Gold-catalyzed heteroannulation and allyl migration: Synthesis of highly functionalized indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.09.108

Highly substituted indole derivatives have been prepared in good to excellent yields by a novel gold-catalyzed cyclization accompanied by [3,3]-migration of the allyl strategy. We have been able to introduce an allyl group at the C1 position of pyrano[3,2

Full text of DOI:10.1016/j.tetlet.2011.09.108

Tetrahedron Letters 52 (2011) 6697–6701
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Gold-catalyzed heteroannulation and allyl migration: synthesis of highly
functionalized indole derivatives
K.C. Majumdar a,b, , Somjit Hazra a, B. Roy a,
⇑
⇑
a Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
b Department of Chemistry, Tezpur University, Tezpur, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly substituted indole derivatives have been prepared in good to excellent yields by a novel gold-
catalyzed cyclization accompanied by [3,3]-migration of the allyl strategy. We have been able to
introduce an allyl group at the C1 position of pyrano[3,2-e]indol-6(7H)-one and pyrrolo[3,2-f]quinolin-
7(6H)-one moieties that provide a scope for further transformation.
Received 19 August 2011
Revised 16 September 2011
Accepted 22 September 2011
Available online 1 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
[3,3]-Sigmatropic rearrangement
AuCl3
Cyclization
Substituted indoles
Pyrrolo coumarin
Pyrrolo quinolone
Nitrogen containing heterocycles such as substituted indole
derivatives have found their place as a topic of interest in the
fore-front of various scientific branches especially in synthetic
chemistry since this basic motif is present in various natural prod-
ucts and biologically active substances.1 Coumarins and quino-
lones on the other hand are the important subunits present in a
number of natural products showing broad spectrum biological
activity.2,3 In particular, the pyrrole-annulated coumarin deriva-
tives exhibit photobiological activity,4a antiproliferative effect,4b
DNA-binding properties,5 photophysical properties,6 anti-inflam-
matory, and antioxidant activities.7 These also act as ideal dyes
for various modern fluorescent imaging technologies such as
FRET.8 Pyrrole-annulated quinolone derivatives are also important
as these can act as phosphodiesterase 5 inhibitors,9a show analge-
sic activity,9b and are important precursors for the antibiotic
martinelline.10
tionalization of the C1 position in pyrano[3,2-e]indol-6(7H)-one
and pyrrolo[3,2-f]quinolin-7(6H)-one moieties and at the C3 posi-
tion of indole moieties are carried out with Friedel–Craft acylation
or halogenation. However it is very difficult to attach alkyl and allyl
groups as alkyl halides and allyl halides are less reactive in nature
compared to acyl halides.
The advantage of having an allyl group at the C1 position in pyr-
ano[3,2-e]indol-6(7H)-one, pyrrolo[3,2-f]quinolin-7(6H)-one moi-
eties and at the C3 position of indole moieties derives from the
fact that it can be easily manipulated by simple methods12 and
thereby rendering access to some important heterocyclic com-
pounds which are otherwise difficult to synthesize.13
Noble metal-catalyzed skeletal rearrangements into some
important heterocyclic compounds have been studied by some
groups previously (Fig. 1).14,15 Platinum has been used most exten-
sively; though Au and Pd have also been used but to a lesser extent.
In recent years we have put forward a number of efficient proto-
cols for synthesizing substituted pyrano[3,2-e]indol-6(7H)-one,
and pyrrolo[3,2-f]quinolin-7(6H)-one derivatives.11 But none of
these methods are useful in preparing pyrano[3,2-e]indol-6(7H)-
one, and pyrrolo[3,2-f]quinolin-7(6H)-one derivatives where both
the C1 and C2 positions are being functionalized. In general func-
R2
[M]
N
N
R1
R1
R2
⇑
Corresponding authors. Tel.:+91 33 2582 7521; fax: +91 33 25828282 (K.C.M.).
E-mail addresses: kcm_ku@yahoo.co.in (K.C. Majumdar), broybs@rediffmail.com
(B. Roy).
