Rh(III)-Catalyzed Domino [4 + 2] Annulation/Aza-Michael Addition of N-(Pivaloyloxy)benzamides with 1,5-Enynes via C-H Activation: Synthesis of Functionalized Aromathecins

Article abstract of DOI:10.1021/acs.joc.0c00615

Reported herein are the Rh(III)-catalyzed cascade annulation reactions of N-(pivaloyloxy)benzamides with 1,5-enynes to access diversely substituted aromathecin derivatives involving C-H activation. The developed procedure offers an efficient synthetic tool for the assembly of a wide range of N-(pivaloyloxy)benzamides and 1,5-enynes with good atom economy and functional group tolerance. The key reactions involved in this annulation are alkyne insertion and aza-Michael addition under oxidant-free mild reaction conditions.

Full text of DOI:10.1021/acs.joc.0c00615

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Article
Rh(III)-Catalyzed Domino [4+2] Annulation/aza-Michael
Addition of N-(pivaloyloxy)benzamides with 1,5-Enynes via
C-H Activation: Synthesis of Functionalised Aromathecins
Chada Raji Reddy, Kathe Mallesh, Srinivas Bodasu, and Ramachandra Reddy Donthiri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00615 • Publication Date (Web): 20 May 2020
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Rh(III)-Catalyzed Domino [4+2] Annulation/aza-Michael Addition
of N-(pivaloyloxy)benzamides with 1,5-Enynes via C-H Activation:
Synthesis of Functionalised Aromathecins
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Chada Raji Reddy,*, a, b Kathe Mallesh,a, b Srinivas Bodasua and
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Ramachandra Reddy Donthiria
aDepartment of Organic Synthesis & Process Chemistry
CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad 500007, India
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
E-mail: rajireddy@iict.res.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT: Reported herein is the Rh(III)-catalyzed cascade annulation reactions of N-
(pivaloyloxy)benzamides with 1,5-enynes to access diversely substituted aromathecin derivatives
involving C-H activation. The developed procedure offers an efficient synthetic tool for the
assembly of a wide range of N-(pivaloyloxy)benzamides and 1,5-enynes with good atom-
economy and functional group tolerance. The key reactions involved in this annulation are
alkyne insertion and aza-Michael addition under oxidant-free mild reaction conditions.
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KEYWORDS: [4+2]-Annulation, C-H activation, N-(pivaloyloxy)benzamide, aromathecin
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derivatives, 1,5-enyne, cascade annulation
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INTRODUCTION
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Activation of arene C-H bond via transition metal catalysis is considered to be a very powerful
tool to form the carbon-carbon or carbon-heteroatom bonds for the synthesis of various complex
molecules due to its excellent selectivity as well as atom and step economy.1 Over the past
decade, directing group (DG) assisted Rh-catalyzed C-H activation followed by the annulation
with unsaturated bonds played a significant role in the synthesis of hetero and carbocycles.2
Recently in rhodium catalysis, N-O bond containing DGs were used to make the reaction redox-
neutral where the N-O bond assists for the catalyst turnover without an external oxidant and also
facilitates the further cyclisation after the alkyne insertion.3 Despite these advantages, the use of
N-O bond containing DGs in tandem annulation reactions are less explored. For example, in the
year 2014, Tian and Lin research group reported an interesting rhodium-catalyzed dual
annulation reaction of N-(pivaloyloxy)benzamides with 1,6-enynes for the first time.4 This work
paved a way for the development of few other rhodium-catalysed cascade reactions.5 These
reports along with the advantage of the aforementioned directing groups inspired us to develop a
rhodium-catalyzed cascade reaction for the synthesis of aromathicin derivatives from N-
(pivaloyloxy)arylamides with 1,5-enynes.
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Figure 1. Representative Structures of Camptothecin and Aromathecins
Aromathecins are hybrid molecules of camptothecin (a topoisomerase inhibitor) which were
designed to overcome the limitations of camptothecin derivatives such as limited solubility,
dose-limiting toxicities and the in vivo formation of corresponding secoacid by the hydrolysis of
lactone ring.6. The requirement of potential topoisomerase inhibitor encouraged the researchers
to develop the new synthetic methods to acquire diversely functionalised aromathecins.
Rosettacin, acuminatine and 22-hydroxyacuminatine are the few examples of previously
synthesised aromathecins (Figure-1).7 Recently, we have developed a facile method for the
synthesis of aromathecins through rhodium-catalysed cascade reaction of N-
(pivaloyloxy)benzamides with 2-alkynyl aldehydes, wherein the 1,2-addition of the amide N-H
to the aldehyde group facilitated the second cyclisation to generate the hydroxyl functionality on
the formed five membered ring (Scheme 1a).5a During the same time, Erik and co-workers
reported the similar results wherein the chemoselectivity of the reaction was also studied with
sterically hindered diaryl-substituted alkynes (Scheme 1a).5b These results combined with our
interest on enyne-assisted annulations8 encouraged us to explore the 1,4-addition of the amide
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Scheme 1. Rh (III)-Catalyzed Cascade Reactions
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N-H bond to the activated olefins (aza-Michael addition) in rhodium(III)-catalyzed cascade
reaction of N-(pivaloyloxy)benzamides with 2-alkynyl benzylidenes to yield the functionalized
aromathecins.
RESULTS AND DISCUSSION
To implement our assumption, N-(pivaloyloxy)benzamide 1a and (E)-4-(2-(hept-1-yn-1-
yl)phenyl)but-3-en-2-one (2a) were taken as the starting materials for the rhodium-catalyzed
cascade annulation reactions. Initially, the reaction was performed between 0.3 mmol of 1a and
0.2 mmol of 2a in the presence of 5 mol % of rhodium catalyst and 200 mol % of CsOAc in 2
mL of acetone at room temperature for 12 h, after completion of the reaction (monitored by the
TLC) the desired product 3a was isolated in 80% yield (Table 1 entries 1). Among the other
solvents used such as tert-butanol, methanol, acetonitrile and dimethylformamide, no solvent
was found to be the better than that of acetone for this reaction (Table 1 entries 2-5). Next, the
effect of the base on the yield of the product 3a was studied, by replacing CsOAc with NaOAc,
KOAc, Cs2CO3, K2CO3 and Na2CO3 (Table 1 entries 6-10). From this study, it is understood that
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the base CsOAc gave the maximum yield of the product 3a (Table 1, entry 1) in the present
rhodium-catalysed cascade reaction.
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Table 1. Optimization of Reaction Conditions for the Synthesis of 3aa
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With the optimised conditions, the substrate scope of the reaction has been studied to validate the
generality of the present reaction. Initially, the annulations of different electronically substituted
benzamides 1 with 2a were examined (Table 2). Irrespective of the nature of the substituent
(withdrawing or donating group) present on the aromatic ring of N-(pivaloyloxy)benzamide, the
reaction proceeded efficiently to offer the good yield of the products (3b-3j). Benzamides with
electron-withdrawing groups Br, Cl and NO2 on phenyl ring (1b, 1c and 1d) were well reacted
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Table 2. Reaction of 2a with Various N-(Pivaloyloxy)benzamidesa
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with 2a to provide the corresponding annulated products 3b, 3c and 3d in good yield (entries 2 to
4, Table 2). Substrates containing donating groups –Me, -OMe and methlenedioxy (1e, 1f and
1g) also participated in the rhodium-catalyzed cascade reaction with 2a to afford the products 3e,
3f and 3g in 72, 68 and 73% yields, respectively (entries 5 to 7, Table 2). Notably, N-
(pivaloyloxy)-2-naphthamide (1h), heterocyclic amides such as N-(pivaloyloxy)thiophene-2-
carboxamide (1i) and 1-methyl-N-(pivaloyloxy)-1H-indole-2-carboxamide (1j) were all capable
of proceeding to the cyclised products 3h, 3i and 3j in 70, 69 and 74% of the yield (entries 8 to
10, Table 2). The efficiency of this rhodium-catalyzed domino [4+2] annulation/aza-Michael
addition was further demonstrated by doing a gram-scale reaction of 1a with 2a and the required
annulated product 3a was afforded in 76% of the yield.
