Molecular iodine-mediated cascade reaction of 2-alkynylbenzaldehyde and indole: An easy access to tetracyclic indoloazulene derivatives

Article abstract of DOI:10.1002/adsc.201300421

The synthesis of iodo-substituted tetracyclic indole fused azulene derivatives was achieved from the reaction of 2-(substituted phenylethynyl)-benzaldehydes and different indoles in the presence of molecular iodine. The reaction involves the formation of a bisindole from the corresponding 2-(substituted phenylethynyl)benzaldehyde and indole followed by iodocyclization in a one-pot cascade process. A wide range of 2-(substituted phenylethynyl)-benzaldehydes and indoles were utilized in this protocol to derive a diverse range of iodo-substituted tetracyclic indole fused azulene derivatives in moderate to good yields. Further functionalizations of the iodo-substituted tetracyclic indole fused azulenes were achieved by various palladium-catalyzed crosscoupling reactions to generate highly substituted tetracyclic indole fused azulene derivatives.

Full text of DOI:10.1002/adsc.201300421

FULL PAPERS
DOI: 10.1002/adsc.201300421
Molecular Iodine-Mediated Cascade Reaction of
2-Alkynylbenzaldehyde and Indole: An Easy Access to
Tetracyclic Indoloazulene Derivatives
Sachin D. Gawande,a Veerababurao Kavala,a Manoj R. Zanwar,a Chun-Wei Kuo,a
Hsiu-Ni Huang,a Chiu-Hui He,a Ting-Shen Kuo,a and Ching-Fa Yaoa,*
a
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, R.O.C.
E-mail: cheyaocf@ntnu.edu.tw
Received: May 13, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300421.
Abstract: The synthesis of iodo-substituted tetracy- tocol to derive a diverse range of iodo-substituted
clic indole fused azulene derivatives was achieved tetracyclic indole fused azulene derivatives in moder-
from the reaction of 2-(substituted phenylethynyl)- ate to good yields. Further functionalizations of the
benzaldehydes and different indoles in the presence iodo-substituted tetracyclic indole fused azulenes
of molecular iodine. The reaction involves the forma- were achieved by various palladium-catalyzed cross-
tion of a bisindole from the corresponding 2-(substi- coupling reactions to generate highly substituted tet-
tuted phenylethynyl)benzaldehyde and indole fol- racyclic indole fused azulene derivatives.
lowed by iodocyclization in a one-pot cascade pro-
cess. A wide range of 2-(substituted phenylethynyl)- Keywords: azulenes; cascade process; cross-coupling;
benzaldehydes and indoles were utilized in this pro- indoles; indoloazulenes; iodocyclization
Introduction
The electrophilic iodine-triggered cyclization of
ortho-substituted arylalkynes is one of the prominent
Medium-ring annulated indole derivatives are an im- methods for the synthesis of iodine-containing fused
portant class of pharmaceutically active compounds, heterocyclic derivatives.[6] A wide variety of fused het-
which exhibit a wide variety of biological activities.[1] erocycles including 5-iodopyrrolo
ACHTUNGTRENNUNG
Particularly, the seven-membered ring (azulene) an- fused
nulated tetracyclic indole moiety occurs in numerous benzimid
benzimidazoles,
azoles, iodofuro
N
ACHTUNGTRENNUNG
biologically active natural products and pharmaceuti- stituted indoloazepinones, 2-iodospiro[indene-1,10-
cal intermediates, which display potent antihistaminic, isobenzofuran]-30-ones, dihydrocyclopenta[b]indole,
antimicrobial and anticancer activities.[1,2] In general, furo
ACTHNUTRGENNU[G 2,3-b]quinoline, iodopyranoACHTUGNTREN[NUNG 4,3-b]quinolines and
the construction of medium sized rings is unambigu- pyrralopyridines etc. were constructed using the iodo-
ously considered to be a cumbersome task due to cyclization strategy.[7]
a combination of the transannular interactions and
On the other hand, 2-alkynylbenzaldehyde is
unfavourable entropic and enthalpic factors.[3] Howev- a handy and an interesting structural motif for the
er, there are some reports describing the synthesis of generation of functionalized polycyclic compounds
seven-membered ring (azulene) annulated indole de- and is also a very good electrophilic species for iodo-
rivatives in the literature.[4] Most of the reported cyclization.[8] Our group has been interested in explor-
methodologies for the construction of tetracyclic ing the iodine-mediated transformations for some
indole derivatives are associated with the use of ex- time.[9] In this context, we found that the reaction of
pensive metal catalysts like gold and palladium and aldehyde with various indoles in the presence a cata-
very few of them are non-metallic protocols which re- lytic amount of iodine produced the corresponding bi-
quire higher temperatures or having less broad sub- sindole in high yields. On the other hand, recently,
strate scopes.[5] Hence, developing an efficient and Verma and his co-workers have reported the synthesis
non-metallic protocol for the synthesis of azulene an- of indoloACTHNUTRGNE[NUG 1,2-a]quinolines via (6-endo-dig) iodocycli-
nulated indole tetracycle is highly desirable.
zation using molecular iodine.[7d] Moreover, recently,
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Scheme 1. Plausible pathway for the formation of products.
Enders and co-workers observed the formation of
seven-membered (7-endo-dig) fused tetracyclic azu-
lene derivatives using a gold catalyst.[4c] Based on
these two observations, we envisioned that the reac-
tion of 2-(phenylethynyl)benzaldehyde and indole in
the presence of iodine could initially produce the cor-
responding bisindole which would further undergo io-
docyclization to produce either indole fused azulene
compound 3a or benzo-fused carbazole derivative 4a
(Scheme 1).
Results and Discussion
Figure 1. ORTEP diagram of single crystal X-ray diffraction
structure of 3a.[12]
To investigate our assumption, we choose 2-(phenyl-
ACHTUNGTRENNUNGethynyl)benzaldehyde and indole as model substrates.
In our initial reaction, we treated 2-(phenylethynyl)-
benzaldehdye (1 equiv.) and indole (2 equiv.) in the
To determine the best conditions for the formation
presence of 2 equiv. of iodine (I2) in dichloromethane of indole fused azulene (3a), we screened various re-
at 08C to room temperature (Table 1, entry 1). Under action conditions. In this regard, we first evaluated
these conditions, the reaction produced bisindole de- the efficiency of the iodine reagent for the reaction of
rivative (i) as a sole product. However, when 2 equiv. 2-(phenylethynyl)benzaldehdye (1 equiv.), indole
of sodium bicarbonate were used as base (entry 2), (2 equiv.) and sodium bicarbonate (2 equiv.) in di-
two products were formed. Among the two products, chloromethane at 08C. The reaction results indicate
1
the major product was bisindole and the H NMR, that the use of molecular iodine below 3 equiv. produ-
13C NMR, LR-MS, HR-MS, single crystal X-ray dif- ces the desired indole fused azulene 3a along with bi-
fraction analysis revealed that the minor product was sindole as a minor product. However, the reaction
indole fused azulene compound 3a (Figure 1). Inter- with 3.2 equiv. iodine and 2 equiv. NaHCO3 resulted
estingly, indole fused azulene derivatives exhibit anti- in 66% of compound 3a as a single product (entry 4).
cancer and antineoplastic properties.[2] In fact, the Next, we screened the reaction with different solvents
syntheses of some indole fused tetracyclic azulene de- like acetonitrile, 1,4-dioxane, THF and diethyl ether.
rivatives have reported in the literature using various The reaction worked in most of the solvents but did
metal catalysts.[4] However, to the best of our knowl- not produce high yields, however, chloroform pro-
edge, there is no efficient, non-metallic protocol avail- duced the best yield of the desired product (entry 9).
able for the construction of indole fused azulene tet- After solvent screening, we screened different bases
racyclic derivatives. This fact prompted us to investi- such as K2CO3, Cs2CO3 and t-BuOK. The desired
gate the iodocyclization reaction in more detail.
product was obtained in poor yields (entries 11, 12
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
Table 1. Optimization of the reaction conditions.
[a]
Reactions were performed on a 0.25-mmol scale.
