Synthesis of novel 1,7-annulated 4,6-dimethoxyindoles

Article abstract of DOI:10.1016/j.tetlet.2010.01.076

A range of new 1,7-annulated indole derivatives has been prepared via a ring-closing metathesis approach starting from N-allyl-7-formyl indoles.

Full text of DOI:10.1016/j.tetlet.2010.01.076

Tetrahedron Letters 51 (2010) 1606–1608
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Tetrahedron Letters
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Synthesis of novel 1,7-annulated 4,6-dimethoxyindoles
Kasey Wood a, David StC Black a, Irishi N. N. Namboothiri b, Naresh Kumar a,
*
a School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
b Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of new 1,7-annulated indole derivatives has been prepared via a ring-closing metathesis
approach starting from N-allyl-7-formyl indoles.
Received 27 November 2009
Revised 6 January 2010
Accepted 22 January 2010
Available online 28 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,7-Annulated indole
4,6-Dimethoxyindole
Ring-closing metathesis
H
Many natural and synthetic products containing functionalized
medium-sized rings display potent biological activities. For
example, the natural alkaloid manzamine A 1 possesses significant
antileukaemic and antimicrobial activities.1 Paullones 2 are cyclin-
dependent kinase inhibitors2 while bisindolylmaleimides 3 have
been developed to treat diabetic complications.3
N
O
COOC2H5
O
R
N
N
N
H
n = 2-3
n = 1-4
5
4
H
Therefore, developing versatile synthetic routes to functional-
ized medium-sized ring 1,7-annulated indoles is of interest. In gen-
eral, routes to 1,7-annulated indoles are restricted by the lack of
N
O
O
N
H
NH
OH
O
NH
N
N
N
R1
R1
OMe
OMe
R1
OMe
N
H
MgBr
n = 1,2
RCM
N
R2
R2
R2
O
N
N
N
MeO
O2N
MeO
MeO
R
2
3
1
n = 1,2
n = 1,2
NO2
NO2
Medium-sized ring 1,7-annulated indoles, however, have not
been extensively studied. Thus, synthetic approaches towards these
structures are currently limited. Al-awar and co-workers reported
the synthesis of 1,7-annulated bisindolyl maleimides 4 and related
indolocarbazoles from the 7-bromoindole via Stille coupling with
tributylvinyltin followed by N-alkylation with 5-bromopentene
and subsequent ring-closing metathesis.2 Conversely, van Wijinga-
arden et al. began with a tetrahydrobenzazepine or a tetrahydro-
quinoline derivative, reacting with ethyl bromopyruvate and then
with magnesium chloride to produce annulated indoles 5.4
9
12 n = 1
13 n = 2
10 n = 1
11 n = 2
CH3NO2
base
R1
OMe
R1
OMe
R1
OMe
N-protect
MeO
R2
R2
R2
N
MeO
N
N
MeO
H
H
CHO
CHO
7
6
8
R
R
1 = Ph, 4-BrC6H4, 4-ClC6H4, 4-MeC6H4
2 = Ph, H
* Corresponding author. Tel.: +61 293854698; fax: +61 293856141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.076

K. Wood et al. / Tetrahedron Letters 51 (2010) 1606–1608
1607
R1
R1
OMe
OMe
R1
OMe
POCl3 / DMF
66-96%
R2
R2
R2
N
N
MeO
MeO
N
MeO
H
H
CHO
MgBr
R1
6a Ph
6b 4-BrC6H4
6c 4-ClC6H4
6d 4-MeC6H4
R2
Ph
H
H
H
7a-d
NO2
R1
OMe
THF
52-99%
10a-d
R2
allyl bromide
KOH / DMSO
89-93%
N
MeO
MgBr
NO2
R1
OMe
R1
OMe
R1
OMe
THF
CH3NO2
NH4OAc
R1
9a Ph
9b 4-BrC6H4
9c 4-ClC6H4
9d 4-MeC6H4
R2
Ph
H
H
H
R2
R2
17-54%
R2
N
N
MeO
MeO
N
MeO
79-98%
CHO
NO2
11a-d
NO2
9a-d
8a-d
Scheme 2.
Scheme 3.
reactivity of indoles at C7. However, functionalization at C7 can be
readily achieved through the use of specifically activated indoles.5
We have used this synthetic strategy to construct 1,7-annulated
five- and six-membered indoles.6 Here, we report a facile route
to functionalized eight- and nine-membered 1,7-annulated indoles
from substituted 4,6-dimethoxyindoles.
R1
OMe
R1
OMe
R2
R2
Grubbs catalyst
40-61%
N
MeO
N
MeO
O2N
NO2
Based upon the reports by Deb et al.7 and Comer et al.,8 it was
envisaged that a ring-closing metathesis approach would allow ac-
cess to the target compounds (Scheme 1). Ring-closing metathesis
is a powerful and versatile approach to construct medium size
rings.9 The Michael addition to nitroalkenes used in this methodol-
ogy is an efficient synthetic step to more complex molecules, and
the nitro group also serves as a masked functionality which could
be further transformed if desired.10
12a-d
10a-d
R1
OMe
R1
OMe
Grubbs catalyst
40-42%
N
MeO
N
MeO
O2N
NO2
Formylation of indoles 6a–d with one equivalent of the Vilsme-
ier reagent was regioselective and afforded the 7-carbaldehydes
7a–d in good yields, without the formation of the 2-isomer. The
11b-d
13b-d
Scheme 4.
Figure 1. ORTEP diagram of compound 13c.13