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Subsequently, the feasibility of the various 1,5-enynes (2) was tested for the rhodium-catalysed
annulation reaction (Table 3). Substrates with alkyl groups such as n-propyl (2b), n-butyl (2c),
cyclohexyl (2d) and -CH2OH (2e) tethered to alkyne were found to be suitable in the cascade
reactions with 1a under the present reaction conditions to deliver the corresponding products 4a,
4b, 4c and 4d in good to excellent yield (entries 1 to 4, Table 3). 1,5-enynes with donating
groups on aromatic ring underwent the reaction smoothly and delivered the products 4e, 4f and
4g in 82, 83 and 76% yields, respectively (entries 5 to 7, Table 3). Nitro derivative, (E)-4-(2-
(hept-1-yn-1-yl)-5-nitrophenyl)but-3-en-2-one (2i), was compatible with the reaction conditions
and affording the required product 4h in 82% yield (entry 8, Table 3). Gratifyingly, the reaction
of 1a with heteroaryl-1,5-enyne, (E)-4-(2-(hept-1-yn-1-yl)quinolin-3-yl)but-3-en-2-one (2j) led
to the formation of Rosettacin analogue 4i in 76% yield (entry 9, Table 3).
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Table 3. Reaction of 1a with Various 1, 5-Enynesa
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Further, the effect of diverse functional groups in 1,5-enynes were evaluated in the present
annulation reaction with 1a (Table 4). To our delight, the anticipated transformation was well
ensued with 1,5-enynes containing cyano (2k) and ester (2l) groups on olefin, affording the
desired products 4j and 4k in 68% and 62% yield, respectively (Table 4, entry 1 and 2).
However, the reaction of terminal olefin substrate, 1-(hex-1-yn-1-yl)-2-vinylbenzene (2m), failed
to give the desired product via the aza-Michael addition of N-H to the terminal olefin was not
observed under these reaction conditions, instead it gave the mono-annulated product 6 in 54%
yield (Table 4, entry 3). It is noteworthy to mention that the reaction between malonate-bridged
1,5-enyne, triethyl (E)-hex-1-en-5-yne-1,3,3-tricarboxylate (5), and 1a is successfully delivered
the product 7 in 31% yield.
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Table 4. Reaction of 1a with 1,5-Enynes Having Various Functional Groupsa
On the basis of the present experimental results and previous reports,5 a plausible mechanism
was proposed (Figure.2). Initially, the activated Rh(III)-catalyst I forms a five membered
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rhodocycle II with 1a via C-H activation. Addition of alkyne 2a to the rhodocycle II leads to the
intermediate IV through C-C bond formation. Next, the C-N bond formation involving reductive
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Figure 2: Possible Reaction Mechanism
elimination and oxidative addition of N-O bond followed by the protonation generates the
isoquinolinone V. In the presence of base, intramolecular conjugate 1,4-addition of N-H to the
double bond of V produces the product 3a.
CONCLUSION
In conclusion, a domino [4+2] annulation/aza-Michael addition of N-(pivaloyloxy)benzamides
with 1,5-enynes catalyzed by Rh(III)-complex was developed. This efficient method provides an
easy access to distinctly substituted aromathecins in good to excellent yields from readily
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accessible starting materials. Oxidant-free mild reaction conditions and broad substrate scope
with good functional group tolerance makes the present method valuable.
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EXPERIMENTAL SECTION
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General Methods: All the reactions were performed in oven-dried glass apparatus, the air and
moisture sensitive reactions were carried out under inert atmosphere (nitrogen) using freshly
distilled anhydrous solvents. Commercially available reagents were used as such without any
further purification. All reactions were monitored by thin-layer chromatography carried out on
silica plates using UV-light and anisaldehyde for visualization. Column chromatography was
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performed on silica gel (100-200 mesh) using hexanes and ethyl acetate as eluent. H NMR was
recorded in CDCl3 on 500 MHz, 400 MHz and 300 MHz instruments, 13C NMR was recorded on
125 MHz, 100 MHz and 75 MHz, using TMS as an internal standard. Chemical shifts are given
in ppm and J values are given in Hz (hertz). δ 7.26 and δ 77 are the residual peaks of CDCl3 in
1H NMR and 13C NMR respectively. FTIR spectra were recorded on Alpha (Bruker) infrared
Spectrophotometer. High resolution mass spectra (HRMS) [ESI+] were obtain using either a
TOF or a double focusing spectrometer.
N-(pivaloyloxy)arylamides (1a-1j),9 2-alkynyl arylaldehydes10 and 2- alkynyl enynones (2b, 2c
and 2m)11 were prepared using the literature procedures, NMR data of all these compounds was
compared with the corresponding reported data.
General procedure for the Synthesis of 2- alkynyl enynones (2):
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A solution of the aldehyde (1 equiv.) and (acetylmethylene)triphenylphosphorane (1.2 equiv.) in
toluene (0.5 M) was stirred at 90 °C for 4 h. After completion of the reaction (confirmed by the
TLC), the reaction mixture was allowed to attain room temperature and concentrated under
reduced pressure. The obtained crude product was purified by column chromatography over
silica gel using hexane/EtOAC as an eluent.
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(E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one (2a): Following the general procedure, 2-(hept-
1-yn-1-yl)benzaldehyde10d (0.5g, 2.5 mmol) in toluene was allowed to react with (acetylmethy
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lene)triphenylphosphorane (0.95 g, 3.0 mmol) at 90 C for 4 h. After that the reaction mixture
was cooled to room temperature and concentrated under reduced pressure. The obtained residue
was purified by column chromatography on silica gel (3% EtOAc in petroleum ether) and got the
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compound 2a (0.42 g, 70% yield) as a yellow liquid ; Rf = 0.4 (hexanes: EtOAc = 19: 1); H
NMR (400 MHz, CDCl3): δ 8.05 (d, J = 16.5 Hz, 1H), 7.64 – 7.60 (m, 1H), 7.49 – 7.43 (m, 1H),
7.32 – 7.28 (m, 2H), 6.72 (d, J = 16.5 Hz, 1H), 2.50 (t, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.58 –1.72
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(m, 2H), 1.34 – 1.51 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ
198.9, 142.1, 135.6, 132.9, 130.0, 128.4, 127.9, 125.9, 125.3, 97.3, 78.9, 31.2, 28.5, 26.9, 22.3,
19.7, 14.0; IR(Neat): 3011, 2937, 1660, 1605, 1482, 1259, 1035, 758 cm-1; HRMS (ESI) m/z: (M
+ H)+ Calcd for C17H21O 241.1592; Found 241.1577.
