Synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles en route to murrapanine analogue

Article abstract of DOI:10.1016/j.tetlet.2011.10.003

A three-step procedure has been developed for the synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles. TBAF was proved to be an effective reagent for dehydrobromination and carbomethoxy deprotection in one step to give 3-[2-(1,3-butadienyl)]-1H-indoles from the corresponding bromo-derivatives. Suitably substituted indolyl-1,3-butadiene has been successfully applied to prepare murrapanine analogue via Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2011.10.003

Tetrahedron Letters 52 (2011) 6635–6638
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles en route to
murrapanine analogue
⇑
Amrita Chakraborty, Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-step procedure has been developed for the synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles. TBAF
was proved to be an effective reagent for dehydrobromination and carbomethoxy deprotection in one
step to give 3-[2-(1,3-butadienyl)]-1H-indoles from the corresponding bromo-derivatives. Suitably
substituted indolyl-1,3-butadiene has been successfully applied to prepare murrapanine analogue via
Diels–Alder reaction.
Received 2 September 2011
Revised 29 September 2011
Accepted 2 October 2011
Available online 8 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Dehydrobromination
3-[2-(1,3-Butadienyl)]-1H-indoles
Diels–Alder reaction
Murrapanine analogue
The indole nucleus is a prominent structural motif found in
numerous biologically active natural products1 and synthetic com-
pounds with vital medicinal value. Therefore, assembly of func-
tionalized indoles has captured the attention of synthetic
chemists for decades and continues to be an active research
area.1a,2 In continuation of our research effort directed towards dis-
covering new indole scaffolds for medicinal application and indole
alkaloids synthesis, we sought to prepare 3-[2-(1,3-butadienyl)]-
1H-indoles in which the 2-position of the indole ring is suitably
substituted.
(2.5 mol %) in Et3N and afforded o-alkynylanilines (3a–3h) in mod-
erate to excellent yields. Under the same condition, the acetylenes
2i and 2j did not undergo Sonogashira coupling reactions. Hence, 3i
and 3j were synthesized using modified Sonogashira conditions in
moderate to fair yields.5 For the preparation of 3i, bearing a CO2Et
group on the alkynyl moiety, the Sonogashira reaction was carried
out using Na2CO3 as a base replacing triethyl amine under heating
conditions in dioxane–water mixture. Compound 3j was prepared
by the coupling between 2-bromothiophene and 2-ethynylaniline
followed by carbomethoxy protection of aromatic amine.
Upon examination of the literature, we were surprised that
there is no report on the synthesis of 3-[2-(1,3-butadienyl)]-1H
-indoles though a few reports are available on the synthesis of
3-[1-(1,3-butadienyl)]-1H-indoles.3 The literature also revealed
that alkaloids having a (3-indolyl)-planar system as a structural
feature shows important biological activities.4 The indole-substi-
tuted dienes could serve as a precursor for the synthesis of these
alkaloids and their analogues. Prompted by these studies, we wish
to disclose a methodology for the synthesis of such dienes using
dehydrobromination and carbomethoxy deprotection in one step
mediated by TBAF (Scheme 1) and application of such dienes to-
wards the synthesis of Diels–Alder adducts including the synthesis
of murrapanine analogue.
R1
R1
(2)
I
Pd(PPh3)2Cl2
NHCO2Me
1a,1b
R = H, Cl
R
R
NHCO2Me
CuI, Et3N
3a-h
Br
Br
THF
O
Pd(MeCN)2Cl2
Our synthesis commenced with the formation of o-alkynylani-
lines (3a–3j) (Table 1). Thus, a series of terminal acetylenes
(2a–2h) were reacted with methyl carbamate protected iodoani-
lines (1a and 1b) in the presence of CuI (5 mol %) and Pd(PPh3)2Cl2
TBAF (7equiv)
Br
R1
R1
THF
R
N
N
H
R
CO2Me
4a-g
reflux
5a-g
⇑
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocss5@iacs.res.in (S. Sinha).