Yields refer to isolated and purified compound. Values in parentheses correspond to
[b]
the NMR yield using CH2Br2 as an internal standard.
and 14). However, the reactions furnished good yields Na2CO3 and K3PO4 were used instead (entries 10 and
of the expected product when the mild bases such as 13).
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Table 2. Iodine-mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and
various indole derivatives.
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
Table 2. (Continued)
[a]
All reactions were performed with 0.25 mmol of aldehyde 1a and 0.5 mmol of
indole 2a–2h.
[b]
Iodine (3.2 equiv.) and triethylamine (2.0 equiv.) in CHCl3.
Yields refer to isolated and purified compound. Values in parentheses correspond
[c]
to the NMR yield using CH2Br2 as an internal standard.
The reactions were carried out at 608C.
[d]
Moreover, we screened the reaction in the presence sponding product 3a in excellent yield (Table 2,
of organic bases. When the reaction was carried out entry 1). However, moderately electron-withdrawing
in the presence of strong organic bases such as groups such as chloro and bromo on the indoles pro-
DIPEA (N,N-diisopropylethylamine), DBU (1,8-di- duces the corresponding compounds 3b and 3c in
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
product was obtained in moderate yields (entries 16, (methyl and ethyl) also provided the desired products
17 and 18). To our delight, in the presence of TEA 3d and 3e in good yields with longer reaction times
(triethylamine) the reaction gave the best result with (entries 4 and 5). On the other hand, the reaction of
84% isolated yield (100% NMR yield) of the desired 1a with indole bearing a strong electron-donating
product in 9 h (entry 15). Furthermore, we also group such as methoxy gave the desired product 3f in
screened different iodine sources for this reaction. moderate yield (entry 6). It is worthy of note that re-
NIS (N-iodosuccinimide) and ICl (iodine monochlor- actions of indoles possessing electron-donating groups
ide) gave the desired product in poor yields (en- required longer reaction times compared to indoles
tries 19 and 20). Molecular iodine was found to be the with electron-withdrawing groups. Furthermore under
best choice for this reaction. The reaction was also the standard reaction conditions, those indole deriva-
tested using varied quantities of iodine with TEA as tives possessing strong electron-withdrawing groups
base (entries 21-ꢁ-23). However, in the presence of like nitro or cyano furnished only traces of the inter-
iodine at less than 3.2 equiv., the reactions were in- mediate bisindole derivatives. However, when the re-
complete and resulted in poor yield of the desired actions were carried out at 608C, they produced the-
product.
corresponding tetracyclic derivatives 3g and 3h in
To compare the stepwise and one-pot reactions, the good yields. The need for higher temperature may be
intermediate bisindole (i) was prepared by the reac- due to the less nucleophilic nature of the indoles.
tion of 1 equiv. of aldehyde (1a) and 2 equiv. of indole
Next, we investigated the tandem iodocyclization of
(2a) in the presence of a catalytic amount of iodine. various substituted 2-(phenethynyl)benzaldehydes
Then, the bisindole was treated with 2.2 equiv. of and substituted indoles. As depicted in Table 3, the
iodine and 2 equiv. of triethylamine. The reaction re- reactions of 2-(phenylethynyl)benzaldehydes having
sulted in 100% NMR yield and 88% isolated yield of both electron-donating (OMe) and electron-with-
the desired product in 8 h. The stepwise and one-pot drawing (NO2) substitutions with indole delivered the
reaction produced almost similar results. Hence, the desired products 3i and 3j in good yields (entries 1
scope of reaction was examined with the one-pot re- and 2). However, the nitro aldehyde forms the corre-
action conditions.
sponding compound faster than the methoxy alde-
After the optimization of reaction conditions, the hyde. Moreover, the aldehydes possessing strong elec-
scope and limitations of this one-pot tandem iodocyc- tron-donating groups such as 1d and 1e gave the ex-
lization of the indole fused tetracyclic azulene was pected products 3k and 3l in moderate yields, with
further investigated by using various 2-(phenylethy- longer reaction times (entries 3 and 4). On the other
nyl)benzaldehydes and substituted indole derivatives.
hand, the reactions of methyl-substituted indole (2d)
The reaction of 1a with unsubstituted indole under with aldehydes 1b and 1c furnished the desired prod-
the optimized reaction conditions, gave the corre- ucts 3m and 3n in good yields but nitro aldehyde 1c
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Table 3. Iodine-mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and vari-
ous indole derivatives.
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
Table 3. (Continued)
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Table 3. (Continued)
[a]
All reactions were performed on a 0.25-mmol scale of aldehyde 1a–1h and 0.5 mmol of
indole 2a–2f.
[b]
[c]
Iodine (3.2 equiv.) and triethylamine (2.0 equiv.) in CHCl3.
Yields refer to isolated and purified compound. Values in parentheses correspond to
the NMR yield using CH2Br2 as an internal standard.
Inseparable mixture of products.
[d]
took a longer time. A similar trend was observed lead to decomposition or formation of several other
when ethyl-substituted indole (2e) was used (entries 7 products. (entry 16).
and 8) to obtain the corresponding products 3o and
In order to extend the scope of our protocol, we
3p. The reactions of indoles containing moderate elec- synthesized N-{(1H-indol-3-yl)[2-(phenylethynyl)phe-
tron-withdrawing groups such as chloro and bromo nyl]methyl}-N-methylaniline (5a) using N-methyl-
gave the desired products in good yields with 5-me-
ACHTUNGTRENaNGNU niline (2 equiv.), 2-(phenylethynyl)benzaldehyde
thoxy-2-(phenylethynyl)benzaldehyde (1b) and 5- (1 equiv.) and indole (1 equiv.) in ethanol with bromo-
nitro-2-(phenylethynyl)benzaldehyde (1c) (entries 9– dimethylsulfonium bromide (BDMS, 10 mol%) to
12). Furthermore, the scope of the reaction was exam- obtain crude compound 5a.[11] Then, the crude com-
ined with mild and strong electron-donating substitu- pound (5a) was treated with iodine (2 equiv.) and trie-
tion at the aromatic alkynes. The moderately elec- thylamine (2 equiv.) to yield compound (6a) in 65%
tron-donating methyl-substituted alkyne aldehyde 1f yield together with 10% unreacted starting material
produced the compound 3v in better yield and shorter (Scheme 2). The unreacted starting material was not
reaction time than compound 3w when the strong consumed even after the addition of extra iodine to
electron-donating methyleneoxy alkyne aldehyde was the reaction mixture.
used as a substrate (entries 14 and 15). This protocol
The presence of an iodo group in the tetracyclic
failed to produce the corresponding product with ali- system gave us the opportunity to generate diverse
phatic 2-(hex-1-yn-1-yl)benzaldehyde. Probably the functionalized indole fused tetracyclic azulene deriva-
À
bulky long chain alkyl group may prevent the attack tives by various palladium-catalyzed C C bond cou-
of indole on the intermediate iodonium ion to form pling reactions (Scheme 3).[11] In this regard, com-
the corresponding tetracyclic compound. This may pound 3a was treated with 4-methoxyphenylboronic
Scheme 2. Synthesis of amino-substituted tetracyclic indole fused azulene (6a).