(E)-4-(2-(cyclohexylethynyl)phenyl)but-3-en-2-one (2d): Following the general procedure, 2-
(cyclohexylethynyl)benzaldehyde10e (0.5 g, 2.35 mmol) in toluene was allowed to react with
o
(acetylmethylene)triphenylphosphorane (0.89 g, 2.82 mmol) at 90 C for 4 h. After that the
reaction mixture was cooled to room temperature and concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (4% EtOAc in petroleum
ether) and got the compound 2d (0.38 g, 64% yield) as a white solid; Rf = 0.4 (Hexanes: EtOAc
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o
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= 19: 1); mp: 52-54 C; H NMR (400 MHz, CDCl3): δ 8.08 (d, J = 16.5 Hz, 1H), 7.65 – 7.58
(m, 1H), 7.49 – 7.43 (m, 1H), 7.33 – 7.28 (m, 2H), 6.72 (d, J = 16.5 Hz, 1H), 2.78 – 2.65 (m,
1H), 2.41 (s, 3H), 1.87 – 1.96 (m, 2H), 1.83 – 1.75 (m, 2H), 1.64 – 1.53 (m, 3H), 1.46 – 1.36
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(m, 3H); C{1H} NMR (100 MHz, CDCl3): δ 198.8, 142.1, 135.6, 132.8, 129.9, 128.4, 127.9,
125.9, 125.3, 101.2, 78.3, 32.7, 29.9, 26.8, 25.9, 24.8; IR(KBr): 3366, 2959, 1607, 1481, 1220,
1604, 769 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H21O 253.1592; Found 253.1576.
(E)-4-(2-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-en-2-one(2e):
Following
the
general
procedure, 2-(3-hydroxyprop-1-yn-1-yl) benzaldehyde10e (0.5 g, 3.12 mmol) in toluene was
o
allowed to react with (acetylmethylene)triphenylphosphorane (1.19 g, 3.74 mmol) at 90 C for 4
h. After that the reaction mixture was cooled to room temperature and concentrated under
reduced pressure. The obtained residue was purified by column chromatography on silica gel (15
% EtOAc in petroleum ether) and got the compound 2e (0.45 g, 72% yield) as a liquid; Rf = 0.4
(Hexanes: EtOAc = 3: 2); 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 16.4 Hz, 1H), 7.65 – 7.58
(m, 1H), 7.49 – 7.44 (m, 1H), 7.35 – 7.28 (m, 2H), 6.75 (d, J = 16.4 Hz, 1H), 4.57 (s, 2H), 2.40
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(s, 3H); C{1H} NMR (100 MHz, CDCl3): δ 199.1, 141.4, 135.7, 133.1, 130.0, 128.8, 128.3,
126.1, 123.9, 94.0, 82.9, 51.5, 27.7; IR (KBr): 3015, 2958, 2865, 2228, 1672, 1220, 744 cm-1;
HRMS (ESI) m/z: [M + Na]+ Calcd for C13H12NaO2 223.0735; Found 223.0721.
(E)-4-(2-(hex-1-yn-1-yl)-5-methoxyphenyl)but-3-en-2-one (2f): Following the general
procedure, 2-(hex-1-yn-1-yl)-5-methoxybenzaldehyde10c (0.5 g, 2.31 mmol) in toluene was
allowed to react with (acetylmethylene)triphenylphosphorane (0.88 g, 2.77 mmol) at 90 oC for 4
h. After that the reaction the mixture was cooled to room temperature and concentrated under
reduced pressure. The obtained residue was purified by column chromatography on silica gel
(5% EtOAc in petroleum ether) and got the compound 2f (0.415 g, 70% yield) as a liquid; Rf =
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0.4 (Hexanes: EtOAc = 4: 1); 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 16.4 Hz, 1H), 7.38 (d,
J = 7.6 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.4, 2.6 Hz, 1H), 6.68 (d, J = 16.5 Hz,
1H), 3.83 (s, 3H), 2.51 (t, J = 6.9 Hz, 2H), 2.41 (s, 3H), 1.58 – 1.67 (m, 2H), 1.47 – 1.57 (m,
2H), 0.98 (t, J = 7.2, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.7, 159.0, 142.0, 136.8,
134.0, 133.9, 128.5, 117.8, 116.7, 110.1, 95.3, 55.3, 30.8, 26.7, 22.0, 19.3, 13.6; IR(KBr): 3222.
2936, 2437, 1766, 1718, 1644, 1367, 768 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C17H21O2
257.1542; Found 257.1542.
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(E)-4-(6-(hex-1-yn-1-yl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-one (2g): Following the general
procedure, 6-(hex-1-yn-1-yl)benzo[d][1,3]dioxole-5-carbaldehyde10a (0.5 g, 2.17 mmol) in
toluene was allowed to react with (acetylmethylene)triphenylphosphorane (0.82 g, 2.60 mmol)
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at 90 C for 4 h. After that the reaction mixture was cooled to room temperature, and
concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (5% EtOAc in petroleum ether) and got the compound 2g (0.45
1
g, 76 % yield) as a white solid; Rf = 0.4 (hexanes: EtOAc = 9: 1); mp: 61-63 oC; H NMR (400
MHz, CDCl3): δ 8.02 (d, J = 16.4 Hz, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 6.53 (d, J = 16.4 Hz, 1H),
6.00 (s, 2H), 2.48 (t, 2H), 2.38 (s, 3H), 1.66 – 1.60 (m, 2H), 1.56 – 1.49 (m, 2H), 0.97 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.7, 149.4, 148.0, 141.9, 130.6, 126.6, 120.5,
112.0, 104.9, 101.9, 96.0, 78.1, 30.8, 26.8, 22.1, 19.3, 13.7; IR(KBr): 2950, 2873, 1728, 1515,
1255, 1093 763 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C17H19O3 271.1334; Found
271.1336.
(E)-4-(2-(hex-1-yn-1-yl)-4,5-dimethoxyphenyl)but-3-en-2-one (2h): Following the general
procedure, 2-(hex-1-yn-1-yl)-4,5-dimethoxybenzaldehyde10g (0.5 g, 2.03 mmol) in toluene was
allowed to react with (acetylmethylene)triphenylphosphorane (0.77 g, 2.43 mmol) at 90 oC for 4
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h. After that the reaction mixture was cooled to room temperature and concentrated under
reduced pressure. The obtained residue was purified by column chromatography on silica gel
(4% EtOAc in petroleum ether) and got the compound 2h (0.45 g, 77% yield) as a white solid; Rf
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= 0.4 (Hexanes: EtOAc = 4: 1); mp: 57-59 oC; H NMR (500 MHz, CDCl3): δ 8.13 (d, J = 16.4
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Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 8.60 (d, J = 16.4 Hz, 1H) 3.91 (s, 2H), 3.90 (s, 3H), 2.51 (t, J
= 7.0 Hz, 2H), 2.40 (s, 3H) 1.62 – 1.68 (m, 2H), 1.48 – 1.57 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 198.7, 150.7, 149.0, 142.0, 128.7, 126.4, 118.9, 114.4,
107.5, 95.3, 78.0, 55.95, 55.86, 30.8, 26.5, 22.05, 19.25, 13.6; IR(KBr): 3366, 2959, 1607, 1481,
1220, 1604, 769 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H23O3 287.1647; Found:
287.1636.