Figure 1. Metal-catalyzed heteroannulation.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.108

6698
K. C. Majumdar et al. / Tetrahedron Letters 52 (2011) 6697–6701
Table 1
With Pt though the yield was very good, it required higher tem-
perature.16 However, Pd as catalyst gave lower yield, and required
high temperature and also the presence of an electron withdraw-
ing group attached to the N-atom of the amine.17 Therefore, in or-
der to explore further scope of this methodology we have
undertaken a study to synthesize allyl functionalized pyrrolo-
coumarin, pyrroloquinolone, and indole heterocycles by the appli-
cation of AuCl3 as a catalyst. Herein we report the result of our
investigation.
Optimization of the gold catalyzed cyclization
Ph
Ph
N
NMe
Me
O
O
O
O
2a
The precursors 2a–i for our present study were synthesized in
good to moderate yields by the reaction of either N-methyl or N-
ethyl o-substituted amines 1a–h with allyl bromide or crotyl
bromide in refluxing ethyl methyl ketone in the presence of
potassium carbonate, and sodium iodide (Finkelstein condition,
Scheme 1). The o-substituted N-methyl or N-ethyl amines were
prepared from N-methyl or N-ethyl aromatic amines by bromina-
tion and subsequent Sonogashira cross coupling with phenyl
acetylene.11a
In order to optimize the reaction condition for the heterocycli-
zation we have initially tested the suitability of the transition me-
tal catalysts with 6-(allyl(methyl)amino)-5-(phenylethynyl)-2H-
chromen-2-one (2a)18 as a model substrate. AuCl3 turned out to
be the most effective of the lot. We also found 2 mol % of catalyst
was necessary as the reaction takes longer (2 h) time and reduces
the yield with lower amount. We also tried InCl3, AgSbF6 as cata-
lysts, while with increase in temperature the yield of the product
increases slightly for InCl3 and AgSbF6, AuCl3 gave the best results
at room temperature. Other catalysts such as PdCl2 and CuCl2 were
found to be ineffective for the reaction. The reaction with AuCl3 in
acetonitrile proceeds slowly over 4 h giving 85% yield of 3a,19
while the use of THF as a solvent gave a somewhat lower yield
(80%). The reaction of 2a with AuCl3 proceeded smoothly in tolu-
ene at room temperature giving an excellent yield (95%) of 3a
within just 45 min (Table 1).
3a
Entry
Catalysta
Solvent
Time
Temp (°C)
Yield (%)c
1b
2
3
4
5
6
7
8
9
AuCl3
AuCl3
AuCl3
AuCl3
InCl3
Toluene
CH3CN
THF
CH3OH
Toluene
CH3CN
Toluene
CH3CN
Toluene
Toluene
45 min
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
95
85
80
60
25
30
nr
nr
15
nr
InCl3
PdCl2
PdCl2
AgSbF6
CuCl2
10
4 h
a
b
c
Catalyst used 2 mol %.
Optimized reaction condition.
Isolated yield, nr = no reaction, r.t. = room temperature.
With this optimized condition (AuCl3, toluene at room temper-
ature) we explored this protocol with other substrates 2b–i for the
synthesis of various heterocycles (Table 2). The reaction of all the
substrates 2a–i did proceed smoothly providing excellent yields
especially with coumarin and quinolone moieties, probably due
to the electron deficient nature of these heterocyclic moieties the
reaction occurred very fast and went to completion within
45 min–1 h. With benzene moiety reaction took a little longer time
again giving excellent yields of 90% and above at room tempera-
ture. This is a significant improvement compared to some earlier
reports.16
The initial steps involved in the formation of products 3 from
the substrates 2 can be rationalized in a similar way to that pro-
posed by Nakamura and co workers,15 where AuCl3 first coordi-
Ph
Ph
R2
Allyl bromide/Crotyl
bromide,
NaI,K2CO3
nates to the triple bond of 2i to form the
P complex. Then a
NHR1
nucleophilic attack by the nitrogen atom to the alkynyl moiety
leads to the cyclized intermediate 4. In order to get a further in-
sight into the nature of migration of the allyl group we have intro-
duced a crotyl group in place of the simple allyl group. The cyclized
intermediate 4, in accordance with our assumption underwent a
[3,3]-sigmatropic rearrangement followed by the elimination of
AuCl3 from 5 giving the product 3i exclusively and thus providing
ample evidence in favor of intramolecular nature of the rearrange-
ment step (Scheme 2).