Scheme 1. Synthesis of butadiene-substituted indoles.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.003

6636
A. Chakraborty, S. Sinha / Tetrahedron Letters 52 (2011) 6635–6638
Table 1
indoles in very poor yields (10%). However, refluxing the reaction
Synthesis of acetylenes (3a–3j)
mixture provided the disubstituted indoles 4d and 4e in 45% and
46% yields, respectively. The yields did not improve even after pro-
longed heating.
Having secured access to a range of 2,3-disubstituted indoles,
we began our studies by evaluating the effect of different bases
on dehydrobromination and carbomethoxy deprotection in a sin-
gle step using 4a as a standard substrate (Table 3).
Entry
R
R1
Time (h)
Productb
Yielda (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
CI
H
H
H
C6H5
4-CH3C6H4
n-C3H7
C6H11
CH2OH
CH2CH2OH
C6H5
2-NO2C6H4
CO2Et
12
12
8
10
7
8
12
5
3a
3b
3c
3d
3e
3f
3g
3h
3ic
3jd
84
80
76
83
69
69
86
55
35
75
To optimize the reaction condition, when compound 4a was
treated with methanolic KOH,7 a mixture of undetermined prod-
ucts was obtained. Thus we decided to carry out the dehydrobro-
mination and carbomethoxy deprotection in stepwise fashion.
Accordingly, when different bases like Et3N, DIPEA and DBU were
tested to carry out the dehydrobromination reaction, no desired
product was obtained. In case of NaH, a trace amount of dehydro-
halogenated product 6a was obtained. Further addition of NaH and
increase of reaction temperature was ineffective to improve the
yield of product 6a. In order to increase the yield, we decided to en-
hance the acidity of alpha hydrogen adjacent to the 3-position of
the indole ring, thus facilitating the dehydrobromination reaction.
We envisioned that replacement of methylcarbamate with more
electron withdrawing group like tosyl might enhance the acidity
of that alpha hydrogen. Primarily, we examined K2CO3, TMSI and
LiOH to deprotect the carbomethoxy group, but only in the case
of LiOH, we obtained a trace amount of deprotected product. Inter-
estingly, when the reaction mixture was heated to reflux in the
presence of TBAF8 (5 equiv), we observed a mixture of products
containing 5a and 6a, where diene 5a was the major product. We
realized that under this reaction condition, dehydrobromination
is more facile than carbomethoxy deprotection. Accordingly, we
became intrigued by the possibility that increasing the amount of
TBAF might offer a straightforward approach to the synthesis of
3-[2-(1,3-butadienyl)]-1H-indole derivatives in one pot. To our de-
light, using TBAF (7 equiv) ultimately provided the desired indolyl
butadiene 5a in 71% yield.
0.5
14
10
2-Thiophene
a
Isolated yield.
b
Reactions were carried out at room temperature using 1.2 equiv of alkyne.
Refs. 5a,b were followed.
c,d
We next turned our attention to the synthesis of 2,3
-disubstituted indoles (4a–4j), in which the 3-position of the in-
dole ring is substituted with homoallyl bromide. Surprisingly, only
one report6 was available on the synthesis of such indole deriva-
tives and no spectral data were reported regarding the stereo-
chemistry of the allyl moieties. Therefore, we tried this reaction
following the report by Utimoto et al.6 for the installation of homo-
allyl bromide in the 3-position of indoles by way of palladium
catalysis. Accordingly, 3a was reacted with trans 1,4-dibromo-
but-2-ene (3.5 equiv) to get the desired product 4a in the presence
of Pd(MeCN)2Cl2 (5 mol %), and propylene oxide was used as a pro-
ton scavenger. Applying this method, several other indole deriva-
tives (4b–4g) were prepared and the results are summarized in
Table 2. Unfortunately, alkynylanilines 3h and 3i did not undergo
the reaction and the starting materials were recovered. In case of
3j, a trace amount of carbomethoxy-protected 2-thiophene indole
was obtained. The spectral data revealed that there is no incorpo-
ration of homoallyl bromide at the 3-position of the indole ring.
Alkynylanilines (3a–3c), 3g and 3l reacted smoothly with trans
1,4-dibromo-2-butene at room temperature and afforded the cor-
responding 2,3-disubstituted indoles in moderate to good yields.