(E)-4-(2-(hex-1-yn-1-yl)-5-nitrophenyl)but-3-en-2-one (2i): Following the general procedure, 2-
(hex-1-yn-1-yl)-5-nitrobenzaldehyde10b (0.5 g, 2.16 mmol) in toluene was allowed to react with
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(acetylmethylene)triphenylphosphorane (0.82 g, 2.59 mmol) at 90 C for 4 h. After that the
reaction mixture was cooled to room temperature and concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (4% EtOAc in petroleum
ether) and got the compound 2i (0.39 g, 66% yield) as a yellow liquid; Rf = 0.5 (Hexanes:
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EtOAc = 19: 1); H NMR (500 MHz, CDCl3): δ 8.47 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 8.6, 2.3
Hz, 1H), 7.99 (d, J = 16.4 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 16.4 Hz, 1H), 2.56 (t, J
= 7.0 Hz, 2H), 2.43 (s, 3H), 1.71 – 1.65 (m, 2H), 1.57 – 1.51 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 197.6, 146.8, 139.0, 137.0, 133.8, 131.3, 130.1, 123.9,
120.9, 103.1, 77.4, 30.4, 27.8, 22.1, 19.5, 13.5; IR(KBr): 3366, 2959, 1607, 1481, 1220, 1604,
769 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C16H18NO3 272.1287; Found 272.1275.
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(E)-4-(2-(hex-1-yn-1-yl)quinolin-3-yl)but-3-en-2-one (2j): Following the general procedure, 2-
(hex-1-yn-1-yl)quinoline-3-carbaldehyde10f (0.5 g, 2.10 mmol) in toluene was allowed to react
with (acetylmethylene)triphenylphosphorane (0.8 g, 2.52 mmol) at 90 oC for 4 h. After that the
reaction mixture was cooled to room temperature and concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (5% EtOAc in petroleum
ether) and got the compound 2j (0.43 g, 74% yield) as a pale yellow solid; Rf = 0.4 (hexanes:
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EtOAc = 4: 1); mp: 142-144 C; H NMR (500 MHz, CDCl3): δ 8.36 (s, 1H), 8.13 (d, J = 16.4
Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71 – 7.75 (m, 1H), 7.53 – 7.56 (m,
1H), 6.87 (d, J = 16.4 Hz, 1H), 2.65 – 2.56 (t, 2H), 2.46 (s, 3H), 1.77 – 1.68 (m, 2H), 1.62 – 1.52
(m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 198.0, 148.4, 143.9,
139.8, 133.3, 131.1, 129.9, 129.0, 128.9, 128.0, 127.5, 126.7, 97.1, 78.9, 30.3, 27.1, 22.2, 19.3,
13.6; IR(KBr): 3366, 2959, 1607, 1481, 1220, 1604, 769 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd
for C19H20NO 278.1545; Found: 278.1545.
(E)-3-(2-(hept-1-yn-1-yl)phenyl)acrylonitrile (2k): Following the general procedure, 2-(hept-1-
yn-1-yl)benzaldehyde10d (0.5 g, 2.5 mmol) in toluene was allowed to react with
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(triphenylphosphoranylidene)acetonitrile (0.9 g, 3.0 mmol) at 90 C for 4 h. After that the
reaction mixture was cooled to room temperature and concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (5% EtOAc in petroleum
ether) and got the compound 2k (0.38 g, 68% yield) as a colorless liquid; Rf = 0.4 (Hexanes:
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EtOAc = 9: 1); H NMR (300 MHz, CDCl3): δ 7.90 (d, J = 16.8 Hz, 1H), 7.55 – 7.41 (m, 2H),
7.39 – 7.24 (m, 2H), 5.99 (d, J = 16.8 Hz, 1H), 2.48 (t, J = 7.1 Hz, 2H), 1.73 – 1.60 (m, 2H), 1.52
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– 1.35 (m, 4H), 0.95 (t, J = 7.0 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 149.1, 134.5,
133.2, 130.6, 127.9, 125.4, 124.7, 118.4, 97.9, 97.3, 77.8, 31.2, 28.3, 22.2, 19.6, 14.0; IR(KBr):
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3092, 2946, 2869, 2225, 1678, 1519, 1344, 1258, 750cm-1; HRMS (ESI) m/z: (M + H)+ Calcd
for C16H18N 224.1439; Found: 224.1445.
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Ethyl (E)-3-(2-(hept-1-yn-1-yl)phenyl)acrylate (2l): Following the general procedure, 2-(hept-1-
yn-1-yl)benzaldehyde10d (0.5 g, 2.5 mmol) in toluene was allowed to react with ethyl
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(triphenylphosphoranylidene)acetate (1.04 g, 3.0 mmol) at 90 C for 4 h. After that the reaction
mixture was cooled to room temperature and concentrated under reduced pressure. The obtained
residue was purified by column chromatography on silica gel (5% EtOAc in petroleum ether)
and got the compound 2l (0.45 g, 66% yield) as a colorless liquid; Rf = 0.4 (Hexanes : EtOAc =
4: 1); 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 16.1 Hz, 1H), 7.57 – 7.61 (m, 1H), 7.42 – 7.46
(m, 1H), 7.25 – 7.30 (m, 2H), 6.50 (d, J = 16.1 Hz, 1H)), 4.32 – 4.20 (q, J = 7.1 Hz 2H), 2.49 (t,
J = 7.1 Hz, 2H), 1.61 – 1.71 (m, 2H), 1.41 – 1.51 (m, 2H), 1.37 – 1.41 (m, 2H), 1.36 – 1.32 (t, J
= 7.1 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 142.9,
135.7, 132.9, 129.6, 127.8, 126.1, 125.0, 119.4, 97.1, 78.3, 60.5, 31.2, 28.4, 22.3, 19.7, 14.4,
14.0; IR(KBr): 3366, 2959, 1607, 1481, 1220, 1604, 769 cm-1; HRMS (ESI) m/z: [M + H]+
Calcd for C18H23O2 271.1698; Found: 271.1685.
triethyl (E)-hex-1-en-5-yne-1,3,3-tricarboxylate (5): To a stirred solution of diethyl 2-(prop-2-
yn-1-yl)malonate ( 990 mg, 5 mmol) in 10 mL of acetonitrile at room temperature, 10 mol % of
triphenyl phosphine was added, after stirring for few minutes ethyl propiolate (5 mmol) was
added drop wise to the reaction mixture and continued the stirring for 30 min at same
temperature. After that the reaction mixture was concentrated under reduced pressure without
doing any work up and the obtained crude product was purified by column chromatography on
silica gel (10 % EtOAc in petroleum ether) and obtained the compound triethyl-hex-1-en-5-yne-
1,3,3-tricarboxylate 2n (1.2 g, 81 % yield, E/Z 9:1) as a colorless liquid; Rf = 0.5 (Hexanes :
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EtOAc = 8:2 ); H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 16.3 Hz, 1H), 6.01 (d, J = 16.3 Hz,
1H), 4.34 – 4.18 (m, 6H), 2.98 (d, J = 2.6 Hz, 2H), 2.04 (t, J = 2.6 Hz, 1H), 1.33 – 1.22 (m, 9H);
13C NMR (100 MHz, CDCl3) δ 167.9(2C), 165.6, 141.9, 123.8, 78.0, 72.0, 62.5(2C), 60.8, 59.0,
24.7, 14.2, 13.9(2C); IR(neat): 3297, 2984, 1728, 1653, 1190, 1034, 747 cm-1 HRMS (ESI) m/z:
[M + H]+ Calcd for C15H21O6 297.1338; Found: 297.1345.