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
Scheme 3. Functionalization of indolotetracyclic azulene (3a).
acid under Suzuki reaction conditions to afford com- tained. The present method was applied to synthesize
pound 7a in 76% yield.[11a] Next, 3a was treated with the amino-substituted tetracyclic indole fused azulene
ethyl acrylate in the presence of bis(triphenylphosphi- derivative (6a). Finally, the iodo compound (3a) was
ne)palladium(II) dichloride and K2CO3 as a base in successfully utilized for further functionalization with
À
DMF to afford the Heck-type product 8a in excellent C C bond coupling reactions such as Suzuki, Heck
yield (98%).[11b] Finally, compound 3a was deiodinat- and deiodination to furnish a diverse array of func-
ed by tetrakis(triphenylphosphine)palladium(0) and tionalized tetracyclic indole fused azulene derivatives.
sodium formate to furnish the product 9a in moderate
yield (74%).[11c]
Experimental Section
Conclusions
General Information
In conclusion, we have developed an easy, efficient
and non-metallic protocol for the construction of tet- All chemicals were purchased from various sources and
were used directly without further purification. Analytical
thin-layer chromatography was performed using silica gel
60F glass plates and silica gel 60 (230–400 mesh) was used in
flash chromatographic separations. NMR spectra were re-
corded in DMSO-d6 with DMSO and CDCl3 with CHCl3 as
the internal standards for 1H NMR (400 MHz) and
13C NMR (100 MHz). Coupling constants were expressed in
Hertz. HR-mass spectra were recorded using the MALDI,
ESIÀ or ESI+ mode. Melting points were recorded using an
electrothermal capillary melting point apparatus and are un-
racyclic indoloazulene derivatives by the sequential
iodocyclization of 2-(phenylethynyl)benzaldehyde and
indole via bisindole in the presence of molecular
iodine and base. Wide ranges of 2-(substituted phe-
nylethynyl)benzaldehydes and indoles were utilized in
this reaction to derive a diverse array of iodo-substi-
tuted tetracyclic indole fused azulene derivatives in
good to moderate yields. Interestingly, the reaction is
completely regioselective and only iodo-substituted
tetracyclic indole fused azulene derivatives were ob- corrected.
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8 h. The progress of reaction was monitored by TLC. After
the completion of the reaction, the solution was allowed to
cool, was diluted with ice/water (25 mL) and then extracted
with ethyl acetate (3ꢂ40 mL). The organic layer washed
with water and brine. The organic layer was dried over
MgSO4, filtered and then concentrated under reduced pres-
sure to obtain the crude product. The crude compound was
then purified by column chromatography using hexane-ethyl
acetate as the eluent to yield compound 7a as a light pink
solid.
2-(1H-Indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo-
[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13(18),
14,16-octaene (3a); Typical Procedure for the
Synthesis of 3a–3w
To an ice-cold solution of 1a (0.25 mmol) and indole
(0.5 mmol) in CHCl3 (5 mL) was added a solution of I2
(1.1 equiv.) in CHCl3 (5 mL) dropwise. After stirring of the
reaction mixture for 10 min, triethylamine (2 equiv.) was
added dropwise. To this resulting mixture, an additional so-
lution of I2 (2.1 equiv.) in CHCl3 was added followed by stir-
ring at room temperature. The progress of the reaction was
monitored by TLC. After the completion of the reaction, sa-
turated aqueous Na2S2O3 (5 mL) was added to the mixture,
which was further stirred for 2 min. The resulting mixture
was then extracted with CHCl3 (2ꢂ20 mL). The organic
layer washed with water and brine. The organic layer was
dried over MgSO4, filtered and then concentrated under re-
duced pressure to obtain the crude product. The crude com-
pound was then purified by column chromatography using
hexane-ethyl acetate as the eluent to yield compound 3a.
Ethyl (2E)-3-{2-(1H-Indol-3-yl)-10-phenyl-12-aza-
tetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
13,15,17-octaen-9-yl}prop-2-enoate (8a)
To a stirred solution of 3a (1 mmol) in 5 mL DMF in a 10-
mL flask was added PdCl2ACHTNUGTRENUNG(PPh3)2 (10 mol%) and the mix-
ture stirred for 15 min under an argon atmosphere. Then
ethyl acrylate (2.5 equiv.) was added to the reaction mixture.
After 15 min, K2CO3 (2.5 equiv.) was added. The reaction
mixture was then stirred at 1008C for 7 h. The progress of
the reaction was monitored by TLC. After the completion
of the reaction, the reaction mixture was cooled to room
temperature, dilued with ice/water (50 mL) and extracted
with ethyl acetate (3ꢂ50 mL). The organic layer was
washed with cold water (100 mL) and finally with brine
(50 mL). The ethyl acetate later was dried over MgSO4, fil-
tered and then concentrated under reduced pressure. The
crude compound was then purified by column chromatogra-
phy using hexane-ethyl acetate as the eluent to afford com-
pound 8a as a white solid.
Synthesis of 9-Iodo-N-methyl-N,10-diphenyl-12-aza-
tetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
13,15,17-octaen-2-amine (6a)
To a stirred solution of 1a (0.5 mmol) and N-methylaniline
(1 mmol) in EtOH (2 mL) was added BDMS (10 mol%).
The mixture was then stirred at room temperature for
20 min followed by the addition of indole (0.5 mmol). The
reaction mixture was then stirred at room temperature for
15 h. The progress of reaction was monitored by TLC. After
completion of the reaction, the solution was diluted with
water (25 mL) and then extracted with ethyl acetate (3ꢂ
30 mL). The organic layer washed with water and brine. The
organic layer was dried over MgSO4, filtered and then con-
centrated under reduced pressure to obtain the crude prod-
uct 5a. The crude compound was directly used for next step
due to its poor stability.
To an ice-cold solution of 5a in CHCl3 (10 mL) was added
a solution of I2 (2 equiv.) in CHCl3 (20 mL) dropwise. Then
to this was added TEA (2 equiv.) dropwise. The reaction
mixture was then stirred at room temperature. The progress
of reaction was monitored by TLC. After the completion of
the reaction, CHCl3 (20 mL) was added. The excess of
iodine was removed by washing with saturated aqueous
Na2S2O3, water and brine successively. The organic layer
was dried over MgSO4, filtered and then concentrated under
reduced pressure to yield crude product. The crude com-
pound was then purified by column chromatography using
hexane-ethyl acetate as the eluent to afford compound 6a as
a white solid.
2-(1H-Indol-3-yl)-10-phenyl-12-azatetracyclo-
[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-
octaene (9a)
To a stirred solution of compound 3a (0.5 mmol) and
sodium formate (3 equiv.) in DMF (5 mL) was added Pd-
AHCTUNTGREN(NGNU PPh3)4 (5 mol%) and the mixture heated at 1108C for 6 h.
The progress of the reaction was monitored by TLC. After
the completion of the reaction, the reaction mixture was
cooled to room temperature. The solution was diluted with
water (25 mL) and then extracted with ethyl acetate (3ꢂ
30 mL). The organic layer washed with water and brine. The
organic layer was dried over MgSO4, filtered and then con-
centrated under reduced pressure to obtain the crude prod-
uct. The crude compound was the purified by column chro-
matography using ethyl acetate-hexane for afford pure com-
pound 9a as a white solid.
Spectral Data of New Compounds
3,3’-{[2-(Phenylethynyl)phenyl]methylene]bis(1H-indole) (i):
Yield: 89%; white solid; mp 250–2528C; FT-IR (KBr): n=
1
3431, 1635, 754 cmÀ1; H NMR (400 MHz, CDCl3): d=10.86
2-(1H-Indol-3-yl)-9-(4-methoxyphenyl)-10-phenyl-12-
azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
13,15,17-octaene (7a)
(brs, 2H), 7.57 (d, J=7.16 Hz, 1H), 7.38 (m, 2H), 7.35 (m,
8H), 7.24–7.31 (m, 2H), 7.05 (t, J=7.44 Hz, 2H), 6.85 À6.90
(m, 4H), 6.44 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
147.2, 137.1, 132.4, 131.6, 129.1, 129.0, 128.9, 127.2, 126.6,
124.3, 122.9, 122.0, 121.5, 119.1, 118.8, 117.9, 112.0, 93.9,
88.9, 37.9; LR-MS (ESI): m/z (relative intensity)=421 (80)
[MÀH]À, 127 (20); HR-MS (ESI): m/z=421.1704, calcd. for
C31H22N2 [MÀH]À: 421.1705.