1608
K. Wood et al. / Tetrahedron Letters 51 (2010) 1606–1608
2. Al-awar, R.; Ray, J.; Hecker, K.; Huang, J.; Waid, P.; Shih, C.; Brooks, H.; Spencer,
C.; Watkins, S.; Patel, B.; Stamm, N.; Ogg, C.; Schultz, R.; Considine, E.; Faul, M.;
Sullivan, K.; Kolis, S.; Grutsch, J.; Joesph, S. Bioorg. Med. Chem. Lett. 2004, 14,
3217–3220.
N-allyl derivatives 8a–d were furnished in high yields through
treatment with potassium hydroxide in dimethylsulfoxide fol-
lowed by the addition of allyl bromide (Scheme 2).
3. Faul, M.; Winneroski, L.; Krumrich, C. J. Org. Chem. 1998, 63, 6053–6058.
4. van Wijingaarden, I.; Hamminga, D.; van Hes, R.; Standaar, P.; Tipker, J.; Tulp,
M.; Mol, F.; Olivier, B.; de Jonge, A. J. Med. Chem. 1993, 36, 3693–3699.
5. Black, D.; Bowyer, M.; Catalano, M.; Ivory, A.; Keller, P.; Kumar, N.; Nugent, S.
Tetrahedron 1994, 50, 10497–10508.
6. (a) Jumina; Keller, P.; Kumar, N.; Black, D. Tetrahedron 2008, 64, 11603–11610;
(b) Jumina; Kumar, N.; Black, D. Tetrahedron 2009, 65, 2591–2598; (c)
Wahyuningsih, T.; Pchalek, K.; Kumar, N.; Black, D. Tetrahedron 2006, 62,
6343–6348; (d) Black, D.; Kumar, N.; Mitchell, P. J. Org. Chem. 2002, 67, 2462–
2473.
Indoles 8a–d then underwent a Henry reaction with refluxing
nitromethane in isopropanol for 3 h. The nitroalkenes 9a–d were
obtained in high yields upon cooling (Scheme 2).
The next step was to introducethe second alkene unit in the prep-
aration for the ring-closing metathesis. Different alkyl groups could
be used at this point to provide access to rings of different sizes.
Initially nitroalkenes 9a–d were stirred under inert conditions
in dry THF with allylmagnesium bromide for 2–3 h to afford the
Michael adducts 10a–d in good yields as low melting solids
(Scheme 3).11 An extension of the alkenyl chain was attempted
by the reaction of indoles 9a–d with butenylmagnesium bromide.
However, these reactions were noticeably slower and required
approximately three days and a larger excess of the Grignard re-
agent to reach completion. Compounds 11a–d were obtained as
oils in significantly lower yields of 17–54% (Scheme 3).
The ring-closing metathesis reactions were achieved by reflux-
ing the Michael adducts 10a–d in dry, degassed toluene in the
presence of 5–10 mol % of Grubbs’ 2nd generation catalyst. The
reactions reached completion within 4 h, and upon work up pro-
duced the indole-fused eight-membered ring compounds 12a–d
in moderate yields (Scheme 4).12 The ring-closing metathesis of in-
doles 11b–d was also successful under similar conditions, forming
the corresponding indole-fused nine-membered rings 13b–d in
40–42% yield (Scheme 4).
The structures of all the 1,7-annulated indoles were established
on the basis of 1D and 2D NMR spectroscopy data. The 1,7-annu-
lated structure of compound 13c was confirmed by X-ray crystal-
lography (Fig. 1).
In summary, the unique reactivity of 4,6-dimethoxyindoles has
been utilized to produce a range of novel eight- and nine-mem-
bered 1,7-annulated indoles. This methodology is an effective
and flexible route to 1,7-annulated indoles and enables a system-
atic evaluation of their biological properties.
7. Deb, I.; John, S.; Namboothiri, I. Tetrahedron 2007, 63, 11991–11997.
8. Comer, E.; Rohan, E.; Deng, L.; Porco, J. Org. Lett. 2007, 9, 2123–2126.