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General procedure for the Rh(III)-catalyzed annulation:
To a solution of N-(pivaloyloxy) arylamide 1 (1.5 equiv) and 2-alkynyl enone 2 (1 equiv) in dry
acetone (2.0 mL), [RhCp*Cl2]2 (0.05 equiv.) and CsOAc (2 equiv.) were added under nitrogen
atmosphere at room temperature. The reaction mixture was stirred vigorously at room
temperature till the completion of the reaction (monitored by TLC), the reaction mixture was
filtered through celite pad and washed with CH2Cl2 (10 mL × 3).The filtrate was concentrated
under reduced pressure and the obtained crude mixture was purified by column chromatography.
Gram scale reaction procedure for compound
7-(2-Oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one(3a): Following the general
procedure, N-(Pivaloyloxy)benzamide9c 1a (66 mg, 0.30 mmol) was allowed to react with (E)-4-
(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg,
0.20 mmol) in the presence of
[RhCp*Cl2]2 (6.2 mg 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After filtration the
filtrate was concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (14 % EtOAc in petroleum ether) and got the compound 3a
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(57.4 mg, 80% yield) as a white solid; Rf = 0.4 (hexanes: EtOAc = 7:3); mp: 126 -128 C; H
NMR (500 MHz, CDCl3): δ 8.51 (dd, J = 8.0, 1.0 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d, J =
8.2 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.54 – 7.47 (m, 2H), 7.40-7.46 (m, J
= 7.2 Hz, 1H), 6.03 (dd, J = 8.1, 3.0 Hz, 1H), 3.94 (dd, J = 17.6, 3.1 Hz, 1H), 3.22 – 3.08 (m,
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(m, 2H), 0.97 (t, J = 7.3 Hz, 3H); C{1H} NMR (125 MHz, CDCl3): δ 205.8, 160.4, 142.7,
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45.9, 32.1, 30.4, 28.9, 26.1, 22.6, 14.1; IR (KBr): 3210, 2958, 1718, 1650, 1608, 1479, 1365,
768, cm1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H26NO2 360.1964; Found: 360.1974.
Gram scale reaction procedure for compound 3a:
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To a solution of N-(Pivaloyloxy)benzamide9c 1a (1.5 equiv) and (E)-4-(2-(hept-1-yn-1-yl)phenyl)
but-3-en-2-one 2a (1g, 4.16 mmol, 1equiv) in dry acetone (25 mL), [RhCp*Cl2]2 (0.05 equiv.)
and CsOAc (2 equiv.) were added under nitrogen atmosphere at room temperature. The reaction
mixture was stirred vigorously at room temperature till the completion of the reaction (24 h
monitored by TLC), the reaction mixture was filtered through celite pad and washed with
CH2Cl2 (15 mL × 3).The filtrate was concentrated under reduced pressure and the obtained crude
mixture was purified by column chromatography on silica gel to obtained the compound as white
solid (1.13g )76% yield.
2-Bromo-7-(2-oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one (3b): Following
the general procedure, 4-bromo-(pivaloyloxy)benzamide9b 1b (90 mg, 0.3 mmol) was allowed
to react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.2 mmol) in the
presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After
filtration the filtrate was concentrated under reduced pressure. The obtained residue was purified
by column chromatography on silica gel (12 % EtOAc in petroleum ether) and got the
compound 3b (66.5 mg, 76% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 162-
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164 oC; H NMR (500 MHz, CDCl3): δ 8.34 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.88
(d, J = 7.9 Hz, 1H), 7.59 (dd, J = 8.5, 1.6 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.46 (dt, J = 7.4, 3.8
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Hz, 1H), 5.99 (dd, J = 8.1, 3.0 Hz, 1H), 3.90 (dd, J = 17.7, 3.1 Hz, 1H), 3.14 – 3.06 (m, 2H),
2.83 (dd, J = 17.7, 8.2 Hz, 1H), 2.19 (s, 3H), 1.67 – 1.77 (m, 2H), 1.62 – 1.56 (m, 2H), 1.42 –
1.51 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 205.6, 160.0, 143.0,
139.6, 138.9, 133.3, 129.7, 129.5, 129.4, 128.9, 127.7, 125.7, 124.0, 123.8, 123.7, 112.6, 59.3,
45.8, 32.1, 30.4, 28.9, 26.1, 22.6, 14.1; IR (KBr): 3016, 2953, 1708, 1622, 1362, 1218, 762 cm-1;
HRMS (ESI) m/z: Calcd for C24H25NO2Br [M + H]+ 438.1069; Found: 438.1073.
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2-Chloro-7-(2-oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one (3c): Following the
general procedure, 4-chloro-N-(pivaloyloxy)benzamide9b 1c (77 mg, 0.3 mmol) was allowed to
react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg 0.2 mmol) in the presence
of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76 mg, 3.22 mmol) for 12 h. After filtration
the filtrate was concentrated under reduced pressure. The obtained residue was purified by
column chromatography on silica gel (13 % EtOAc in petroleum ether) and got the compound
3c (56.6 mg, 72% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 168-170 oC; 1H
NMR (400 MHz, CDCl3): δ 8.43 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 1.8
Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.48 – 7.42 (m, 2H), 6.00 (dd, J = 8.1,
3.0 Hz, 1H), 3.91 (dd, J = 17.6, 3.1 Hz, 1H), 3.06 – 3.14(m, 2H), 2.84 (dd, J = 17.6, 8.1 Hz, 1H),
1.78 – 1.67 (m, 2H), 1.62 – 1.58 (m, 2H), 1.42 – 1.51 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (100 MHz) δ 205.6, 159.9, 143.0, 139.4, 139.0, 138.9, 133.3, 129.7, 129.5, 128.9, 126.7,
124.0, 123.7, 123.5, 122.5, 112.7, 59.3, 45.8, 32.1, 30.4, 28.9, 26.2, 22.6, 14.1; IR (KBr): 3213,
2975, 1776, 1660, 1477, 1078, 699 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H25NO2Cl
394.1574; Found: 394.1573.
2-Nitro-7-(2-oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one (3d): Following the
general procedure, 4-nitro-N-(pivaloyloxy)benzamide9c 1d (80 mg, 0.30 mmol) was allowed to
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react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.20 mmol) in presence of
[RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76 mg, 0.4 mmol) for 14 h. After filtration the
filtrate was concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (14 % EtOAc in petroleum ether) and got the compound 3d
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(61 mg, 75% yield) as a yellow solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 135-137 C; H
NMR (400 MHz, CDCl3): δ 8.71 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.24 (dd, J = 8.8,
2.1 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.57 – 7.47 (m, 2H), 6.03 (dd, J =
8.0, 3.0 Hz, 1H), 3.89 (dd, J = 17.7, 3.1 Hz, 1H), 3.17 – 3.25 (m, 2H), 2.89 (dd, J = 17.7, 8.0 Hz,
1H), 2.20 (s, 3H), 1.71 – 1.81 (m, 2H), 1.65 – 1.59 (m, 2H), 1.44 – 1.53 (m, 2H), 0.99 (t, J = 7.3
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Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 205.4, 159.3, 150.4, 143.0, 140.0, 138.8, 132.9,
130.2, 129.8, 129.1, 128.5, 124.3, 123.7, 119.6, 118.8, 113.3, 59.6, 45.4, 32.0, 30.4, 29.0, 26.2,
22.5, 14.0; IR (KBr): 2950, 2734, 1710, 1649, 1603, 1469, 766 cm-1; HRMS (ESI) m/z: [M + H]+
Calcd for C24H25N2O4 405.1814; Found: 405.1816.