To a solution of 3a (1 equiv.) and 4-methoxyphenylboronic
acid (1.2 equiv.) in DMF (10 mL) was added PdCl2ACTHNUTRGEN(UNG PPh3)2
(10 mol%). The mixture was then stirred at room tempera-
ture for 15 min followed by the addition of K2CO3
(2 equiv.). The reaction mixture was the stirred at 1108C for
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
2-(1H-Indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo-
[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13(18),14,16-octaene
(3a): Yield: 84%; white solid; mp 209–2118C; FT-IR (KBr):
2188C; FT-IR (KBr): n=3489, 3469, 650 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=8.07 (d, J=7.68 Hz, 1H), 7.96 (d, J=
7.92 Hz, 1H), 7.85 (brs, 1H), 7.49–7.51 (m, 3H), 7.34–7.41
(m, 3H), 7.25–7.32 (m, 3H), 7.12–7.14 (m, 2H), 6.96–7.02
(m, 2H), 6.85 (t, J=7.44 Hz, 1H), 6.72 (brs, 1H), 6.03 (s,
1H), 2.83 (q, J=7.48 Hz, 15.0 Hz, 2H), 2.67 (q, J=7.28 Hz,
14.80 Hz, 2H), 1.35 (t, J=7.52 Hz, 3H) 1.25 (t, J=7.5 Hz,
3H); 13C NMR (100 MHz, DMSO-d6): d=144.8, 143.7,
139.3, 139.1, 135.6, 135.5, 130.2, 129.6, 129.3, 128.8, 128.6,
128.2, 127,7, 126.6, 126.4, 126.2, 125.7, 122.9. 122.6, 121.8,
120.5, 120.5, 119.6, 117.6, 116.1, 115.6, 105.4, 40.3, 23.9, 23.6,
13.9, 13.4; LR-MS (EI): m/z (relative intensity)=604 (100)
[M]+, 603 (40); HR-MS: m/z=604.1372, calcd. for C35H29IN2
[M]+: 604.1376.
1
n=3468, 3431, 1635, 704 cmÀ1; H NMR (400 MHz, DMSO-
d6): d=10.74 (brs, 1H), 10.25 (brs, 1H), 8.08–8.09 (m, 1H),
7.89 (d, J=7.56 Hz, 1H), 7.60–7.62 (m, 2H), 7.36–7.40 (m,
2H), 7.28–7.33 (m, 5H), 7.13–7.15 (m, 3H), 6.96–6.99 (m,
2H), 6.71 (t, J=7.48 Hz, 1H), 6.62 (s, 1H), 6.06 (s, 1H);
13C NMR (100 MHz, DMSO-d6): d=144.7, 144.1, 139.5,
138.8, 136.8, 134.9, 130.3, 129.2, 128.9, 128.0, 127.7, 127.4,
126.4, 126.4, 125.5, 123.0, 122.3, 121.2, 120.5, 119.1, 118.9,
117.9, 117.8, 113.5, 111,7, 111.2, 105.3, 38.8; LR-MS (EI):
m/z (relative intensity)=549 (90) [M+H]+, 307 (40); HR-
MS: m/z=549.0826, calcd. for C31H21IN2 [M+H]+: 549.0828.
16-Chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-10-phenyl-12-
azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
9-Iodo-16-methoxy-2-(5-methoxy-1H-indol-3-yl)-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3f): Yield: 68%; grey solid; mp 220–
13,15,17-octaene (3b): Yield: 77%; yellow solid; mp 213–
2158C; FT-IR (KBr): n=360, 3400, 580 cmÀ1
;
1H NMR
2228C; FT-IR (KBr): n=3500, 3450, 1650 cmÀ1 1H NMR
;
(400 MHz, DMSO-d6): d=10.99 (brs, 1H), 10.49 (brs, 1H),
8.22 (s, 1H), 7.88 (d, J=7.72 Hz, 1H), 7.67 (d, J=7.60 Hz,
2H), 7.39–7.42 (m, 2H), 7.31- 7.34 (m, 4H), 7.29 (s, 1H),
(400 MHz, CDCl3): d=8.07 (d, J=7.56 Hz, 1H), 7.79 (s,
1H), 7.52 (m, 3H), 7.38–7.47 (m, 2H), 7.29–7.36 (m, 3H),
7.06–7.15 (m, 3H), 6.90 (d, J=7.92 Hz, 1H), 6.74 (d, J=
7.32 Hz, 1H), 6.62 (s, 1H), 6.40 (s, 1H), 5.92 (s, 2H), 3.96 (s,
3H), 3.32 (s, 3H); 13C NMR (100 MHz, CDCl3): d=154.8,
153.6, 152.2, 144.9, 143.9, 139.6, 138.9, 135.1, 132.2, 131.5,
130.9, 129.3, 129.1, 128,0, 127.6, 126,7, 125.9, 125.3, 123.5,
121.0, 113.5, 112.9, 112.5, 111.6, 110.3, 105.1, 101.3, 99.5,
55.5, 54.6, 38.8; LR-MS (EI): m/z (relative intensity)=608
(100) [M]+, 607 (95); HR-MS; m/z=608.0959, calcd. for
C33H25IN2O2 [M]+: 608.0961.
7.14–7.16ACHTUNGTRENNUNG(m, 2H), 6.99 (dd, J=1.19 Hz, 8.52 Hz, 1H), 6.89
(d, J=1.96 Hz, 1H), 6.70 (s, 1H), 6.11 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d=144.5, 143.4, 139.2, 138.8, 135.1,
135.0, 134.9, 131.9, 129.4, 128.9, 128.2, 127.9, 127.4, 127.4,
126.5, 125.6, 124.8, 123.8, 122.5, 122.4, 120.5, 120.3, 118.1,
117.1, 113.4, 113.3, 112.8, 106.5, 38.1; LR-MS (ESI): m/z
(relative intensity)=615 (100) [MÀH]À, 553 (60); HR-MS:
m/z=614.9898, calcd. for C32H21Br2IN2O [MÀH]À: 614.9892.
16-Bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-10-phenyl-
12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
13,15,17-octaene (3c): Yield: 80%; light yellow solid; mp
2-(5-Cyano-1H-indol-3-yl)-10-iodo-9-phenyl-12-azatetracy-
clo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene-
16-carbonitrile (3g): Yield: 77%; white solid; mp 216–
245–2468C; FT-IR (KBr): n=3808, 3372, 1447, 585 cmÀ1
;
2188C; FT-IR (KBr): n=3480, 3494, 2280, 650 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=11.0 (brs, 1H), 10.50
(brs, 1H), 8.36 (s, 1H), 7.87 (d, J=7.68 Hz, 1H), 7.67 (d, J=
6.92 Hz, 1H), 7.39–7.42 (m, 3H), 7.31–7.34 (m, 2H), 7.28
(m, 1H), 7.25- 7.26 (m, 3H), 7.10–7.11 (m, 1H), 7.07–7.08
(m, 2H), 6.68 (s, 1H), 6.11 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d=144.4, 143.6, 139.1, 138.8, 135.3, 135.0, 131.6,
129.4, 128.9, 128.2, 128.1, 127.9, 127.4, 127.2, 125.6, 124.9,
124.5, 122.9, 121.2, 120.3, 120.2, 117.4, 113.7, 113.3, 113.2,
111.8, 110.5, 106.4, 38.8; LR-MS (ESI): m/z (relative intensi-
ty)=703 (65) [MÀH]À, 643 (80); HR-MS: m/z=702.8878,
calcd. for C31H19Br2IN2 [MÀH]À: 702.8881.
1H NMR (400 MHz, DMSO-d6): d=11.46 (bs, 1H), 10.97
(bs, 1H), 8.79 (s, 1H), 7.88 (d, J=7.61 Hz, 1H), 7.68–7.70
(m, 2H), 7.46–7.52 (m, 5H), 7.35 (m, 4H), 7.22 (m, 2H),
6.87 (s, 1H), 6.27ACTHNUTRGNEUNG
(s, 1H); 13C NMR (100 MHz, DMSO-d6):
d=144.1, 143.3, 138.9, 138.8, 138.3, 135.2, 132.7, 129.8, 128.5,
128.3, 127.5, 127.4, 126.2, 126.0, 125.8, 125.8, 125.3, 125.1,
124.4, 124.1, 123.4, 121.2, 120.8, 120.7, 114.6, 113.1, 112.9,
107.5, 101.5, 100.1, 37.8; LR-MS (EI): m/z (relative intensi-
ty)=598 (100) [M]+; HR-MS: m/z=598.0654, calcd. for
C35H19IN4 [M]+: 598.0650.