In conclusion, we have demonstrated the development of a
gold-catalyzed intramolecular carboamination strategy for synthe-
sizing the potentially biologically active indole derivatives. The
functionalization by allyl at the C1 position of pyrano[3,2-e]in-
dol-6(7H)-one and pyrrolo[3,2-f]quinolin-7(6H)-one and the C3
position of indoles is the most notable feature of this attractive
methodology. We are exploring this functionalization with care-
fully placed other functional groups in the heterocyclic core to syn-
thesize complex bioactive heterocycles. We have also provided
further insight into the nature of the allyl migration in this reac-
tion. Moreover, the transformation proceeds with excellent yield
at room temperature in a very short time making it a useful and
attractive strategy for the synthesis of allyl functionalized bioac-
tive heterocycles.
NR1
O
X
Ethyl methyl
ketone,reflux
20 h
O
X
1
1
2
1a
1b
. X = O, R = Me
. X = O, R = Et
1c. X = NME R1 = Me
1d. X = NMe R1 = Et
1e. X = NEt R1 = Me
1f. X = NEt R1 = Et
2a
2b
. X = O, R = Me, R =H
. X = O, R = Et, R =H
1
1
2
2c. X = NME, R1 = Me, R2=H
2d. X = NMe, R1= Et, R2=H
2e. X = NEt, R1 = Me, R2=H
2f. X = NEt, R1 = Et, R2=H
2i. X = O, R1 = Me, R2=CH3
NHR1
Ph
NR1
Ph
Allyl bromide,
NaI, K2CO3
Ethyl methyl
ketone,reflux
20 h
1
1
2g
2h
1g
1h
. R = Me
. R = Et
. R = Me
1
1
. R = Et
Scheme 1. Preparation of pre-cursors 2a–h.

K. C. Majumdar et al. / Tetrahedron Letters 52 (2011) 6697–6701
6699
Table 2
Summarized results of the gold catalyzed cyclization reaction under optimized conditions
Entry
Substrate
Time
Product
Yield
Ph
Ph
1
45 min
95
92
95
NMe
NMe
O
O
O
O
O
2a
3a
Ph
Ph
Ph
2
45 min
NEt
NEt
O
O
O
O
O
O
3b
2b
Ph
3
1 h
NMe
NMe
N
2c
N
Me
Me
3c
3d
Ph
Ph
Ph
Ph
4
5
6
1 h
1 h
1 h
91
NEt
NEt
N
O
O
O
N
2d
Me
Me
Ph
96
NMe
NMe
N
2e
O
N
Et
3e
Et
Ph
95
NEt
NEt
N
O
N
3f
2f
Et
Et
Ph
MeN
NMe
Ph
Ph
7
2 h
90
3g
2g
Ph
EtN
NEt
8
2 h
91
3h
2h
(continued on next page)

6700
K. C. Majumdar et al. / Tetrahedron Letters 52 (2011) 6697–6701
Table 2 (continued)
Entry
Substrate
Time
Product
Yield
90
Ph
Ph
9
45 min
NMe
3i
NMe
2i
O
O
O
O
O
O
O
O
Ph
Ph
N
O
O
3i
Ph
O
N
N
x
AuCl3
2i
O
AuCl3
Ph
O
AuCl3
Ph
O
N
O
Cl3Au
N
Ph
O
5
x[1r,e3a]-rsraignmgeamtroepnitc
N
[3,3]-sigmatropic
rearrangement
π complex
O
O
AuCl3
3
2
Ph
1
N
1
3
2
4
Scheme 2. Proposed mechanism of the reaction.
5. Gia, O.; Mobilio, S.; Chilin, A.; Rodghiero, P.; Palumbo, M. J. Photochem.
Photobiol., B 1988, 2, 435.