2-Methyl-7-(2-oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one (3e): Following the
general procedure, 4-methyl-N-(pivaloyloxy)benzamide9b 1e (70 mg, 0.3 mmol) was allowed to
react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.20 mmol) in presence of
[RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After filtration the
filtrate was concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (12% EtOAc in petroleum ether) and got the compound 3e
(54 mg, 72% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp 145-147 oC; 1H NMR
(500 MHz, CDCl3): δ 8.39 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 10.5 Hz,
2H), 7.49 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.00 (dd, J = 8.1,
2.7 Hz, 1H), 3.93 (dd, J = 17.6, 3.1 Hz, 1H), 3.09 – 3.18 (m, 2H), 2.81 (dd, J = 17.6, 8.2 Hz,
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1H), 2.56 (s, 3H), 2.19 (s, 3H), 1.69 – 1.78 (m, 2H), 1.53 – 1.63 (m, 2H), 1.43 – 1.51 (m, 2H),
0.98 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.9, 160.5, 142.9, 142.6, 138.1,
137.6, 133.8, 129.2, 128.7, 127.9, 127.7, 123.9, 123.7, 123.1, 122.8, 113.6, 59.1, 46.1, 32.2, 30.4,
29.0, 26.2, 22.6, 22.3, 14.2; IR (KBr): 2953, 1717, 1648, 1473, 1359, 1172, 769, cm-1; HRMS
(ESI) m/z: [M + H]+ Calcd for C25 H28NO2 374.2120; Found 374.2121.
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2-Methoxy-7-(2-oxopropyl)-12-pentylisoindolo[2,1-b]isoquinolin-5(7H)-one(3f): Following the
general procedure, 4-methoxy-N-(pivaloyloxy)benzamide9b 1f (70 mg, 0.3 mmol) was allowed to
react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.20 mmol) in presence of
[RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 15 h. After filtration the
filtrate was concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (12 % EtOAc in petroleum ether) and got the compound 3f
(53 mg, 68% yield) as a white solid; Rf = 0.4 (hexanes: EtOAc = 3:2); mp 127-129 oC; 1H NMR
(400 MHz, CDCl3): δ 8.43 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H),
7.49 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.9, 2.3
Hz, 1H), 5.99 (dd, J = 8.1, 3.0 Hz, 1H), 3.96 (s, 3H), 3.95 -3.90 (dd, J = 17.6, 3.1 Hz 1H), 3.19 –
3.07 (m, 2H), 2.82 (dd, J = 17.5, 8.2 Hz, 1H), 2.18 (s, 3H), 1.79 – 1.70 (m, 2H), 1.61 – 1.55 (m,
13
2H), 1.42 – 1.52 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 206.0,
162.9, 143.1, 140.1, 138.2, 133.7, 129.8, 129.3, 128.7, 123.9, 123.7, 119.3, 114.6, 114.6, 113.3,
105.4, 59.1, 55.5, 46.2, 32.2, 30.5, 28.8, 26.3, 22.6, 14.2; IR (KBr): 3019, 2958, 1715, 1648,
1471 ,1218 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H28NO3 390.2069; Found 390.2061.
7-(2-Oxopropyl)-12-pentyl-[1,3]dioxolo[4,5-g]isoindolo[2,1-b]isoquinolin-5(7H)-one (3g):
Following the general procedure, N- (pivaloyloxy)benzo[d][1,3]dioxole-5-carboxamide9a 1g (79
mg, 0.30 mmol) was allowed to react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a
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(50 mg, 0.20 mmol) in presence of [RhCp*Cl2]2 (6.4 mg, 0.01 mmol) and CsOAc (79 mg, 0.41
mmol) for 15 h. After filtration the filtrate was concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (13 % EtOAc in
petroleum ether) and got the compound 3g (59 mg, 73% yield) as a white solid; Rf = 0.5
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(Hexanes: EtOAc = 7:3); mp: 155-157 C; H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.5 Hz,
1H), 7.88 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.50 – 7.39 (m, 2H), 7.06 (d, J = 8.5 Hz,
1H), 6.15 (dd, J = 2.9, 1.5 Hz, 2H), 5.97 (dd, J = 8.0, 2.8 Hz, 1H), 3.87 (dd, J = 17.5, 2.8 Hz,
1H), 2.97 – 3.54 (m, 2H), 2.82 (dd, J = 17.5, 8.1 Hz, 1H), 2.18 (s, 3H), 1.66 – 1.78 (m, 2H), 1.57
– 1.49 (m, 2H), 1.40 – 1.47 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 205.8, 159.8, 150.2, 142.8, 142.3, 137.6, 133.6, 129.3, 128.7, 124.1, 123.9, 123.6, 123.3, 120.8,
112.1, 108.7, 101.4, 59.1, 46.2, 32.1, 30.4, 29.6, 27.7, 22.5, 14.1; IR (KBr): 2953, 2866, 1708,
1622, 1218, 762 cm-1; HRMS (ESI) m/z: [M + Na]+ Calcd for C25H25NO4Na 426.1681; Found:
426.1675.
5-(2-Oxopropyl)-14-pentylbenzo[g]isoindolo[2,1-b]isoquinolin-7(5H)-one (3h): Following the
general procedure N-(pivaloyloxy)-2-naphthamide9c 1h (81 mg, 0.30 mmol) was allowed to react
with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.20 mmol) in presence of
[RhCp*Cl2]2 (6 mg, 0.01 mmol) and CsOAc (76 mg, 0.4 mmol) for 13 h. After filtration the
filtrate was concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (14 % EtOAc in petroleum ether) and got the compound 3h (57
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mg, 70% yield) as a white solid; Rf = 0.4 (hexanes:EtOAc = 7:3); mp: 173-175 C; H NMR
(400 MHz, CDCl3): δ 9.07 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.3 Hz,
1H), 7.89 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.4
Hz, 1H), 6.02 (dd, J = 7.9, 2.7 Hz, 1H), 3.90 (dd, J = 17.5, 3.2 Hz, 1H), 3.26 –3.20 (m, 2H), 2.85
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(m, 2H), 0.99 (t, J = 7.3 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 205.9, 161.0, 142.7,
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123.6, 121.6, 113.6, 58.8, 46.5, 32.2, 30.4, 28.8, 26.3, 22.6, 14.1; IR(KBr): 3221, 2951, 2592,
1646, 1609, 1474, 1230, 766 cm-1; HRMS (ESI) m/z: [M + H]+: Calcd for C28H28NO2 410.2120
Found 410.2118.
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9-(2-Oxopropyl)-4-pentylthieno[3',2':4,5]pyrido[2,1-a]isoindol-11(9H)-one (3i): Following the
general procedure, N-(pivaloyloxy)thiophene-2-carboxamide9a 1i (68 mg, 0.3 mmol) was
allowed to react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one 2a (50 mg, 0.20 mmol) in
presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 15 h. After
filtration the filtrate was concentrated under reduced pressure. The obtained residue was purified
by column chromatography on silica gel (12 % EtOAc in petroleum ether) and got the compound
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3i (50 mg, 69% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 3:2); mp: 154-157 C; H
NMR (500 MHz, CDCl3): δ 7.84 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 5.2 Hz 1H), 7.58 (d, J = 7.6
Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 5.3 Hz, 1H), 5.98 (dd, J =
8.1, 3.0 Hz, 1H), 4.00 (dd, J = 17.7, 3.1 Hz, 1H), 3.16 – 3.06 (m, 2H), 2.84 (dd, J = 17.7, 8.2 Hz,
1H), 2.19 (s, 3H), 1.76 – 1.70 (m, 2H), 1.69 –1.78 (m, 2H), 1.48 – 1.55 (m, 2H), 1.38 – 1.46 (m,
2H), 0.94 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.8, 156.9, 147.8, 142.7,
139.3, 133.5, 133.0, 129.1, 128.8, 128.6, 123.7, 123.3, 123.0, 113.4, 59.3, 45.6, 32.0, 30.4, 29.4,
28.3, 22.6, 14.1; IR (KBr): 2966, 2824, 1616, 1453, 1361, 770 cm-1; HRMS (ESI) m/z: [M + H]+
Calcd for C22H24NO2S 366.1528; Found 366.1529.