10-Iodo-16-nitro-2-(5-nitro-1H-indol-3-yl)-9-phenyl-12-
azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,
15,17-octaene (3h): Yield: 71%; yellow solid; mp 220–
9-Iodo-14-methyl-2-(7-methyl-1H-indol-3-yl)-10-phenyl-
12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,
13,15,17-octaene (3d): Yield: 80%; white solid; mp 246–
2228C; FT-IR (KBr): n=3500, 3455, 1650 cmÀ1 1H NMR
;
2488C; FT-IR (KBr): n=3446, 3422, 1620, 745 cmÀ1
;
(400 MHz, DMSO-d6): d=11.62 (bs, 1H), 11.13 (bs, 1H),
9.29 (s, 1H), 8.07 (dd, J=1.76 Hz, 7.28 Hz, 1H), 7.89–7.91
1H NMR (400 MHz, DMSO-d6): d=10.69 (brs, 1H), 9.93
(brs, 1H), 7.89 (dd, J=15.08 Hz, 7.96 Hz, 2H), 7.56–7.59 (m,
2H), 7.32–7.37 (m, 2H), 7.29–7.30 (m, 3H), 7.04–7.08 (m,
2H), 6.92–6.97 (m, 2H), 6.79 (d, J=6.84 Hz, 1H), 6.64–6.67
(m, 2H), 6.00 (s, 1H), 2.41 (s, 3H), 2.32 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=144.4, 144.4, 139.6, 139.2, 136.3,
135.9, 134.9, 130.2, 129.5, 129.1, 127.7, 127.6, 127.3, 126.1,
125.5, 125.3, 123.2, 122.7, 121.1, 120.8, 119.9, 119.4, 118.0,
116.5, 115.5, 114.6, 113.7, 105, 39.0, 16.9, 16.6; LR-MS (EI):
m/z (relative intensity)=577 (100) [M+H]+, 578 (60); HR-
MS: m/z=577.1135, calcd. for C33H25IN2 [M+H]+: 577.1141.
14-Ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-10-phenyl-12-
azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,
15,17-octaene (3e): Yield: 79%; yellow solid; mp 216–
(m, 2H), 7.82–7.87 (m, 2H), 7.80
ACHTUGTNREN(UNG s, 1H), 7.49–7.44ACHTUNGTERN(NUGN m, 4H),
7.38–7.35 (m, 4H), 6.92
AHCTUNGTRENNUNG
(100 MHz, DMSO-d6): d=144, 143.1, 141.2, 139.9, 139.9,
139.7, 138.9, 138.8, 135.2, 133.8, 129.9, 128.5, 128.3, 127.6,
126.9, 126.1, 125.6, 124.9, 122.5, 117.9, 116.3, 116.2, 116.1,
115.8, 112.3, 112.3, 111.9, 107.9, 37.8; LR-MS (EI): m/z (rel-
ative intensity)=638 (100) [M]+, 637 (95); HR-MS: m/z=
638.0459, calcd. for C31H19IN4O4 [M]+: 638.0451.
2-(1H-Indol-3-yl)-9-iodo-5-methoxy-10-phenyl-12-azate-
tracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-oc-
taene (3i): Yield: 83%; yellow solid; mp 180–1818C; FT-IR
(KBr): n=3468, 1636, 339 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=10.73 (brs, 1H), 10.19 (brs, 1H), 8.09 (s,
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
These are not the final page numbers!

Sachin D. Gawande et al.
FULL PAPERS
1H), 7.81 (d, J=8.64 Hz, 1H), 7.27–7.29 (m, 5H), 7.13–7.20
(m, 4H), 6.95–7.00 (m, 2H), 6.88–6.90 (d, J=8.24 Hz, 1H),
6.69 (t, J=7.32 Hz, 1H), 6.63 (s, 1H), 6.01 (s, 1H), 3.83 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d=160.0, 145.5,
144.9, 138.3, 136.7, 136.6, 136.4, 131.7, 130.5, 129.0, 127.9,
127.6, 126.4, 125.7, 122.2, 120.6, 120.5, 119.0, 118.9, 117.9,
117.8, 113.6, 112.0, 111.7, 111.3, 111.1, 105.6, 55.3, 38.9; LR-
MS: m/z (relative intensity)=579 (100) [M+H]+, 541 (80),
527 (30); HR-MS: m/z=579.0934, calcd. for C32H23IN2O
[M+H]+: 579.0933.
(m, 2H), 6.96–6.98 (m, 2H), 6.90 (dd, J=2.44 Hz, 8.76 Hz,
1H), 6.80 (d, J=6.88 Hz, 1H), 6.65–6.69 (m, 2H), 5.99 (s,
1H), 3.83 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d=159.9, 145.8, 144.6, 138.5, 13.5,
13.2, 135.9, 131.9, 130.4, 129.6, 127.6, 127.5, 126.1, 123.1,
122.6, 122.1, 121.1, 120.8, 119.9, 119.3, 118.1, 116.5, 115.5,
113.8, 111.9, 111.2, 105.6, 55.3,39.09, 17.0, 16.3; LR-MS (EI):
m/z (relative intensity)=606 (60) [M]+, 605 (100); HR-MS:
m/z=606.1161, calcd. for C34H27IN2O [M]+: 606.1168.
9-Iodo-14-methyl-2-(7-methyl-1H-indol-3-yl)-5-nitro-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3n): Yield: 61%; red solid; mp 208–
2-(1H-Indol-3-yl)-9-iodo-5-nitro-10-phenyl-12-azatetracy-
clo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene
(3j); Yield: 78%; yellow solid; mp 223–2258C; FT-IR (KBr):
2108C; FT-IR (KBr): n=3445, 1580, 1385 cmÀ1 1H NMR
;
1
n=3450, 1530, 1365, 600 cmÀ1; H NMR (400 MHz, DMSO-
(400 MHz, [DMSO-d6): d=10.77 (brs, 1H), 10.13 (brs, 1H),
8.61 (d, J=2.04 Hz, 1H), 8.08–8.12 (m, 2H), 8.03 (d, J=
7.88 Hz, 1H), 7.31 (m, 4H), 7.08 (t, J=7.78 Hz, 1H), 6.98
(d, J=7.04 Hz, 1H), 6.78–6.83 (m, 3H), 6.63–6.67 (m, 2H),
6.34 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=147.2, 145.6, 145.4, 143.8, 141.7, 136.6, 136.2,
136.0, 130.2, 129.5, 128.0, 127.8, 125.9, 125.4, 123.7, 122.9,
122.4, 121.8, 121.2, 120.9, 120.1, 119.9, 119.6, 118.2, 116.5,
116.1, 112.5, 101.7, 38.4, 17.0, 16.6; LR-MS (EI): m/z (rela-
d6): d=10.81 (brs, 1H), 10.40 (brs, 1H), 8.65 (s, 1H), 8.19–
8.22 (s, 1H), 8.12–8.13 (m, 2H), 7.31–7.34 (m, 4H), 7.28–
7.29 (m, 2H), 7.15–7.19 (m, 3H), 6.98 (t, J=7.32 Hz, 1H),
6.86–6.88 (m, 1H), 6.70 (t, J=7.40 Hz, 1H), 6.62 (s, 1H),
6.39 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d=147.3,
145.1, 144.9, 144.1, 141.6, 137.1, 136.5, 136.2, 130.2, 128.8,
128.1, 127.9, 126.2, 125.4, 123.8, 122.8, 121.9, 120.9, 120.6,
119.9, 119.3, 118.8, 118.5, 117.9, 112.3, 111.8, 111.3, 101.8,
38.3; LR-MS (EI): m/z (relative intensity)=593 (100) [M]+,
547 (55); HR-MS: m/z=593.0591, calcd. for C31H20IN3O2
[M]+: 593.0600.
tive intensity)=621ACTHNUTRGNEUNG
(100) [M+], 595.2 (70); HR-MS: m/z=
621.0909, calcd. for C33H24IN3O2 [M+]: 621.0913.