9. Deiters, A.; Martin, S. Chem. Rev. 2004, 2199–2238.
10. Berner, O.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877–1894.
11. Representative procedure for compound 10b: Indole 9b (0.30 g, 0.68 mmol)
was dissolved in dry THF (15 ml), cooled in a salt/ice bath and placed under an
argon atmosphere. Allylmagnesium bromide (3 ml, 1 M) in dry THF (5 ml) was
added dropwise. The reaction mixture was stirred at room temperature for 3 h
before being quenched with saturated NH4Cl solution (10 ml) and then with
water (50 ml). The solution was extracted with CH2Cl2 (3 Â 10 ml) and the
combined organic layers were dried over Na2SO4 and reduced in vacuo to give
10b as a brown solid (0.33 g, 99%). Mp 72–74 °C. 1H NMR (300 MHz, CDCl3): d
2.64 (t, J = 7.3 Hz, 2H, CH2), 3.78 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.18 (m, 1H,
CH), 5.05 (m, 8H, 4 Â CH2), 5.66 (m, 1H, CH), 6.13 (m, 1H, CH), 6.33 (s, 1H, H7),
6.82 (s, 1H, H2), 7.38 (d, J = 9.0 Hz, 2H, Haryl), 7.45 (d, J = 9.0 Hz, 2H, Haryl). 13C
NMR (75 MHz, CDCl3): d 30.9, 35.2, 36.6, 51.9, 54.9, 56.2, 78.6, 89.3, 103.6,
112.5, 115.9, 116.6, 117.3, 119.5, 128.9, 130.3, 131.2, 134.0, 134.8, 135.8, 136.3,
153.6, 155.7. IR (KBr): mmax 3415, 3075, 2936, 2839, 1609, 1585, 1548, 1463,
1403, 1375, 1336, 1204, 1127, 1070, 1047, 1008, 918, 832, 797 cmÀ1. UV–vis
(MeOH): kmax 203 nm (e
39,100 cmÀ1 MÀ1), 226 (28,100), 295 (13,100). HRMS
(+ESI): C24H25BrN2O4 [M+Na]+ requires 507.0890, found 507.0892.
12. Representative procedure for compound 12b: Indole 10b (0.22 g, 0.45 mmol)
was dissolved in dry, degassed toluene (30 ml) and placed under an argon
atmosphere. Grubbs’ 2nd generation catalyst (5–10 mol %) was added and the
reaction mixture was refluxed for 4.5 h. The solution was reduced in vacuo and
the crude product was column chromatographed using 50:50 CH2Cl2/hexane to
give 12b as an off-white solid (83 mg, 40%). Mp 164–166 °C. 1H NMR
(300 MHz, CDCl3): d 2.62 (m, 1H, CH2), 2.86 (m, 1H, CH2), 3.78 (s, 3H, OCH3),
3.87 (s, 3H, OCH3), 4.33 (dd, J = 8.0 Hz, J = 15.2 Hz, 1H, CH), 4.84 (dd, J = 3.1 Hz,
J = 12.9 Hz, 1H, CH), 5.08 (m, 2H, CH2), 5.47 (dd, J = 8.0 Hz, J = 15.2 Hz, 1H, CH),
5.74 (m, 2H, CH2), 6.27 (s, 1H, H5), 6.83 (s, 1H, H2), 7.39 (d, J = 8.7 Hz, 2H, Haryl),
7.45 (d, J = 8.7 Hz, 2H, Haryl). 13C NMR (75 MHz, CDCl3): d 34.2, 34.7, 46.1, 54.1,
55.4, 79.7, 88.5, 103.5, 111.6, 115.0, 118.6, 122.4, 127.8, 128.4, 129.5, 130.0,
130.1, 132.2, 133.7, 136.9, 152.9, 153.4. IR (KBr):
mmax 3547, 3474, 3414, 2929,
2834, 1613, 1587, 1547, 1510, 1463, 1375, 1337, 1201, 1178, 1125, 1070, 1051,
1007, 795 cmÀ1 38,900 cmÀ1 MÀ1), 227
. UV–vis (MeOH): kmax 203 nm (e
Acknowledgements
(24,100), 298 (13,200). HRMS (+ESI): C22H21BrN2O4 [M+Na]+ requires
479.0577, found 479.0581.
13. Crystallographic data for the structure in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no.
CCDC 755940 (13c). X-ray crystal structures were obtained by Mohan
Bhadbhade, Crystallography Laboratory, UNSW Analytical Centre, Sydney,
Australia.
We thank the University of New South Wales and the Australian
Research Council for their financial support.
References and notes
1. Pandit, U.; Borer, B.; Bieraugel, H.; Deerenberg, S. Pure Appl. Chem. 1994, 66,
2131–2134.