5-Methyl-8-(2-oxopropyl)-13-pentyl-5,8-dihydro-6H-benzo[1,2]indolizino[6,7-b]indol-6-one
(3j): Following the general procedure, 1-methyl-N-(pivaloyloxy)-1H-indole-2-carboxamide9a 1j
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(82 mg, 0.30 mmol) was allowed to react with (E)-4-(2-(hept-1-yn-1-yl)phenyl)but-3-en-2-one
2a (50 mg, 0.20 mmol) in presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg,
0.40 mmol) for 14 h. After filtration the filtrate was concentrated under reduced pressure. The
obtained residue was purified by column chromatography on silica gel (14% EtOAc in petroleum
ether) and got the compound 3j (61 mg, 74% yield) as an off-white solid; Rf = 0.5 (Hexane:
EtOAc = 3:2); mp: 182-184 oC; 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.2 Hz, 1H), 7.85 (d,
J = 7.9 Hz, 1H), 7.56 – 7.48 (m, 3H), 7.49 – 7.43 (m, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 – 7.28
(m, 1H), 6.04 (dd, J = 8.2, 2.9 Hz, 1H), 4.37 (s, 3H), 4.00 (dd, J = 17.5, 3.1 Hz, 1H), 3.44 – 3.39
(m, 2H), 2.80 (dd, J = 17.5, 8.3 Hz, 1H), 2.20 (s, 3H), 1.82 – 1.95 (m, 2H), 1.71 – 1.62 (m, 2H),
1.54 – 1.44 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 205.9, 154.4,
142.2, 141.4, 134.1, 134.0, 128.6, 127.9, 126.5, 126.3, 125.7, 123.5, 122.9, 122.3, 121.8, 120.3,
114.6, 110.2, 59.2, 46.1, 32.2, 31.3, 30.4, 28.7, 28.0, 22.7, 14.12; IR (KBr): 3224, 2929, 2856,
1719, 1645, 1478, 1367, 766 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C27 H29 N2O2:
413.2229; Found 413.2237.
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7-(2-Oxopropyl)-12-propylisoindolo[2,1-b]isoquinolin-5(7H)-one (4a): Following the general
procedure, N-(Pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed to react with (E)-4-(2-
(pent-1-yn-1-yl)phenyl)but-3-en-2-one11a 2b (42. mg, 0.2 mmol) in presence of [RhCp*Cl2]2
(6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After filtration the filtrate was
concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (12 % EtOAc in petroleum ether) and got the compound 4a (52
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mg, 79% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 166-168 C; H NMR
(400 MHz, CDCl3): δ 8.50 (dd, J = 8.0, 0.9 Hz, 1H), 7.86 (dd, J = 12.9, 8.1 Hz, 2H), 7.76 – 7.69
(m, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54 – 7.46 (m, 2H), 7.39 – 7.45 (m, 1H), 6.01 (dd, J = 8.0, 2.8
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Hz, 1H), 3.93 (dd, J = 17.6, 3.0 Hz, 1H), 3.16 – 3.12 (m, 2H), 2.82 (dd, J = 17.6, 8.1 Hz, 1H),
2.19 (s, 3H), 1.70 – 1.81 (m, 2H), 1.18 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
205.8, 160.5, 142.8, 138.0, 137.6, 133.6, 132.2, 129.3, 128.7, 127.6, 126.2, 125.1, 123.9, 123.6,
123.0, 113.5, 59.2, 45.9, 30.4, 28.1, 22.5, 14.3; IR (KBr): 3064, 2960, 1716, 1648, 1606, 1477,
1363, 766 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C22H22NO2 332.1651; Found 332.1644.
12-Butyl-7-(2-oxopropyl)isoindolo[2,1-b]isoquinolin-5(7H)-one (4b): Following the general
procedure, N-(Pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed to react with (E)-4-(2-
(hex-1-yn-1-yl)phenyl)but-3-en-2-one11b 2c (45 mg, 0.2 mmol), in presence of [RhCp*Cl2]2
(6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After filtration the filtrate was
concentrated under reduced pressure. The obtained residue was purified by column
chromatography on silica gel (12 % EtOAc in petroleum ether) and got the compound 4b (56
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mg, 81% yield) as an off-white solid; Rf = 0.4 (Hexanes: EtOAc = 7:3); mp: 142-145 C; H
NMR (300 MHz, CDCl3): δ 8.51 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 14.2, 8.0 Hz, 2H), 7.74 (t, J =
7.4 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.39 – 7.55 (m, 3H), 6.02 (d, J = 6.1 Hz, 1H), 3.94 (d, J =
17.5 Hz, 1H), 3.21 – 3.12 (m, 2H), 2.82 (dd, J = 17.6, 8.1 Hz, 1H), 2.19 (s, 3H), 1.79 – 1.67 (m,
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2H), 1.67 – 1.56 (m, 2H), 1.06 (t, J = 6.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 205.8,
160.5, 142.8, 137.9, 137.4, 133.6, 132.2, 129.2, 128.7, 127.6, 126.2, 125.1, 123.8, 123.6, 122.9,
113.6, 59.1, 45.9, 31.4, 30.4, 25.9, 23.1, 14.0; IR (KBr): 3407, 3011, 1715, 1643, 1481, 764 cm-1;
HRMS (ESI) m/z: [M + H]+ Calcd for C23H24NO2 346.1807; Found 346.1801.
12-Cyclohexyl-7-(2-oxopropyl)isoindolo[2,1-b]isoquinolin-5(7H)-one (4c): Following the
general procedure, N-(pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed to react with
(E)-4-(2-(cyclohexylethynyl)phenyl)but-3-en-2-one 2d (50.4 mg, 0.2 mmol) in presence of
[RhCp*Cl2]2 (6.2 mg 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After filtration the
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mg, 78% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 3:2); mp: 171-173 C; H NMR
(500 MHz, CDCl3): δ 8.51 (dd, J = 8.0, 1.3 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.9
Hz, 1H), 7.65 – 7.69 (m, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46 – 7.50(m, 2H), 7.43 (td, J = 7.5, 0.9
Hz, 1H), 6.01 (dd, J = 8.1, 3.1 Hz, 1H), 3.91 (dd, J = 17.6, 3.1 Hz, 1H), 3.79 (tt, J = 12.7, 3.5 Hz,
1H), 2.80 (dd, J = 17.6, 8.1 Hz, 1H), 2.42 – 2.28 (m, 2H), 2.20 (s, 3H), 1.83 – 2.05 (m, 5H), 1.45
– 1.4 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 205.9, 160.4, 143.1, 137.7, 137.6, 134.0,
131.0, 129.3, 128.6, 127.8, 126.0, 125.9, 125.7, 124.3, 123.8, 118.8, 59.0, 46.2, 39.0, 31.4, 30.9,
30.4, 27.6, 27.5, 26.1; IR (KBr): 3018, 2930, 2856, 1716, 1639, 1216, 751 cm-1; HRMS (ESI)
m/z: Calcd for C25H26NO2 [M + H]+ 372.1964; Found 372.1972.