Acknowledgments
6. Quanten, E.; Adriaens, P.; Schryver, F. C.; Roelandts, R.; Degreef, H. Photochem.
Photobiol. 1986, 43, 485.
We thank the CSIR (New Delhi) and DST (New Delhi) for finan-
cial assistance. One of us (S.H.) is grateful to CSIR (New Delhi) for
his research fellowship. We also thank DST (New Delhi) for provid-
ing NMR spectrometer (400 MHz), CHN analyzer, and FT–IR
instruments.
7. Kontogiorgis, C.; Litinas, K. E.; Makri, A.; Nicolaides, D. N.; Vronteli, A.; Litina, D.
J. H.; Pontiki, E.; Siohou, A. J. Enzyme Inhib. Med. Chem. 2008, 23, 43.
8. Chen, L.; Hu, T.-S.; Yao, Z.-J. Eur. J. Org. Chem. 2008, 36, 6175.
9. (a) Jiang, W.; Alford, V. C.; Qiu, Y.; Bhattacharjee, S.; John, T. M.; Johnson, D. H.;
Kraft, P. J.; Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. 2004, 12, 1505; (b)
Yamashkin, S. A.; Yudin, L. G.; Kost, A. N. Chem. Heterocycl. Compd. (Engl. Transl.)
1983, 19, 401.
References and notes
10. Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287.
11. (a) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2008, 49, 2418; (b) Majumdar,
K. C.; Chattopadhyay, B.; Samanta, S. Synthesis 2009, 311; (c) Majumdar, K. C.;
Chakravorty, S.; Shyam, P. K.; Taher, A. Synthesis 2009, 403; (d) Majumdar, K.
C.; Samanta, S.; Nandi, R. K.; Chattopadhyay, B. Tetrahedron Lett. 2010, 51,
3807; (e) Majumdar, K. C.; De, N.; Roy, B. Synthesis 2010, 4207.
12. Trost, B. M.; Yong, Z. Chem. Eur. J. 2011, 17, 2916.
13. May, J. A.; Hwang-Hsing, C.; Rusinko, A.; Lynch, V. M.; Sharif, N. A.; McLaughlin,
M. A. J. Med. Chem. 2003, 46, 4188.
14. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
10546.
15. (a) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto, Y. Angew. Chem.
2007, 119, 2334; (b) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2006, 45, 4473–4475.
16. Rstner, A. F.; Davies, W. P. J. Am. Chem. Soc. 2005, 127, 15024.
17. Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001–1011.
1. (a) Glasby, J. S. Encyclopedia of Alkaloids; Plenum Press: New York, 1975; (b)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (c) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Oxford: Pergamon, 2000. Chap. 3.
2. (a) Hagen, S. E.; Domagala, J. M.; Heifetz, C. L.; Sanchez, J. P.; Solomon, M. J. Med.
Chem. 1990, 33, 849; (b) Raski, S. R.; Williams, R. M. Chem. Rev. 1998, 98, 2723;
(c) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito, C.; Furukawa, H.; Takahasi,
D.; Koshimizu, K.; Ohigash, H. Bioorg. Med. Chem. Lett. 2000, 10, 59; (d) Laborde,
E.; Kiely, J. S.; Culbertson, T. P.; Lesheski, L. E. J. Med. Chem. 1993, 36, 1964.
3. (a) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71; (b) Piorung, M. C.; Blume, F. J.
Org. Chem. 1999, 64, 3642; (c) Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.;
Mackerracher, D.; Malone, J. F. J. Chem. Soc., Perkin Trans. 1 2000, 3397.
4. (a) Rodighiero, P.; Chilin, A.; Pastorini, G.; Guiotto, A. J. Heterocycl. Chem. 1987,
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Rodighiero, P. Farmaco 1995, 50, 479.