Compound 3l was synthesized by routine functional group trans-
formations from compound 3f. On the other hand, the reaction
with alkynylanilines 3d and 3k (THP protected form of 3e) was
very sluggish at room temperature and afforded 2,3-disubstituted
With the optimized condition, we next evaluated the substrate
scope of this reaction. Several 2,3-disubstituted indoles (4a–4g)
were successfully reacted with TBAF to give the corresponding
indolyl butadiene derivatives (5a–5e) and 5g in good to excellent
yields (Table 4). This reaction is tolerant to a variety of substituents
on the indole ring. It is noteworthy that compound 4f underwent
Table 2
Table 3
Synthesis of 2,3-disubstituted indoles
Optimization of the reaction conditions
R1
Br
Br
Br
R1
CO2Me
4a-h
Br
Pd(MeCN)2Cl2
R
NHCO2Me
R = H, Cl
3a-h
N
R
N
R
N
O
THF
,
CO2Me
R = H; 5a or CO2Me; 6a
4a
Entry Substrate
R1
Temp
(°C)
Time
(h)
Product
(4)
Yielda
(%)
Base
Equiv
Solvent
Temp (°C)
Time (h)
Yielda,b (%)
5a 6a
(3)
1
2
3
3a
3b
3c
C6H5
4-CH3C6H4
n-C3H7
C6H11
C6H5
2-NO2C6H4
CO2Et
2-Thiophene
CH2OTHP
25
25
25
66
25
66
66
66
66
5
5
5
2.5
5
4a
4b
4c
4d
4g
4h
4i
4j
4e
4f
51
51
56
45
71
0
0
0
46
50
KOH
Et3N
DIPEA
DPU
NaH
NaH
NaH
TBAF
TBAF
1.5
1.5
1.5
1.5
1.5
3
3
5
7
MeOH
THF
THF
DMF
THF
THF
THF
THF
THF
25
66
66
60
25
25
66
66
66
1
0
0
10
10
1.5
8
8
5
nrc
nrc
0
Trace
Trace
Trace
43
4
5
6
7
3d
3gb
3hc
3ic
3j
0
5
12
12
2.5
5
8
9
10
3k
3l
2.5
2.5
12
0
CH2CH2NHBoc 25
71
a
b
c
a
b
c
Isolated yield.
R = Cl.
Starting material was recovered.
Isolated yield.
All the reactions were carried out in 1 mmol scale.
No conversion was observed.

A. Chakraborty, S. Sinha / Tetrahedron Letters 52 (2011) 6635–6638
6637
Table 4
O
O
Synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles
Br
R1
O
O
+
R1
CO2Me
Ph
R1
+
N
H
Ph
N
H
N
R
N
N
H
R
CO2Me
R
11, 48%
10,
39%
R=H,Cl 4a-g
6a-g
5a-g
Entry
Substrate (4)
R1
Productb
Yielda (%)
O
5
6
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
C6H5
4-CH3C6H4
n-C3H7
C6H11
CH2OTHP
5a
5b
5c
5d
5e
6f
71
91c
66
60
62
0
0
0
0
0
0
O
N
H
63d
0
Ph
CH2CH2NHBoc
C6H5
4ge
5g
73
9
a
b
c
Isolated yield.
Reaction mixture was stirred for 2 h.
Reaction time was 3.5 h.
1.5 equiv NaH was used and stirred for 1.5 h.
R = Cl.
1,4-benzoquinone
(5 equiv)
acetone
rt, 5 d
d
e
CO2Me
CO2Me
MeO2C
CO2Me
(5 equiv)
Boc deprotection with TBAF, thereby resulted in a free amine and
no eliminated product was obtained. When 4f was treated with
NaH, diene 6f was obtained in 63% yield, presumably due to the
fact that initial deprotonation from NHBoc, followed by abstraction
of the alpha hydrogen was beneficial for dehydrobromination.
