.; Lehmann, F. Bioorg. Med.
Chem. Lett. 2009, 19, 1461–1464; (c) Nakkady, S. S.; Fathy, M. M.; Hishmat, O.
H.; Mahmond, S. S.; Ebeid, M. Y. Boll. Chim. Farm. 2000, 139, 59–66.
17. For example: (a) Black, D. S. C.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.;
Keller, P. A.; Kumar, N.; Nugent, S. J. Tetrahedron 1994, 50, 10497–10508; (b)
Clayton, K. A.; Black, D. S. C.; Harper, J. B. Tetrahedron 2008, 64, 3183–3189.
18. Experimental procedure for the synthesis of 16: Chlorosulfonyl isocyanate
(4.08 mL, 47.0 mmol) in acetonitrile (10 mL) was added dropwise over
15 min to an acetontrile/CO2-cooled (ca. À45 °C), stirred solution of 4-
benzyloxy-1H-indole (10.0 g, 44.8 mmol) in acetonitrile (100 mL). Over the
course of the addition a fine precipitate formed. The mixture was stirred at ca.
À45 °C under nitrogen for 10 min. DMF (100 mL) was then slowly added, and
the mixture was removed from the bath and allowed to warm to room
temperature. It was then poured into a mixture of ice and water (500 mL), and
extracted with ethyl acetate (3 Â 250 mL). The combined organics were
C
10H7N3O2Á0.1H2O: C, 59.17; H, 3.58; N, 20.70. Found: C, 58.97; H, 3.37; N,
20.50.