14-Ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-5-methoxy-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3o): Yield: 75%; yellow solid; mp
2-(1H-Indol-3-yl)-9-iodo-5,6-dimethoxy-10-phenyl-12-aza-
tetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-
octaene (3k): Yield: 61%; white solid; mp 230–2328C; FT-
1
167–1698C; FT-IR (KBr): n=3520, 3489, 670 cmÀ1; H NMR
IR (KBr): n=3461, 3444, 1636, 551 cmÀ1
;
1H NMR
(400 MHz, DMSO-d6) d=10.71 (brs, 1H), 9.87 (brs, 1H),
7.91 (d, J=7.92 Hz, 1H), 7.78 (d, J=8.76 Hz, 1H), 7.24–7.27
(m, 4H), 7.15–7.16 (m, 2H), 7.09 (t, J=7.52 Hz, 1H), 6.97–
6.99 (m, 3H), 6.88 (dd, J=2.60 Hz, 8.80 Hz, 1H), 6.79–6.81
(m, 1H), 6.68 (d, J=7.62 Hz, 1H), 6.65 (s, 1H), 5.95 (s, 1H),
3.81 (s, 3H), 2.78 (q, J=11.4 Hz, 7.4 Hz, 2H), 2.69 (m, 2H)
1.19 (t, J=7.48 Hz, 3H), 1.09 (t, J=7.48 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6): d=145.9, 144.7, 138.6, 136.6, 135.4,
135.1, 132.0, 130.3, 129.6, 128.0, 127.6, 127.5, 127.0, 126.6,
126.4, 125.8, 122.5, 122.3, 121.1, 119.5, 119.3, 118.2, 116.6,
115.5, 113.8, 111.9, 111.2, 105.7, 55.3, 39.1, 23.5, 23.1, 14.4,
14.1; LR-MS (EI): m/z (relative intensity)=634 (80) [M+],
508 (45); HR-MS: m/z=634.1475, calcd. for: C36H31IN2O
(M+): 634.1481.
(400 MHz, DMSO-d6): d=10.72 (brs, 1H), 10.17 (brs, 1H),
8.09 (s, 1H), 7.41 (m, 3H), 7.25–7.29 (m, 5H), 7.12–7.15 (m,
3H), 7.04 (d, J=7.88 Hz, 1H), 6.97 (t, J=7.40 Hz, 1H), 6.71
(t, J=7.52 Hz, 1H), 6.65 (s, 1H), 5.99 (s, 1H), 3.87 (s, 3H),
3.78 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=149.7,
145.7, 145.0, 138.6, 137.4, 136.8, 136.4, 130.9, 130.8, 130.4,
128.8, 128.0, 127.6, 126.4, 125.5, 122.9, 122.2, 121.2, 120.4,
119.1, 118.8, 118.0, 117.8, 114.1, 111.6, 111.1, 110.9, 105.9,
55.7, 55.6, 38.2; LR-MS (EI): m/z (relative intensity)=608
(100) [M]+, 481 (80); HR-MS (ESI): m/z=609.1038, calcd.
for C33H25IN2O2 [M+H]+: 609.1039.
2-(1H-Indol-3-yl)-13-iodo-12-phenyl-17,19-dioxa-10-aza-
pentacyclo[12.7.0.03,11.04,9.016,20]henicosa-1(14),3(11),4,6,8,
12,15,20-octaene (3l): Yield: 69%; pink solid; mp 238–
14-Ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-5-nitro-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3p): Yield: 68%; yellow solid; mp
2408C; FT-IR (KBr): n=3550, 3480, 590 cmÀ1 1H NMR
;
(400 MHz, DMSO): d=10.71 (brs, 1H), 10.31 (brs, 1H),
8.05 (d, J=7.12 Hz, 1H), 7.86 (d, J=7.64 Hz, 1H), 7.56 (d,
J=7.40 Hz, 1H), 7.35 (t, J=7.24 Hz, 1H), 7.26–7.29 (m,
3H), 7.11–7.17 (m, 3H), 6.95–6.98 (m, 3H), 6.65–6.69 (m,
2H), 6.57 (s, 1H), 5.99 (s, 1H), 5.96 (s, 2H); 13C NMR
(100 MHz, DMSO-d6): d=147.1, 147.0, 144.5, 139.3, 139.1,
138.9, 137.1, 136.8, 135.4, 130.8, 128.7, 127.7, 126.6, 125.9,
125.8, 123.5, 122.9, 121.4, 121.0, 119.6, 119.2, 118.3, 113.9,
112.1, 111.7, 108.4, 105.9, 101.3, 38.9; LR-MS (EI): m/z (rel-
ative intensity)=591 (100) [M+H]+, 535 (20); HR-MS:
m/z=591.0933, calcd. for C32H21IN2O2 [M+H]+: 591.0933.
9-Iodo-5-methoxy-14-methyl-2-(7-methyl-1H-indol-3-yl)-
10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-
199–2018C; FT-IR (KBr): n=3472, 3431, 1590, 1379 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=10.79 (brs, 1H), 10.12
(brs, 1H), 8.16 (d, J=0.2 Hz, 1H), 8.07–8.14 (m, 2H), 8.03
(d, J=7.92 Hz, 1H), 7.29–7.31 (m, 4H), 7.01–7.13 (m, 3H),
6.88 (d, J=7.84 Hz, 1H), 6.81 (d, J=6.96 Hz, 1H), 6.69 (d,
J=7.60 Hz, 1H), 6.64–6.66 (m, 1H), 6.34 (s, 1H), 2.69–2.81
(m, 4H), 1.19 (t, J=7.48 Hz, 3H), 1.10 (t, J=7.44 Hz, 3H);
13C NMR (100 MHz, DMSO-d6): d=147.2, 145.6, 145.5,
143.8, 141.7, 136.2, 135.8, 135.1, 130.0, 129.6, 127.9, 127.7,
127.3, 126.6, 126.1, 125.5, 122.8, 122.5, 121.7, 121.6, 119.9,
119.7, 119.3, 118.3, 116.5, 116.1, 112.4, 101.7, 38.9, 23.4, 23.1,
14.3, 14.1; LR-MS (EI): m/z (relative intensity)=649 (100)
[M]+, 603 (50); HR-MS: m/z=649.1224, calcd. for
C35H28IN3O2 [M]+: 649.1226.
1(11),3(8),4,6,9,13,15,17-octaene (3m): Yield: 75%; white
solid; mp 219–2128C; FT-IR (KBr): n=3445, 1650,
700 cmÀ1
;
1H NMR (400 MHz, DMSO-d6); d=10.73 (brs,
16-Chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-5-methoxy-
10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),
3(8),4,6,9,13,15,17-octaene (3q): Yield: 73%; pink solid; mp
1H), 9.92 (brs, 1H), 7.95 (d, J=7.88 Hz, 1H), 7.82 (d, J=
8.76 Hz, 1H), 7.27 (m, 3H), 7.19–7.20 (m, 2H), 7.06–7.09
12
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ÝÝ
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Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole
188–1908C; FT-IR (KBr): n=3530, 3470, 1635, 540 cmÀ1
;
2.60 Hz, 8.80 Hz, 1H), 6.79 (dd, J=2.52 Hz, 8.76 Hz, 1H),
6.62- 6.64 (m, 2H), 6.57 (d, J=2.12 Hz, 1H), 5.98 (s, 1H),
1H NMR (400 MHz, DMSO-d6): d=10.99 (brs, 1H), 10.44
(brs, 1H), 8.22 (s, 1H), 7.81 (d, J=8.76 Hz, 1H), 7.28–7.34
(m, 7H), 7.13–7.15 (m, 2H), 6.89–7.00 (m, 3H), 6.73 (s, 1H),
6.06 (s, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d=160.2, 145.1, 144.7, 138.0, 136.7, 135.1, 134.9, 132.1, 131.6,
128.9, 128.2, 127.9, 127.4, 126.7, 124.8, 123.9, 122.6, 122.3,
120.5, 119.8, 118.1, 117.3, 113.5, 113.3, 112.8, 112.1, 111.6,
106.8, 55.4, 38.2; LR-MS (EI): m/z (relative intensity)=647
(95) [M+H]+, 521 (80); HR-MS: m/z=647.0150, calcd. for
C32H22Cl2IN2O [M+H]+: 647.0154.