K. C. Majumdar et al. / Tetrahedron Letters 52 (2011) 6697–6701
18. 6-Allyl(methyl)amino-5-(phenylethynyl)-2H-chromen-2-one(2a); typical
6701
19. 1-Allyl-3-methyl-2-phenylpyrano[3,2-e]indol-7(6H)-one (3a); typical procedure:
6-(N-allyl, N-methylamino)-5-(phenylethynyl)-2H-chromen-2-on 2a (20 mg,
0.634 mmol) was dissolved in dry toluene (5 ml) under N2 atmosphere. AuCl3
(2 mol %, 3.8 mg) was added and allowed to stir for 45 min. at ambient
temperature. After completion (monitored by TLC) water (5 ml) was added and
was extracted with EtOAc (20 mL Â 3). The combined organic layer was
washed with water (10 mL), brine (10 mL) and dried (Na2SO4). The solvent was
evaporated under reduced pressure to furnish a crude mass which was purified
by column chromatography over silica gel (60–120 mesh) using PE–EtOAc
(8:2) as elutant to afford the compound 3a (190 mg) as yellow solid. All the
other compounds 3b–i were prepared similarly following the above procedure.
Yield: 95%; yellow solid; mp 179–181 °C.
procedure: A mixture of 6-(methylamino)-5-(phenylethynyl)-2H-chromen-2-
one 1a (R1 = Me, X = O; 300 mg, 1.09 mmol), allyl bromide (160 mg, 1.3 mmol,
0.11 ml)or crotyl bromide (0.360 g, 1.3 mmol), anhyd K2CO3 (3 g, excess), and
NaI (catalytic amount) was refluxed in anhyd ethyl methyl ketone (50 mL) for
20 h. The reaction mixture was cooled, filtered, and the solvent was removed.
The residual mass was extracted with EtOAc (30 mL Â 3). The combined EtOAc
extract was washed with H2O (30 mL Â 3), brine (10 ml), and dried (Na2SO4).
The residual mass after removal of EtOAc under reduced pressure was
subjected to column chromatography over silica gel (60–120 mesh) using
PE–EtOAc (9:1) as eluent to afford compound 2a (240 mg) as a yellow solid. All
the other compounds 2b–i were prepared similarly following the above
procedure.
IR (KBr): 1586, 1714 cmÀ1
.
Yield: 70%; mp 63–65 °C.
1H NMR (400 MHz, CDCl3): dH = 3.54–3.55 (m, 2H, CH2), 3.68 (s, 3H, NCH3), 4.95
(dd, J = 16.8 Hz, J = 4 Hz, 1Ha, @CHbHa), 5.14 (dd, J = 10 Hz, J = 4 Hz, 1Hb,
@CHbHa), 6.07–6.16 (m, 1H, CH), 6.42 (d, J = 9.6 Hz, 1H, C3-H of coumarin),
7.24–7.26 (m, 1H, ArH), 7.38–7.40 (m, 2H, ArH), 7.46–7.54 (m, 4H, ArH), 8.29
(d, J = 9.6 Hz, 1H, C4-H of coumarin).
IR (KBr): 1567, 1727, 2208 cmÀ1
.
1H NMR (400 MHz, CDCl3): dH = 2.90 (s, 3H, NCH3), 3.60 (d, J = 6 Hz, 2H, CH2),
5.21–5.32 (m, 2H, @CH2), 5.91–6.11 (m, 1H, CH), 6.49 (d, J = 9.6 Hz, 1H, C3-H of
coumarin), 7.17 (d, J = 9.2 Hz, 1H, ArH), 7.23 (d, J = 9.2 Hz, 1H, ArH), 7.39–7.41
(m, 3H, ArH), 7.57–7.60 (m, 2H, ArH), 8.28 (d, J = 9.6 Hz, 1H, C4-H of coumarin).
Anal. calcd for C21H17NO2: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.80; H, 5.59;
N, 4.60.
13CNMR(100 MHz, CDCl3):dC = 29.9,31.1, 110.3, 111.1, 111.2, 113.6, 114.3, 116.2,
122.4, 128.6, 128.7, 130.4, 130.8, 133.6, 137, 141.6, 141.7, 150.6, 161.7. HRMS
(TOF, ES+): m/z [M+Na]+ calcd for C21H17NO2 + Na: 338.116. Found: 338.1169.