Next we were interested in exploring further possibilities for
the assembly of diverse indole-containing skeletons which could
have potential applications in medicinal chemistry. Accordingly,
indolyl butadiene 5a was used for the Diels–Alder reaction against
the dienophiles DMAD, DEAD, N-phenylmaleimide and 1,4-benzo-
quinone and we were pleased to obtain moderate to good yields of
the Diels–Alder adducts4a (Scheme 2). The Diels–Alder reaction
was very slow at room temperature. Attempts to improve it by
heating the reaction mixture in toluene or THF failed to give the
desired product and the starting material was also decomposed.
We figured out that when the reactions were carried out in dark,
better yields were obtained. In the presence of light, butadiene
was not very stable4a and the product was obtained in very poor
yield along with the isolation of an undetermined product.
In the case of Diels–Alder reaction of indolyl butadiene 5a with
1,4-benzoquinone, we obtained a mixture of products containing
almost an equal amount of 6-(2-phenyl-1H-indol-3-yl)naphtha-
lene-1,4(5H,8H)-dione (10) and 6-(2-phenyl-1H-indol-3-yl)naph-
thalene-1,4-dione (11). The formation of the aromatized product
11 was possible by the oxidation of cycloadduct 9 by the presence
of excess p-benzoquinone as was expected. This observation was
rationalized from the HRMS data obtained after 24 h stirring of
the reaction mixture. Cycloadduct 11 is an analogue of alkaloid
murrapanine which has cytotoxicity against cancer cells, particu-
larly demethoxymurrapanines are more cytotoxic than murrapa-
nines9 (Fig. 1).
Ph
N
CH2Cl2, rt, 5 d
H
Ph
5a
N
H
7, 60%
CO2Et
N
CO2Et
N
N
CO2Et
N
EtO2C
(5 equiv)
CH2Cl2, rt, 24 h
Ph
N
H
8,
50%
O
O
H
H
N
Ph
N
Ph
O
O
(1.25 equiv)
N
H
Ph
acetone, rt, 5 d
12, 93%
Scheme 2. Diels–Alder reaction of indolyl butadiene 5a.
R
R
O
O
The reaction of 5a and N-phenymaleimide gave rise to a single
diastereomer cycloadduct 12 with an excellent yield. The stereo-
chemistry of the adduct was determined by X-ray crystallogra-
phy,10,11 which reveals that cycloaddition occurred on the endo
face of the diene (Fig. 2).
O
O
OMe
N
H
N
H
R = Me, H
Demethoxy murrapanines
R = Me murrapanine
R = H normurrapanine
In conclusion, we have developed a method for the synthesis of
suitably substituted 3-[2-(1,3-butadienyl)]-1H-indoles12 in overall
good yields starting from 3a–3g with the easily available reagents.
To the best of our knowledge, this is the first report for the synthesis
of such indolyl butadiene derivatives. Moreover, the synthetic use-
fulness of such diene derivatives has been demonstrated in the
Figure 1. Structure of murrapanine and analogues.
preparation of murrapanine analogue. Further studies using these
dienes to synthesize indole alkaloids and diverse indole scaffolds
are currently underway and results will be reported in due course.

6638
A. Chakraborty, S. Sinha / Tetrahedron Letters 52 (2011) 6635–6638
References and notes
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970; (b)
The Monoterpenoid Indole Alkaloids; Saxton, J. E. Ed.; The Chemistry of
Heterocyclic Compounds; Wiley & Sons: New York, 1983; Vol. 25, Part 4; (c)
Mono-terpenoid Indole Alkaloids; Saxton, J. E. Ed.; The Chemistry of Heterocyclic
Compounds; Wiley & Sons: Chichester, UK, 1994; Vol. 25, Supplement to Part 4.
2. Sundberg, R. J. Indoles; Best Synthetic Methods; Academic Press: London, 1996.
3. (a) Guo, X.; Hu, W.; Cheng, S.; Wang, L.; Chang, J. Synth. Commun. 2006, 36,
781–788; (b) Sheu, J.-H.; Chen, Y.-K.; Chung, H.-F.; Sung, P.-J.; Lin, S.-F.
Heterocycles 1996, 43, 1751–1758.
4. (a) Caballero, E.; Longieras, N.; Zausa, E.; del Rey, B.; Medarde, M.; Tomé, F.