3.87 (s, 3H), 3.85 (s, 3H), 3.37ACHTUNGTRNEUNG
(s, 3H); 13C NMR (100 MHz,
DMSO-d6): d=159.9, 153.6, 152.2, 145.3, 145.2, 138.5, 136.7,
132.1, 131.7, 131.5, 131.2, 128.9, 128.0, 127.5, 126.7, 126.1,
123.4, 120.4, 113.5, 112.7, 112.4, 112.2, 111.6, 111.2, 110.3,
105.4, 101.3, 99.6, 55.5, 55.3, 54.6, 38.9; LR-MS (EI): m/z
(relative intensity)=638 (100) [M]+, 637 (55); HR-MS
(ESI): m/z=639.1152, calcd. for C34H27IN2O3 [M+H]+:
639.1145.
2-(1H-Indol-3-yl)-9-iodo-10-(4-methylphenyl)-12-azatetra-
cyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-oc-
taene (3v): Yield: 68%; yellow solid; mp 210–2128C; FT-IR
16-Chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-5-nitro-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3r): Yield: 85%; light red solid; mp
(KBr): n=3477, 3410, 599 cmÀ1
;
1H NMR (400 MHz,
193–1958C; FT-IR (KBr): n=3490, 1580, 1360 cmÀ1
;
DMSO-d6): d=10.74 (brs, 1H), 10.23 (brs, 1H), 8.07–8.09
(m, 1H), 7.88 (d, J=7.76 Hz, 1H), 7.59–7.61 (m, 2H), 7.37
(t, J=7.16 Hz, 1H), 7.28–7.31 (m, 4H), 7.13–7.15 (m, 4H),
6.96–7.00 (m, 2H), 6.71 (t, J=7.38 Hz, 1H), 6.62 (s, 1H),
6.05 (s, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d=144.2, 141.9, 139.5, 138.9, 136.9, 136.8, 136.4, 135.1, 130.5,
129.5, 129.2, 128.7, 127.4, 126.4, 125.6, 125.4, 123.0, 122.3,
121.1, 120.5, 119.1, 118.9, 117.9, 117.8, 113.6, 111.8, 111.2,
105.2, 38.9, 20.8; LR-MS (EI): m/z (relative intensity)=563
(100) [M+H]+, 562 (80); HR-MS: m/z=563.0982, calcd. for
C32H23IN2 [M+H]+: 563.0984.
1H NMR (400 MHz, DMSO-d6): d=11.08 (brs, 1H), 10.66
(brs, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 8.09–8.14 (m, 2H),
7.36–7.38 (m, 3H), 7.31–7.34 (m, 3H), 7.17–7.19 (m, 2H),
7.00 (dd, J=8.56 Hz, 1.80 Hz, 1H), 6.80 (d, J=1.52 Hz, 1H),
6.74 (s, 1H), 6.43 (s, 1H); 13C NMR (100 MHz, DMSO): d=
147.4, 145.1, 144.6, 143.9, 141.2, 136.4, 135.7, 134.9, 131.8,
128.8, 128.3, 128.2, 127.2, 126.4, 125.2, 124.2, 122.9, 122.7,
122.0, 120.6, 120.3, 119.8, 118.0, 117.8, 113.6, 112.1, 103.2,
37.5; LR-MS (EI): m/z (relative intensity)=662 (100) [M+
H]+; HR-MS: m/z=661.9891, calcd. for C31H18Cl2IN3O2
[M+H]+: 661.9899.
10-(2H-1,3-Benzodioxol-5-yl)-2-(1H-indol-3-yl)-9-iodo-12-
azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,
15,17-octaene (3w): Yield: 62%; yellow solid; mp 225–
16-Bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-5-methoxy-
10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),
3(8),4,6,9,13,15,17-octaene (3s): Yield: 77%; white solid; mp
2278C; FT-IR (KBr): n=3590, 3450, 1630, 558 cmÀ1
;
236–2388C; FT-IR (KBr): n=3525, 3425, 1635, 746 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=10.74 (brs, 1H), 10.22
(brs, 1H), 8.07 (d, J=5.09 Hz, 1H), 7.34 (m, 3H), 7.26–7.29
(m, 3H), 7.24 (m, 2H), 7.12–7.14 (m, 3H), 6.95–6.99 (m,
2H), 6.67–6.72 (m, 2H), 6.09 (s, 1H), 5.98 (d, J=11.69 Hz,
2H); 13C NMR (100 MHz, DMSO): d=148.2, 144.8, 144.8,
139.0, 138.9, 136.9, 136.5, 132.5, 130.5, 128.9, 128.0, 127.7,
126.4, 125.5, 123.0, 122.3, 121.2, 120.5, 119.1, 118.9, 117.9,
117.8, 114.3, 113.7, 111.7, 111.2, 107.1, 105.3, 101.5, 38.4;
LR-MS (EI): m/z (relative intensity)=592 (100) [M]+; HR-
MS: m/z=592.0639, calcd, for C32H21IN2O2: 592.0648.
1H NMR (400 MHz, DMSO): d=11.0 (brs, 1H), 10.44 (brs,
1H), 8.35 (s, 1H), 7.79 (d, J=8.68 Hz, 1H), 7.31 (m, 5H),
7.28 (m, 1H), 7.26 (m, 1H), 7.24 (m, 2H), 7.13 (s, 1H), 7.09
(d, J=8.52 Hz, 1H), 6.91 (d, J=8.24 Hz, 1H), 6.70 (s, 1H),
6.06 (s, 1H), 3.85 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d=160.2, 145.0, 144.7, 137.9, 136.7,135.3, 135.0, 131.9, 131.6,
129.1, 128.3, 128.1, 127.9, 127.4, 124.8, 124.5, 123.0, 121.3,
120.4, 119.0, 113.7, 113.4, 112.0, 111.8, 111.6, 110.6, 106.9,
55.4, 38.1; LR-MS (EI): m/z (relative intensity)=736 (100)
[M+H]+, 734 (80); HR-MS: m/z=733.9062, calcd. for
C30H18N2Br2I [M+H]+: 733.9065.
9-Iodo-N-methyl-N,10-diphenyl-12-azatetracyclo-
[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaen-2-
amine (6a): Yield: 65%; light yellow solid; mp 238–2408C;
16-Bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-5-nitro-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3t): Yield: 78%; red solid; mp 223–
FT-IR (KBr): n=3490, 550 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=10.28 (brs, 1H), 7.91 (d, J=7.72 Hz, 1H),
7.85 (d, J=7.63 Hz, 1H), 7.45–7.47 (m, 2H), 7.33–7.37 (m,
3H), 7.27–7.31 (m, 2H), 7.24 (m, 1H), 7.11 (t, J=7.04 Hz,
1H), 7.03–7.07 (m, 2H), 6.58 (d, J=8.28 Hz, 2H), 6.36 (d,
J=8.40 Hz, 2H), 5.76 (s, 1H), 5.37 (brs, 1H), 2.58 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d=147.9, 144.9, 144.0,
139.9, 138.9, 136.9, 134.9, 130.1, 129.1, 128.9, 128.7, 128.2,
128.2, 127.8, 127.3, 126.3, 125.4, 122.4, 121.9, 119.1, 117.1,
111.7, 110.9, 104.6, 44.3, 29.9; LR-MS (EI): m/z (relative in-
tensity)=538 (100) [M]+, 537 (40); HR-MS: m/z=538.0904,
calcd. for C30H23IN2 [M]+: 538.0906.
2258C; FT-IR (KBr): n=3439, 3400, 1530, 1360 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=11.08 (brs, 1H), 10.66
(brs, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.09–8.15 (m, 2H),
7.34–7.38 (m, 3H), 7.26–7.29 (m, 4H), 7.09–7.12 (m, 2H),
6.97 (s, 1H), 6.72 (s, 1H), 6.44 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d=147.4, 145.1, 144.7, 143.9, 141.3, 136.4, 135.7,
135.1, 131.6, 128.9, 128.4, 128.3, 127.9, 127.1, 125.4, 124.9,
123.2, 122.2, 121.2, 120.9, 120.3, 119.9, 113.9, 113.4, 112.1,
110.7, 103.2, 37.4; LR-MS (EI): m/z (relative intensity)=750
(100) [M+H]+; HR-MS: m/z=749.8894, calcd. for
C31H18Br2IN3O2 [M+H]+: 749.8889.