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12-(Hydroxymethyl)-7-(2-oxopropyl)isoindolo[2,1-b]isoquinolin-5(7H)-one (4d): Following the
general procedure, N-(Pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed to react with
(E)-4-(2-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-en-2-one 2e (40 mg, 0.2 mmol), in presence of
[RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.50 mmol) for 14 h. After filtration
the filtrate was concentrated under reduced pressure. The obtained residue was purified by
column chromatography on silica gel (20 % EtOAc in petroleum ether) and obtained the
compound 4d (48 mg, 75% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 1:1); mp: 160-
162 oC; 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J = 7.9 Hz, 1H), 8.06 (dd, J = 7.9 1.1 Hz, 1H),
7.98 (d, J = 8.3 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (td, J = 7.4 Hz, 1H),
7.35 (d, J = 7.6 Hz, 1H), 7.08 (m, 1H), 5.41 (dd, J = 8.3, 2.8 Hz, 1H), 5.21 (q, J = 12.9 Hz, 2H),
3.66 (dd, J = 17.7, 3.0 Hz, 1H), 3.33 (s, 1H), 2.65 (dd, J = 17.7, 8.4 Hz, 1H), 2.10 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 205.4, 160.6, 142.7, 140.5, 137.1, 132.5, 130.0, 129.0,
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127.4, 126.2, 124.9, 124.1, 123.4, 122.7, 111.2, 59.2, 56.0, 45.3, 30.3; IR (KBr): 3010, 2937,
2859, 1662, 1506, 1260, 752 cm-1; cm-1; HRMS (ESI) m/z: [M + Na]+ Calcd for C18H15NO3Na
342.1106; Found 342.1112.
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12-Butyl-9-methoxy-7-(2-oxopropyl)isoindolo[2,1-b]isoquinolin-5(7H)-one (4e): Following
the general procedure, N- (Pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed to react
with (E)-4-(2-(hex-1-yn-1-yl)-5-methoxyphenyl)but-3-en-2-one 2f (51 mg, 0.2 mmol) in
presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12 h. After
filtration the filtrate was concentrated under reduced pressure. The obtained residue was purified
by column chromatography on silica gel (12 % EtOAc in petroleum ether) and got the compound
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4e (62 mg, 82% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 165 -167 C; H
NMR (400 MHz, CDCl3): δ 8.48 (dd, J = 8.0, 1.1 Hz, 1H), 7.79 (dd, J = 8.4, 5.4 Hz, 2H), 7.75 –
7.68 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 8.7, 2.4 Hz, 1H),
5.95 (dd, J = 8.2, 2.8 Hz, 1H), 3.95 (dd, J = 17.7, 3.0 Hz, 1H), 3.87 (s, 3H), 3.07 – 3.15 (m, J =
19.0, 12.1 Hz, 2H), 2.78 (dd, J = 17.7, 8.3 Hz, 1H), 2.20 (s, 3H), 1.74 – 1.66 (m, 2H), 1.55 – 1.63
(m, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.1, 160.8, 160.6,
145.0, 138.2, 137.6, 132.2, 127.7, 126.2, 125.8, 125.0, 124.7, 122.7, 115.6, 111.8, 108.4, 59.1,
55.7, 46.1, 31.4, 30.4, 25.9, 23.1, 14.1; IR (KBr): 2931, 2862, 1735, 1652, 1608, 1184, 768 cm-1;
HRMS (ESI) m/z: [M + H]+ Calcd for C24H26NO3 376.1913; Found 376.1909.
12-Butyl-5-(2-oxopropyl)-[1,3]dioxolo[4',5':5,6]isoindolo[2,1-b]isoquinolin-7(5H)-one
(4f):
Following the general procedure, N-(Pivaloyloxy)benzamide 1a (66 mg, 0.3 mmol) was allowed
to react with (E)-4-(6-(hex-1-yn-1-yl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-one 2g (54 mg, 0.2
mmol) in presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12
h. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was
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purified by column chromatography on silica gel (12% EtOAc in petroleum ether) and got the
compound 4f (64 mg, 83% yield) as a white solid; Rf = 0.4 (Hexanes: EtOAc = 7:3); mp: 138-
140 oC; 1H NMR (400 MHz, CDCl3 ): δ 8.46 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.71
(t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.29 (s, 1H), 7.03 (s, 1H), 6.06 (d, J = 1.2 Hz, 2H),
5.86 (d, J = 8.0 Hz, 1H), 3.94 (dd, J = 17.7, 2.8 Hz, 1H), 3.10 – 3.01 (m, 2H), 2.73 (dd, J = 17.7,
8.3 Hz, 1H), 2.18 (s, 3H), 1.73 – 1.64 (m, 2H), 1.54 – 1.64 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H); 13C
{1H} NMR (100 MHz, CDCl3 ): δ 206.1, 160.3, 149.0, 148.6, 138.0, 137.7, 137.6, 132.2, 127.6,
126.8, 125.8, 124.6, 122.7, 111.8, 104.2, 103.8, 101.9, 58.8, 45.9, 31.4, 30.4, 25.7, 23.0, 14.0; IR
(KBr): 2957, 1647, 1481, 1281, 1041, 769 cm-1; HRMS (ESI): m/z Calcd for C24H24NO4
(M+H)+: 390.1705, Found:. 390.1712.
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12-Butyl-9,10-dimethoxy-7-(2-oxopropyl)isoindolo[2,1-b]isoquinolin-5(7H)-one(4g):
Following the general procedure, N-(pivaloyloxy)benzamide 1a (66 mg, 0.2 mmol) was allowed
to react with (E)-4-(2-(hex-1-yn-1-yl)-4,5-dimethoxyphenyl)but-3-en-2-one 2h (57 mg, 0.2
mmol) in presence of [RhCp*Cl2]2 (6.2 mg, 0.01 mmol) and CsOAc (76.4 mg, 0.4 mmol) for 12
h. After filtration the filtrate was concentrated under reduced pressure. The obtained residue was
purified by column chromatography on silica gel (12% EtOAc in petroleum ether) and got the
compound 4g (61 mg, 76% yield) as a white solid; Rf = 0.5 (Hexanes: EtOAc = 7:3); mp: 124-
127 oC; 1H NMR (500 MHz, CDCl3): δ 8.47 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H),
7.68 – 7.73 (m, 1H), 7.44 – 7.49 (m, 1H), 7.36 (s, 1H), 7.12 (s, 1H), 5.90 (dd, J = 8.5, 2.7 Hz,
1H), 4.01 (dd, J = 17.8, 3.1 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.08 – 3.02 (m, 2H), 2.62 (dd, J
= 17.7, 8.5 Hz, 1H), 2.14 (s, 3H), 1.70 – 1.77 (m, 2H), 1.58 – 1.65 (m, 2H), 0.99 (t, J = 7.3 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.4, 160.4, 150.6, 149.6, 138.0, 137.9, 136.3, 132.1,
127.6, 125.7, 125.6, 124.6, 122.5, 111.4, 106.3, 106.2, 59.0, 56.12, 56.08, 46.1, 31.5, 30.4, 25.9,
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