Tetrahedron Lett. 2001, 42, 7233–7236; (b) Ferriera, E. M.; Stoltz, B. M.
Tetrahedron Lett. 2006, 47, 8579–8582.
5. (a) Barabanov, L. L.; Fedenok, L. G.; Shvartsberg, M. S. Russ. Chem. Bull. 1998, 47,
2256–2261; (b) Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571–1587.
6. Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1799–1802.
7. (a) Gopal, D.; Rajagopalan, K. Tetrahedron Lett. 1986, 27, 5883–5884; (b)
Nguyen, T.-L.; Dagne, E.; Gruenke, L.; Bhargava, H.; Castagnoli, N., Jr. J. Org.
Chem. 1981, 46, 758–760.
8. (a) Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.; Coudert,
G. Tetrahedron 2004, 60, 10039–10047; (b) Berube, M.; Kamal, F.; Roy, J.;
Poirier, D. Synthesis 2006, 3085–3091; (c) Beshai, M.; Dhuashia, B.; Mills, R.;
Thadani, A. N. Tetrahedron Lett. 2008, 49, 6794–6796; (d) Kutsumura, N.;
Kubokawa, K.; Saito, T. Synthesis 2011, 2377–2382.
9. Sheu, J.-H.; Chen, Y.-K.; Chung, H.-F.; Lin, S.-F.; Sung, P.-J. J. Chem. Soc., Perkin
Trans. 1 1998, 1959–1965.
10. Bruker, Version 2.1-0; Bruker AXS, Inc.: Madison, WI, 2006.
11. X-ray crystallographic data for compound 12 have been deposited to the
Cambridge Crystallographic Data Centre and assigned the deposition numbers
CCDC 837675 for 12.
Figure 2. Thermal ellipsoid plot of compound 12 with thermal ellipsoid drawn at
50% probability level.
12. General procedure for the synthesis of 3-[2-(1,3-butadienyl)]-1H-indoles 5: To a
solution of N-carbomethoxy-2,3-disubstituted indole
4
(0.5 mmol) in
anhydrous THF (5 mL) was added TBAF (3.5 mmol) under argon atmosphere
and the reaction mixture was heated to reflux for 1.5–2.5 h (reaction was
monitored by TLC), cooled to room temperature and the crude mixture was
diluted with ethyl acetate (15 mL), washed twice with saturated NH4Cl
solution, dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using ethyl acetate
in petroleum ether to afford pure indolyldienes 5 in good to excellent yields
Table 4.
Acknowledgments
S.S. thanks DST, India, for financial support by a Grant [SR/S1/
OC-38/2007]. A.C. is thankful to CSIR for her fellowship. We also
thank Mr. N. N. Adarsh, Organic Chemistry Department of this
Institute for his help in crystal structure determination.
Characterization data for the compound 5a is given below:
Yellow crystalline solid. Mp 105–107 °C. IR (KBr)
2997, 2970, 1595, 1450, 1487, 1450, 1415, 1361, 1325, 1301, 1284, 1224, 1147,
1030, 1003, 985, 898, 744 cmÀ1 1H NMR (CDCl3, 500 MHz) d 8.24 (s, 1H), 7.61
m 3398, 3082, 3059, 3026,
;
Supplementary data
(d, J = 7.5 Hz, 2H), 7.54 (d, J = 8 Hz, 1H), 7.40 (t, J = 8 Hz, 3H),7.33–7.30 (m, 1H),
7.23 (t, J = 6.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.69 (dd, J = 17, 10.5 Hz, 1H), 5.58
(d, J = 2 Hz 1H), 5.28 (s, 1H), 5.08 (d, J = 10 Hz, 1H), 5.02 (d, J = 17 Hz, 1H),; 13C
NMR (CDCl3, 125 MHz) d 141.7, 138.4, 135.9, 134.5, 132.9, 129.7, 128.8 (2C),
127.7, 127.3 (2C), 122.7, 120.6, 120.2, 120.2, 117.2, 112.5, 110.8; High
resolution MS (ESI): m/z [M+H]+ calcd for C18H16N: 246.1283, found: 246.1276.
Supplementary data (general procedures and spectral data)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.10.003.