2-(1H-Indol-3-yl)-9-(4-methoxyphenyl)-10-phenyl-12-aza-
tetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-
octaene (7a): Yield: 76%; light pink solid; mp 189–1918C;
9-Iodo-5,16-dimethoxy-2-(5-methoxy-1H-indol-3-yl)-10-
phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),
4,6,9,13,15,17-octaene (3u): Yield: 62%; white solid; mp
1
FT-IR (KBr): n=3490, 3410, 1700 cmÀ1; H NMR (400 MHz,
218–2208C; FT-IR (KBr): n=3490, 3410 cmÀ1
;
1H NMR
DMSO-d6): d=10.77 (brs, 1H), 10.22 (brs, 1H), 7.96 (d, J=
7.36 Hz, 1H), 8.00 (d, J=7.28 Hz, 1H), 7.37–7.40 (m, 2H),
7.33 (d, J=8.08 Hz, 1H), 7.11 (m, 6H), 6.96–6.99 (m, 2H),
6.84–6.88 (m, 3H), 6.69 (t, J=7.12 Hz, 1H), 6.58 (s, 1H),
(400 MHz, DMSO-d6): d=(ppm) 10.56 (brs, 1H), 9.99 (brs,
1H), 7.83 (d, J=8.80 Hz, 1H), 7.66–7.67 (m, 1H), 7.30 (m,
2H), 7.25–7.29 (m, 3H), 7.16–7.19 (m, 3H), 6.91 (dd, J=
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
13
ÞÞ
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Sachin D. Gawande et al.
FULL PAPERS
6.42 (d, J=8.36 Hz, 2H), 6.36 (d, J=8.08 Hz, 2H), 6.08 (s,
1H), 3.56 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
156.9, 144.3, 140.1, 139.8, 138.1, 137.3, 136.6, 134.9, 132.5,
131.6, 131.4, 131.4, 129.6, 127.9, 126.8, 126.2, 126.0, 124.8,
123.2, 121.8, 120.5, 119.4, 118.9, 118.8, 117.9, 117.8, 115.4,
112.3, 111.7, 111.4, 54.7, 38.9; LR-MS (EI): m/z (relative in-
tensity)=528 (100) [M]+, 412 (65); HR-MS: m/z=528.2208,
calcd. for C38H28N2O [M]+: 528.2202.
Kumar, M. A. Eissenstat, J. L. Herrmann, J. R. Wetzer,
D. Rosi, R. E. Philion, S. J. Daum, D. J. Hlasta, R. K.
Kullnig, J. H. Ackerman, D. R. Haubrich, D. A. Lut-
tinger, E. R. Baizman, M. S. Miller, S. J. Ward, J. Med.
Chem. 1991, 34, 1099–1110, and references cited there-
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Ethyl (2E)-3-[2-(1H-Indol-3-yl)-10-phenyl-12-azatetracy-
clo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaen-9-
yl]prop-2-enoate (8a): Yield: 98%; white solid; mp 177–
1798C; FT-IR (KBr): n=3490, 3410, 2899, 1735 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=10.57 (brs, 1H), 10.43
(brs, 1H), 8.06 (d, J=7.40 Hz, 1H), 7.43 (d, J=7.60 Hz,
1H), 7.56–7.57 (m, 1H), 7.39–7.45 (m, 4H), 7.25–7.31 (m,
4H), 7.11–7.19 (m, 3H), 6.86–6.94 (m, 3H), 6.67 (t, J=
7.24 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.58 (d, J=15.6 Hz,
1H), 3.94–3.97 (m, 2H), 1.09 (t, J=7.08 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6): d=166.3, 146.2, 144.6, 138.4, 137.9,
137.6, 136.4, 135.2, 133.9, 132.4, 131.6, 130.2, 128.5, 128.4,
128.4, 128.1, 126.3, 125.8, 124.6, 123.8, 123.0, 122.7, 120.5,
119.3, 118.9, 118.4, 117.8, 113.9, 111.9, 59.7, 39.9, 14.0; LR-
MS (EI): m/z (relative intensity)=520 (100) [M]+, 404 (60);
HR-MS: m/z=520.2148, calcd. for C36H28N2O2 [M]+:
520.2151.
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Zang, Chem. Commun. 2012, 48, 1168–1170; b) A.
Sharma, P. Appukkuttan, E. V. D. Eycken, Chem.
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2-(1H-Indol-3-yl)-10-phenyl-12-azatetracyclo-
[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene
(9a): Yield: 74%; white solid; mp 250–2528C; FT-IR (KBr):
[4] a) S. Xu, Y. Zhou, J. Xu, H. Jiang, H. Liu, Green
Chem. 2013, 15, 718–726; b) S. J. Heffernan, J. P.
Tellam, M. E. Queru, A. C. Silvanus, D. Benito, M. F.
Mahon, A. J. Hennessy, B. I. Andrews, D. R. Carbery,
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J. Badorrek, G. Raabe, D. Enders, Chem. Eur. J. 2011,
17, 13409–13414; d) N. Chernyak, D. Tilly, Z. Li, V. Ge-
vorgyan, Arkivoc 2011, v, 76–91; e) X. Xie, X. Du, Y.
Chen, Y. Liu, J. Org. Chem. 2011, 76, 9175–9181; f) N.
Chernyak, D. Tilly, Z. Li, V. Gevorgyan, Chem.
Commun. 2010, 46, 150–152.
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Chem. Soc. 2011, 133, 2100–2103; b) A. C. Silvanus,
S. J. Heffernan, D. J. Liptrot, G. Kociok-Kçhn, B. I. An-
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Wu, Asian J. Org. Chem. 2012, 1, 302–312; h) B. Godoi,
R. F. Schumacher, G. Zeni, Chem. Rev. 2011, 111,
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Chem. 2011, 76, 10269–10274; j) T. Aggarwal, M.
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Huang, H. Jiang, H. Huang, X. Pan, J. Org. Chem.
2011, 76, 1134–1139; l) R. Mancuso, S. Mehta, B. Gabri-
ele, G. Salerno, W. S. Jenks, R. C. Larock, J. Org.
Chem. 2010, 75, 897–901; m) S. Mehta, R. C. Larock, J.
n=3490, 3410 cmÀ1 1H NMR (400 MHz, DMSO-d6): d=
;
10.74 (brs, 1H), 10.54 (brs, 1H), 7.99 (d, J=7.52 Hz, 1H),
7.82 (d, J=7.48 Hz, 1H), 7.52–7.58 (m, 3H), 7.37–7.49 (m,
5H), 7.25–7.32 (m, 2H), 7.10–7.20 (m, 3H), 7.06 (s, 1H),
6.94 (t, J=7.12 Hz, 1H), 6.80 (t, J=7.05 Hz, 1H), 6.54 (s,
1H), 6.11 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d=
141.6, 140.3, 137.2, 136.4, 134.7, 133.6, 131.5, 131.0, 129.6,
129.1, 128.6, 128.5, 128.3, 127.9, 126.4, 126.2, 125.5, 122.4,
121.9, 120.5, 118.9, 118.8, 117.9, 117.9, 117.8, 114.8, 111.7,
111.2, 38.8; LR-MS (ESI): m/z (relative intensity)=421 (80)
[MÀH]À, 467 (100); HR-MS: m/z=422.1779, calcd. for
C31H22N2 [M]+: 422.1783.
Acknowledgements
Financial support for this work by the National Science
Council of the Republic of China (NSC 100-2113M-003-008-
MY3), National Taiwan Normal University (99T3030-2, 99-
D, 100-D-06) and Instrumentation Centre at National Taiwan
Normal University is gratefully acknowledged.
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FULL PAPERS
16 Molecular Iodine-Mediated Cascade Reaction of 2-
Alkynylbenzaldehyde and Indole: An Easy Access to
Tetracyclic Indoloazulene Derivatives
Adv. Synth. Catal. 2013, 355, 1 – 16
Sachin D. Gawande, Veerababurao Kavala,
Manoj R. Zanwar, Chun-Wei Kuo, Hsiu-Ni Huang,
Chiu-Hui He, Ting-Shen Kuo, Ching-Fa Yao*
16
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These are not the final page numbers!